© 2019. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.
039446
REVIEW
The zebrafish subcortical social brain as a model for studying
social behavior disorders
Yijie Geng and Randall T. Peterson*
ABSTRACT
Social behaviors are essential for the survival and reproduction of
social species. Many, if not most, neuropsychiatric disorders in
humans are either associated with underlying social deficits or are
accompanied by social dysfunctions. Traditionally, rodent models
have been used to model these behavioral impairments. However,
rodent assays are often difficult to scale up and adapt to high-
throughput formats, which severely limits their use for systems-level
science. In recent years, an increasing number of studies have used
zebrafish (Danio rerio) as a model system to study social behavior.
These studies have demonstrated clear potential in overcoming some
of the limitations of rodent models. In this Review, we explore the
evolutionary conservation of a subcortical social brain between
teleosts and mammals as the biological basis for using zebrafish to
model human social behavior disorders, while summarizing relevant
experimental tools and assays. We then discuss the recent advances
gleaned from zebrafish social behavior assays, the applications of
these assays to studying related disorders, and the opportunities and
challenges that lie ahead.
KEY WORDS: Autism, Phylogenetic conservation, Model organism,
Social deficit, Neuropsychiatric disorders, Behavioral assay
Introduction
Social behavior – defined as beneficial interaction between
individuals in the same species – is essential for the survival and
reproduction of social species, including humans and many other
vertebrates. Social behavior involves specific behaviors such as
conspecific preference, social communication, aggression and
mating. Many, if not most, neuropsychiatric disorders are related
to underlying social defects or are accompanied by social
dysfunctions. These include autism, which is associated with
deficits in processing social cues, and William’s syndrome, which is
characterized by an abnormally high enthusiasm for interacting with
strangers. Other disorders that are not primarily social (e.g.
schizophrenia and depression) may still interfere with normal
social functioning. Therefore, developing and studying animal
models with social deficits has far-reaching implications for many
neuropsychiatric diseases, and studying these behavioral aspects
requires developing specific behavioral assays.
Rodents are traditionally used to model disorders associated with
social deficits. As highly social species, rodents possess many
Department of Pharmacology and Toxicology, College of Pharmacy, University of
Utah, 30 S. 2000 East, Salt Lake City, UT 84112, USA.
*Author for correspondence (randall.peterson@pharm.utah.edu)
R.T.P., 0000-0002-4582-4690
This is an Open Access article distributed under the terms of the Creative Commons Attribution
License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use,
distribution and reproduction in any medium provided that the original work is properly attributed.
complex social behavior traits that mimic human behaviors.
Additionally, researchers have established sophisticated protocols
for studying these behaviors in rodents (Hanell and Marklund,
2014). These benefits make the rodents the current ‘go to’ models
for studying disorders associated with social deficits. However,
rodent models are not without drawbacks. They are expensive and
labor intensive. They are predominantly nocturnal and highly
sensitive to environmental disturbances such as light, sound,
temperature changes and odors. Furthermore, they have not been
very amenable to scalable or high-throughput assays. These
drawbacks pose a limit to the broader application of these models
in disease research.
In recent years, the zebrafish has rapidly become an attractive
model for studying behavioral disorders. Adult colonies can be
efficiently maintained at high density. Zebrafish give birth to large
clutch sizes (>100 eggs per female for each round of breeding) and
provide ample offspring for experimental manipulations. The
embryos are small (∼0.7 mm in diameter) and develop ex utero
with no special supplementations needed except for water during
the first week of development, enabling easily scalable embryonic
experimental perturbations. The transparent nature of zebrafish
embryos during early development also facilitates imaging and
analysis of developmental events. Recent advances in genome-
editing technologies such as CRISPR can be applied to zebrafish
embryos (Hwang et al., 2013). Unlike rodents, zebrafish are diurnal
and can perform behavioral tasks under a normal light setting.
Because they remain submerged in water during behavioral tests,
zebrafish are not easily affected by minor environmental
interferences such as weak sounds and smells.
In this Review, we first discuss the neuroanatomical and
neurophysiological evidence supporting the use of zebrafish to
model human social behavior disorders (see Box 1; Figs 1, 2). We
then describe the established experimental methods for studying
social behavior deficits and examples of using these assays to model
related human disorders. Finally, we explore relevant emerging
technological advances and the opportunities and challenges that lie
ahead in applying these technologies to social disorder modeling Disease Models & Mechanisms
using zebrafish.
Zebrafish assays for studying social behavior and deficits
There are typically two approaches to modeling a behavioral
disorder: by using an endophenotype (see Box 2 for a glossary of
terms) assay or a behavioral assay. In this Review, we focus
primarily on the behavioral approach.
As larval zebrafish develop into adults, their behavior becomes
increasingly complex. This is particularly pronounced for socially
relevant behaviors. In this section, we briefly review several
stereotypical social behaviors in zebrafish and discuss recent
advances in developing assay platforms for studying these
behaviors. We begin by describing assay setups for specific
aspects of social behaviors using traditional and new experimental
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REVIEW Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446

A Fig. 1. Previous theoretical models of the social brain. Brain

Social behavior network structures that constitute previous models of social brain
networks, illustrated in a mammalian brain from a lateral view.
(A) The social behavior network (SBN) (Newman, 1999). (B)
The social decision-making (SDM) network (O’Connell and
Hofmann, 2011b), composed of the SBN and the mesolimbic
reward system (MRS). AH, anterior hypothalamus; BLA,
basolateral amygdala; BNSTm, medial bed nucleus of the stria
LS terminalis; HIP, hippocampus; LS, lateral septum; MPOA,
PAG medial preoptic area; NAc, nucleus accumbens; PAG,
periaqueductal gray; STR, striatum; VMH, ventromedial
BNSTm
hypothalamus; VP, ventral pallidum; VTA, ventral tegmental
MPOA area.
VMH
AH

B
Social decision-making network

HIP

STR
LS PAG
NAc
V
VP BNSTm
BLA
MPOA
VTA
VMH
AH

Key

Social behavior network (SBN) Mesolimbic reward system (MRS)

Brain regions belonging to both the SBN and MRS

methods. We then discuss emerging technologies for social
behavior analysis that will help improve the robustness,
consistency and resolution of the current assay methods,
including computer vision, machine learning, computational
modeling, robotics, and virtual reality (VR) technologies.
Social preference assay
Social preference behavior, or the innate tendency of an animal to
observe, mimic and approach a conspecific, is well conserved
among social vertebrate species. Often emerging early during
ontogeny (Fantz, 1963), this simple and perhaps primitive form of
social behavior forms a necessary foundation for the later, higher-
order social functions such as shoaling, schooling and other
complex social interactions. This behavior is routinely tested in
rodents using a three-chamber social preference assay.
To study this behavior during development, it is desirable to
design experimental systems that can pinpoint its earliest
emergence. Hinz and de Polavieja (2017) discovered that
zebrafish larvae start to show attraction toward a conspecific as
early as 6-7 days post-fertilization (dpf ). Although weak at this
stage, the attraction quickly gets stronger each day during
development. An important note for the experimental setup is that
early larval zebrafish are also attracted to borders such as the wall of
a Petri dish. Thus, to detect weak social attractions at the early
developmental stage, a testing chamber with a deep center and
gradually shallower edge may be used to counter this ‘border
attraction’ by deterring the larvae from the border with shallow
water.
Dreosti et al. adopted a design not unlike the three-chamber
social preference assay for rodents and adult zebrafish (Dreosti
et al., 2015): transparent windows divided a U-shaped test arena
into three compartments, including a middle test compartment
and two stimulus compartments (Fig. 3A). A test subject is placed
inside the test compartment, and age-matched social stimulus Disease Models & Mechanisms
fish are placed inside one of the two stimulus compartments, while
the third compartment remains empty and thus stimulus free.
The social preference of a test subject is quantified as the time it
spends near the social stimulus fish. Two-week-old larvae
exhibited a weak social preference, whereas, by 3 weeks, this
preference behavior became highly robust (Fig. 3B). This system
setup is simple to implement and does not require simultaneous
tracking of more than one animal, but limits the test subject’s
input to visual cues, and prevents physical interactions between
the fish.
Social preference behavior of adult fish is typically tested in
larger three-compartmented tanks. Zebrafish of the same or
different (Engeszer et al., 2004) strains, animated images of fish
(Gerlai, 2017), 3D-printed fish models (Bartolini et al., 2016) or

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REVIEW
Box 1. The ‘subcortical social brain’ and its evolutionary
conservation between zebrafish and mammals
Complex higher-order human social behaviors, such as face recognition,
social cognition, perception of social signals, social judgement, social
decision making and theory of mind, rely substantially on cortical input
(Adolphs, 2003). The cerebral cortex is widely considered to be the major
controller of these higher-order social behaviors (Adolphs, 2009;
Blakemore, 2008, 2012; Frith, 2007). Human studies have identified
specific cortical brain regions, such as the medial prefrontal cortex
(mPFC) and the posterior superior temporal sulcus ( pSTS), that
contribute to these functions (Adolphs, 2009; Frith, 2007; Blakemore,
2008, 2012). This focus on cortical inputs sometimes overlooks the
critical functions that subcortical brain regions play in regulating social
behavior. In fact, a complex network of subcortical brain regions
associated with social behavior exists and is highly conserved among
all vertebrates (Newman, 1999; O’Connell and Hofmann, 2011b). Here,
we conceptualize a ‘subcortical social brain’ (SSB) based on theoretical
frameworks and recent experimental findings.
Originally suggested for mammals, Newman (1999) proposed a core
‘social behavior network’ (SBN) based on evidence from neuroendocrine
and behavior studies. The SBN consists of several brain regions as
‘nodes’, including the medial amygdala, medial bed nucleus of stria
terminalis, lateral septum, preoptic area, anterior hypothalamus,
ventromedial hypothalamus and the midbrain periaqueductal gray/
central gray (Fig. 1A). In this model, each node responds to a variety
of social stimuli, and all nodes collaboratively respond with a distinct
pattern to modulate different behavioral outputs.
O’Connell and Hofmann (2011b) pointed out the importance of the
mesolimbic reward system (MRS), consisting of the ventral tegmental
area, nucleus accumbens, basolateral amygdala, striatum, ventral
pallidum, hippocampus and several regions overlapping with the SBN,
in social behavior. They further argued that the SBN and MRS
collectively constitute a larger social decision-making (SDM) network
(O’Connell and Hofmann, 2012, 2011b) (Fig. 1B). Finally, they
demonstrated that this network is largely conserved between zebrafish
and mammals (O’Connell and Hofmann, 2011a, 2012). Functional
analysis of immediate early genes after social interaction supports this
hypothesized network (Teles et al., 2015).
Recent studies have linked additional subcortical brain regions to social
behavior, and homologous structures for these socially relevant brain
regions, such as the dorsal raphe (Dölen et al., 2013), lateral habenula
(Golden et al., 2016) and cerebellum (Carta et al., 2019), are also present
in zebrafish (Yokogawa et al., 2012; Amo et al., 2010; Heap et al., 2013).
The anatomical and functional conservation of these SSB components
are summarized in Table 1 and Fig. 2.
Although many cortical regions in the mammalian brain are also relevant
to social behavior by serving executive functions during social
interactions and have been discussed elsewhere (Adolphs, 2009;
Blakemore, 2008, 2012; Frith, 2007), we chose to focus this Review on
the SSB for its relevance to zebrafish social behavior. We argue that its
strong evolutionary conservation suggests a critical role in supporting the
survival and reproduction of not only fish, but also other vertebrate
species, including humans. Knowledge acquired from investigating the
SSB may therefore provide valuable insights into human social behavior
disorders (Lord et al., 2000).
robotically controlled biomimetic zebrafish (Kopman et al., 2013;
Ruberto et al., 2016, 2017) can be used as social stimuli.
Researchers can place different stimuli in the two test
compartments to assess preference. For example, wild-type (WT)
fish typically prefer a WT conspecific over a nacre (Box 2) fish
(Braida et al., 2012). Interestingly, this tendency is reversed by
Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446
oxytocin, vasopressin, and amphetamine derivatives (Braida et al.,
2012; Busnelli et al., 2016; Ponzoni et al., 2016). A WT test fish
remembers a familiar fish from this assay for at least 24 h, and
prefers to interact with an unfamiliar fish over a familiar one
(Madeira and Oliveira, 2017). A two-compartment design has also
been implemented for testing adult (Liu et al., 2018a) and juvenile
(Patowary et al., 2019) fish, with social preference assessed by the
proximity of a test subject to the social stimulus fish.
As will be demonstrated in examples in later sections, a three- or
two-chamber social preference assay is frequently used to assess
social preference of individuals subjected to different experimental
treatments. A major benefit of this approach may be that test
subjects are examined individually, as opposed to in groups as will
be described in shoaling and schooling assays, such that the degree
of social preference for each test subject can be easily quantified.
A three-chamber assay setup also enables one to assess preference
between two types of stimuli, such as two different fish
strains. However, restrictions in sensory inputs and physical
interactions limit the assay’s ability to evaluate more complex
modes of social behaviors.
Shoaling
Groups of zebrafish naturally form compact aggregations, a
behavior called shoaling, which emerges as early as 15 dpf (Hinz
and de Polavieja, 2017). Benefits of shoaling may include better
detection of and defense against predators, enhanced foraging and
increased mating choices (Krause and Ruxton, 2002). While most
studies choose the number of fish to be tested in a shoaling assay
arbitrarily, a number that balances between minimizing animal
usage and reducing variability may be estimated using a method
based on Shannon entropy (Box 2) (Eguiraun et al., 2018).
Traditionally, shoaling is examined by two-dimensional (2D)
video recording and analysis. A number of freely available
computer vision programs and commercial software have been
developed for detecting this behavior in grouped zebrafish
(reviewed in Franco-Restrepo et al., 2019). Methods for
quantifying shoaling behavior in a 2D recording typically don’t
require the fish to be individually distinguishable. Measurements of
inter-individual distance and nearest-neighbor distance are
commonly used to quantify the tightness of a shoal (Miller and
Gerlai, 2007). Alternatively, analyzing a shoal by Delaunay
triangulation (Box 2) can provide a unique measurement for the
relative positions of each fish in a shoal configuration, as well as its
overall tightness (Xiao et al., 2015). The trajectory of a shoal can be
obtained by tracking its centroid (Eguiraun et al., 2018).
Because fish behave in a three-dimensional (3D) space, 3D
recording and analysis systems are being developed using mirrors
Disease Models & Mechanisms
(Maaswinkel et al., 2013b; Audira et al., 2018b), multiple cameras
(Macrì et al., 2017; Qian and Chen, 2017; Bishop et al., 2016; Al-
Jubouri et al., 2017; Wang et al., 2017b; Butail and Paley, 2012) or a
single camera with depth-sensing capability (Kuroda, 2018) to
assess shoaling more accurately. The complex 3D trajectories of fish
have been modeled using a long short-term memory (Box 2)
network (Wang et al., 2017b).
WT zebrafish form tight shoals. As will be discussed in later
sections, experimental perturbations can lead to changes in shoal
cohesion. A reduction in shoal cohesion is often interpreted as
decreased social interactions among members of the group.
However, simple measurements of aggregation cannot fully reveal
the complex, interactive and inter-dependent forces between
individuals (Katz et al., 2011) or the collective dynamics of a
group (Rosenthal et al., 2015).
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REVIEW Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446

A Teleost brain
Fig. 2. The subcortical social brain (SSB) in
zebrafish and mouse. (A) The teleost SSB
illustrated from a lateral view. (B) The mammalian
(rodent) SSB illustrated from a lateral view. Areas
CB with the same color mark regions that are
homologous between teleosts and mammals.
Dm (BLA) PAG For regions with different nomenclatures
VHb (LHb) between teleosts and mammals, the
Dl (HIP) DR corresponding mammalian nomenclatures are
Vs (MeA/BNSTm)
appended after the teleost nomenclature in
Vd (NAc) parentheses. AH, anterior hypothalamus; ATN,
Vv (LS) V
Vd/Vc (STR) PT (VTA) anterior tuberal nucleus; BLA, basolateral
POA (MPOA) amygdala; BNSTm, medial bed nucleus of the
ATN (VMH) stria terminalis; CB, cerebellum; Dl, lateral dorsal
telencephalon; Dm, medial dorsal
VTN (AH) telencephalon; DR, dorsal raphe; HIP,
hippocampus; LHb, lateral habenula; LS, lateral
septum; MeA, medial amygdala; MPOA, medial
preoptic area; NAc, nucleus accumbens; PAG,
periaqueductal gray; POA, preoptic area; PT,
B Rodent brain
posterior tuberculum; STR, striatum; Vc, central
ventral telencephalon; Vd, dorsal ventral
telencephalon; VHb, ventral habenula; VMH,
ventromedial hypothalamus; VP, ventral
pallidum; Vs, supracommissural nucleus of the
HIP ventral telencephalon; VTA, ventral tegmental
CB area; VTN, ventral tuberal nucleus; Vv, ventral
STR nucleus of the ventral telencephalon.

LS LHb PAG
NAc
DR
VP BNSTm
BLA
MPOA
MeA VTA
VMH
AH

Schooling
In addition to shoaling, a group of zebrafish can ‘school’. While
shoals are simple aggregations of individual fish, schools are shoals
that exhibit polarized formations and synchronized motions.
Density and group size affect shoal cohesion, but not polarization
(Shelton et al., 2015). Acute treatment with alcohol strongly affects
shoal polarization but only modestly inhibits cohesion, whereas
nicotine significantly reduces cohesion but modestly affects
polarization (Miller et al., 2013). These differences indicate that
schooling and shoaling are two differentially regulated behaviors
and that assessing both behavioral endpoints together may more
effectively characterize the effects of experimental treatments. Tang
et al. (2018) developed an unsupervised machine learning approach
to examine schooling of adult zebrafish. Using this assay, the
authors classified group behavior into distinct stereotypical states of
polarization, and found that genetic mutations (see later sections for
details) can alter the proportion of time spent or the tendency to
transition between these states. While this approach provides an
innovative way to quantitatively evaluate the propensities of a group
to adopt stereotypical states of schooling, it is limited to detecting
static patterns of group formation as a whole and cannot reveal
dynamic interactions among group members.
Aggression
Adult male zebrafish fight to establish dominance and hierarchy,
and to compete for important resources such as food and mates
(Huntingford and Turner, 1987). A simple way to assay aggressive
behavior is by introducing a target for the test subject to attack.
A mirror is often used to allow the test subject to attack its own
reflection (Zabegalov et al., 2019). Alternatively, a dummy fish or a
video recording of another fish can trigger aggression (Way et al.,
2015). The number of times a test subject exhibits aggressive
behavior, such as biting and charging, is counted to quantify its
level of aggressiveness. Although this assay provides a simple
means to quantify aggression, the lack of physical contact between
aggressors and targets limits its ability to mimic natural fighting
behaviors. Interestingly, live fish have not been used as targets in
this assay setup. Instead, when two fish interact through a
transparent window, their behaviors were typically interpreted as
social interaction (such as in a two-compartment social preference
assay) rather than aggression.
Dyadic fighting assays examine aggression in a more natural Disease Models & Mechanisms
setting. Although fighting behaviors are highly complex,
stereotypical bouts can be repeatedly observed throughout a fight
(Teles and Oliveira, 2016b; Zabegalov et al., 2019). Traditionally, a
human observer monitors the process, manually annotates these
behavioral bouts and keeps track of the outcomes of a fight (Chou
et al., 2016). Alternatively, a recently developed analysis pipeline
automatically annotates stereotypical fighting behavior with sub-
second precision (Laan et al., 2018) (Fig. 3C), demonstrating great
promise in applying unsupervised machine learning methods to
studying complex natural behaviors.
The social hierarchy of a group can be assessed from dyadic
fighting outcomes. Changes in social status have been associated
with an individual’s altered motor activity (Clements et al., 2018),
reproductive success (Paull et al., 2010), and other physiological

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Box 2. Glossary
Alarm substance: also known as Schreckstoff (startle/shock
substance); a chemical alarm signal released by injured fish that
induces fear in conspecifics. A method for extracting zebrafish alarm
substance can be found in the report by Schirmer et al. (2013).
Bayesian decision theory: a statistical method that calculates the
tradeoff between various decisions using Bayesian estimation.
Chemogenetics: the modification of biological macromolecules, such
as proteins, to interact with previously unrecognized ligands. Engineered
G protein-coupled receptors (GPCRs), such as designer receptor
exclusively activated by designer drugs (DREADDs) (Armbruster et al.,
2007), can be activated by an otherwise inert ligand to modulate the
activity of genetically modified neurons.
Delaunay triangulation: for a given set of discrete points in a plane, a
Delaunay triangulation generates a network of triangles between these
points, which ensures that no point is inside the circumcircle of any triangle.
Endophenotype: an experimentally measurable trait that genetically
segregates with an illness. Frequently used in psychiatric disease
research to connect higher-order complex behavioral symptoms to
genetics.
Fetal alcohol spectrum disorders: a group of conditions, including
physical and behavioral problems, that can occur in a person prenatally
exposed to alcohol.
Fetal valproate syndrome: a condition that can occur in a person by
prenatal exposure to the anti-seizure medication valproic acid (sodium
valproate).
Immediate early gene: a gene that is activated rapidly but often
transiently at the transcription level in response to certain stimuli.
Long short-term memory: abbreviated as LSTM; a recurrent neural
network architecture used in deep learning. It is particularly suitable for
analyzing and making predictions for time-series data containing lags of
unknown duration between important events.
Morphant: in zebrafish, gene expression levels can be knocked down at
the early embryonic stage through embryonic injection of morpholino
antisense oligonucleotides. A zebrafish treated with a morpholino to
temporarily inhibit expression of a targeted gene is called a morphant.
nacre: a zebrafish genetic mutation (Lister et al., 1999). Homozygous
nacre mutants lack melanophores, a type of pigment cell, and are therefore
partially transparent and visually different from wild-type zebrafish.
Optogenetics: an experimental method that uses light to control
activation and/or inhibition of genetically modified neurons expressing
light-responsive ion channels.
Shannon entropy: also known as ‘information entropy’; provides a
measurement of the predictability of the value of a variable. In Eguiraun
et al. (2018), Shannon entropy was used to measure the predictability of
the trajectory of a shoal’s centroid.
Transfer entropy: a measurement of the amount of directed transfer of
information between two random processes. It provides a quantification of
the cause-and-effect relationships between (possibly) coupled time series.
and health consequences (Filby et al., 2010a). Social animals adjust
their behavior based on their status within a group, a phenomenon
called social plasticity, which is also studied using aggression assays
Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446
(Teles et al., 2016a; Maruska et al., 2019; Guayasamin et al., 2017;
Sykes et al., 2018).
An animal can observe interactions between other individuals and
use this information to adjust its own future behavior, a phenomenon
named ‘social eavesdropping’. A common assay uses a two-chamber
test arena divided by a one-way transparent window. An observer fish
is placed in the chamber on the see-through side of the window,
allowing it to observe the outcome of a fight in the opposing chamber
without interacting with these fish (Abril-de-Abreu et al., 2015a). A
video recording of a fight can also be used to train the observer fish
(Abril-de-Abreu et al., 2015b). The time the observer fish spends in
the vicinity of the observation window quantifies its attention. The
observer fish remembers the participants and the outcome of the fight
and adjusts its future dominant or submissive behaviors toward these
individuals accordingly. Attentiveness toward a fight activates genes
linked to neuronal plasticity, memory formation and alertness (Lopes
et al., 2015).
As an assay with clearly separated binary outcomes, the
aggression assay has been used to examine transcriptional (Malki
et al., 2016; Oliveira et al., 2016) and neurophysiological (Teles and
Oliveira, 2016a; Pavlidis et al., 2011; Filby et al., 2010b) outcomes
of winning or losing a fight. Such effects were also examined in fish
with different social statuses (Sneddon et al., 2011; Larson et al.,
2006; Teles et al., 2016b).
Mating
Highly stereotypical mating behaviors have been described for
zebrafish (Darrow and Harris, 2004), although automated computer
vision methods remain to be developed for mating behavior analysis.
Several reports have created VR mimetics of the fish sailfin molly
(Poecilia latipinna) and have used these animated animals to study the
mating choices of live fish (Gierszewski et al., 2018, 2017; Müller
et al., 2017a), an approach that may be transferrable to zebrafish.
Zebrafish imprint visual and olfactory cues at 6 dpf, and use this
phenotypic template to match and avoid mating with its own kin as
adults (Gerlach et al., 2008; Hinz et al., 2013). Interestingly, exposure
to non-kin cues does not result in successful imprinting (Gerlach et al.,
2008), suggesting that additional mechanisms exist that regulate kin
recognition (Biechl et al., 2016; Gerlach et al., 2019).
Social learning
Zebrafish can learn from their peers. Social learning may help
individuals in a group acquire public knowledge on resources such
as food and threats such as predators without each individual paying
the costs for learning. Naïve fish can learn an escape route (Lindeyer
and Reader, 2010) or to find food (Zala and Määttänen, 2013) from
a knowledgeable demonstrator fish. A separate study, however,
reported that observer fish were unable to learn how to find food in a Disease Models & Mechanisms
maze from demonstrators (Roy and Bhat, 2017). Wild-caught
zebrafish are typically more timid than their domesticated
counterparts. Wild zebrafish become bolder when exposed to
domestic fish, without changing the level of boldness of the
domestic fish, and this change in behavior persists after removal of
the domesticated fish (Zala et al., 2012).
Tracking individuals in a group using computer vision
To examine group dynamics during behavioral assays in more
detail, researchers have explored methods to track individual fish in
a group. This is a difficult task, as zebrafish swim in a 3D space, and
individuals in a group will unavoidably cross over each other in
a camera’s view. Conventional solutions focus on deriving
algorithms for predicting the trajectories of each fish. Before each
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REVIEW Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446

A B

Social stimulus
Window chamber 3-week-old test fish

TS SS

Test
chamber

Window Control
chamber
C
(1) Image acquisition

Fish 1 Fish 2

(2) Identification
and tracking
Attack score (log probability)

Fish 1
10 Attack
Coordinates (pixels)

250 No attack
0
(3) Coordinate Fish 2
150
preprocessing –10 Attack
No attack
50
–20
20 40 60 80 20 40 60 80
−50
−1000 100 Time (sampling units)
Coordinates (pixels)
(4) Neural network (5) Attack scores (6) Automated ethogram
annotation

Fig. 3. Examples of zebrafish social behavior assays. (A) The three-chamber social preference assay. Adapted from Dreosti et al. (2015), where it was published
under a CC-BY licence. A test subject (TS) is placed inside a U-shaped chamber. Social stimulus (SS) fish are placed inside one of the chambers at the end of the U-
shaped arena, separated from the test subject’s chamber by a transparent window. The other end of the U-shaped arena is left empty as a control stimulus. (B) Three-
week-old zebrafish develop a robust social preference. A test subject visits the two compartments randomly if both compartments are empty; if social stimulus fish are
introduced into one compartment, the test subject is attracted to and interacts intensively with the social stimulus fish. Adapted from Dreosti et al. (2015), where it was
published under a CC-BY licence. Red, movements in the social interaction zone; black, movements in the middle zone; blue, movements in the control zone. Disease Models & Mechanisms
(C) Analysis of fighting behavior using machine learning. Adapted from Laan et al. (2018), where it was published under a CC-BY licence. Images are acquired (1) and
two animals in the test arena are tracked individually (2). Fractions of the tracking coordinates are manually annotated for fighting behavior (3). This is then used to train
a neural network (4), which automatically detects attacks by generating an attack score for each fish (5). An ethogram is generated based on the attack score (6).

crossover, the program calculates the most likely trajectory of each
fish, so that, immediately after the two fish are separated,
the algorithm assigns identities to each fish based on how well
their new trajectories match the predictions. This method frequently
introduces errors and unavoidably fails after long periods of
tracking.
To solve this problem, the de Polavieja lab developed idTracker,
which identifies and tracks individuals using a distinct digital
fingerprint generated for each fish (Pérez-Escudero et al., 2014)
(Fig. 4A). Crossover events still interfere with tracking, but only
temporarily, as identities are reassigned after each crossover based
on the fingerprint. This method enables researchers to acquire insights
to previously difficult-to-observe behaviors in a group, such as
territorial behavior. Their recently updated method, idTracker.ai,
simultaneously tracks 100 individuals using deep learning with an
impressive identification accuracy of greater than 99.9% (Romero-
Ferrero et al., 2019). Building on the idTracker approach, several
recent attempts have achieved multi-individual identification and
tracking, with varying degrees of success (Bai et al., 2018; Qian
and Chen, 2017; Qian et al., 2016, 2014; Wang et al., 2016a).

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REVIEW Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446

Raw image Segmented image: Intensity map: a 2D histogram showing how

of a fish pixel intensities (i) many pairs of pixels are at a given distance and
and distances (d) have a given sum of intensities

i2
600

No. pairs of pixels

400
i1+i2

i1

200

0
Distance between pixels (d)

B C

Fig. 4. Examples of emerging technologies for social behavior assays and analysis. (A) idTracker for tracking individuals in a group. The raw images of
each fish were first segmented to identify the body of each fish. Two pixels with intensities i1 and i2 are highlighted, which are separated by a distance, d. An intensity
map is generated for each fish to show how many pairs of pixels are at a certain distance (d) and have a certain sum of intensities (i1+i2). This intensity map is
used to identify each individual fish. Adapted with permission from Pé rez-Escudero et al. (2014). This image is not published under the terms of the CC-BY licence of
this article. For permission to reuse, please see Pé rez-Escudero et al. (2014). (B) A virtual reality (VR) fish that mimics a 23-dpf real fish. Reproduced with permission
from Stowers et al. (2017). This image is not published under the terms of the CC-BY licence of this article. For permission to reuse, please see Stowers et al.
(2017). (C) A self-propelled robotic fish. Reproduced with permission from Butail et al. (2013a), where it was published under a CC-BY licence.

Computational modeling of collective behaviors
Computational modeling has been applied to studying group
behaviors of zebrafish and has generated valuable insights into
group dynamics of fish and other species such as humans (Madirolas
and de Polavieja, 2015). Previous methods largely ignored individual
behaviors and focused primarily on examining static features of
collective behavior at each time point, such as group cohesion
calculated based on the distribution of individuals’ positions, and
polarization, which is assessed by individuals’ orientations. This
limitation may be attributed to limited understanding of stereotypic
motions and difficulties in continuous tracking of individuals.
Although ignoring individual identities allows each fish to be
treated as a particle and aids the application of machine learning
methods to characterize group behavior as a whole (Butail et al.,
2013b), it inevitably limits further investigations on how individuals
make behavioral decisions in a group.
One approach to overcome these limitations is to examine the
behaviors of isolated individuals given different social cues, such as
by using a three-chamber social preference setup (Fig. 3A)
(Arganda et al., 2012; Porfiri and Ruiz Marín, 2017). Researchers
have modeled individual behavioral rules in response to the motion
of a social stimulus fish using theoretical frameworks based on the
Bayesian decision theory (Box 2) (Arganda et al., 2012) and transfer
entropy (Box 2) (Porfiri and Ruiz Marín, 2017). Other studies first
improved continuous tracking of individuals and then
computationally modeled pairwise interactions using the optimal
control theory (Laan et al., 2017), deep attention networks (Heras
et al., 2018), transfer entropy (Butail et al., 2016) and other data-
driven methods (Zienkiewicz et al., 2018) to reveal how pairs of
individuals attract, repulse and align with each other. Disease Models & Mechanisms
Recent studies have applied computational and machine learning
methods to model individual stereotypical motions of Caenorhabditis
elegans (Stephens et al., 2008; Brown et al., 2013), fruit flies (Berman
et al., 2014), mice (Wiltschko et al., 2015) and zebrafish (Marques
et al., 2018; Mwaffo et al., 2017; Zienkiewicz et al., 2015).
Combining individual behavioral modeling with continuous
individual tracking provides an opportunity to investigate group
dynamics and individual decision-making with higher resolution. In
one study, individual motions alternated between acceleration and
deceleration bouts. The kinetics of these bouts could be described by
sigmoid and exponential functions, respectively. Individual zebrafish
motions were found to alternate between a ‘passive’ behavioral mode,
in which behaviors of an individual are unaffected by other group
members, and an ‘active’ mode, in which an individual’s behavior

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adjusts to social input from the group. This framework predicted
behaviors of individuals with high precision (Harpaz et al., 2017).
Virtual reality
Collective behaviors such as shoaling are mutual: each individual is
driven by social cues emitted by its shoal mates and at the same time
emits social signals that influence its shoal mates. Owing to the
interactive nature of this closed-loop feedback system, it is difficult to
disentangle a social input from the outputs it triggered. VR systems
have the advantage of providing socially relevant inputs in a controlled
and isolated manner. A projected virtual object moving in a way that
mimics the characteristic kinetics of zebrafish swim bouts was
sufficient to trigger shoaling of juvenile fish. Other previously
implicated social cues, such as a fish-like shape or pigmentation
pattern, were not required to trigger this behavior (Larsch and Baier,
2018). In another example, a virtual zebrafish was created to mimic a
23-dpf fish (Stowers et al., 2017) (Fig. 4B). In this interactive VR
system, the movement trajectory of the virtual zebrafish was
programmed to be influenced to varying degrees by the trajectory of
a real fish. When set to be strongly influenced by the real fish, the
virtual fish spent most of the time following the real fish and thus
minimally affected the real fish’s typical trajectory. Gradually reducing
the level of social feedback resulted in the virtual fish exerting a
stronger influence on the trajectory of the real fish, and therefore it
seemed to ‘lead’ the real fish. Continued reduction in the degree of
social feedback, however, eventually decreased the influence of the
virtual fish on the real fish and led to its failure in leading.
‘Robot zebrafish’
Robotically controlled biomimetics have been developed to mimic
animal behaviors and socially interact with animals such as fruit
flies (Zabala et al., 2012) and cockroaches (Halloy et al., 2007),
providing valuable insights into the social behaviors of these
species. Similarly, a number of research groups have developed
robotic fish (Cazenille et al., 2018). These systems are often
composed of two parts: a biomimetic fish dummy and a robotic
control system. The fish dummies can be directly fixed to a robot
arm, indirectly linked to and moved by a robotic mechanism through
magnetic coupling, or self-propelled (Butail et al., 2013a) (Fig. 4C),
enabling them to ‘swim’ under water. Zebrafish respond to a
robotically controlled dummy in a three-compartment social
preference assay (Kopman et al., 2013; Ruberto et al., 2016,
2017). Compared to VR, a major advantage of robotic systems is
their ability to provide physical contact between a biomimetic and
an animal. Therefore, other groups have developed robot zebrafish
that can come into physical contact with real zebrafish shoals
(Cazenille et al., 2018; Polverino et al., 2012). However, the key
features that allow a biomimetic fish to be socially integrated into a
group of fish are still being debated. While many efforts focused on
identifying socially attractive morphologies such as shape, size and
pigmentation patterns for the dummy, other studies argued that a
robot’s behavior, such as its trajectories and movement kinetics,
exert a greater influence on its ability to socially integrate into a
shoal (Cazenille et al., 2018).
Popular assays and their variations
Among the assays discussed above, the social preference, shoaling
and aggression assays may be the most frequently used. Possible
reasons for their popularity may be that they are relatively easy to set
up, have intuitive relevance to social behaviors in humans, and have
simple and quantifiable readouts. These assays are commonly used
to assess changes in social behavior induced by disease-relevant
Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446
treatments, as discussed further in the next section. Many variations
exist for each assay, including but not limited to dimensions of the
test platforms, numbers of animals used, types of stimulus
( particularly for social preference and aggression assays), and
quantification criteria and methods. This poses a potential challenge
for the field, as the diversity of assays complicates interpretation of
results and comparison between studies. It is worth noting that
similar diversity is also widely present in rodent assays, which are
currently still considered the gold standard for measuring social
behavior. Nevertheless, efforts should be made to standardize
current behavioral assay formats in zebrafish. Carefully designed
experiments should be performed to evaluate these variations and
provide recommendations for the optimal formats of each assay.
Disease-relevant social-deficit models in zebrafish
In this section, we discuss recent advances in using zebrafish to
model human social-behavior-related disorders. Although non-
behavioral endpoints exist, including anatomical changes and
endophenotypes, behavioral assays most directly demonstrate the
relevance of these models to actual human behavioral disorders.
Therefore, we focus on studies that model these disorders using
social behavior assays. We categorize these studies based on the
different methods used to induce social deficits.
Genetic models
Technologies such as CRISPR, transcription activator-like effector
nucleases (TALENs) and zinc-finger nucleases (ZFNs) have been
implemented in zebrafish to generate genetic models. Forward-
genetics methods can also generate mutants through random
mutagenesis.
Autism risk genes
Modulating autism-related genes in zebrafish can induce autism-
related phenotypes. However, the endpoints assessed in these
studies have primarily focused on developmental and physiological
changes or other comorbid behavioral symptoms of autism such as
anxiety, sleep disorders and seizures. For example, cntnap2
knockout induced night-time hyperactivity (Hoffman et al., 2016),
and chd8 morphants (Box 2) and mutants developed macrocephaly
(Sugathan et al., 2014; Bernier et al., 2014). Researchers have
started examining social behavior deficits in more recent studies.
Knocking out the autism gene shank3b (Durand et al., 2007)
induced deficits in shoaling, social preference and kin recognition
(Liu et al., 2018a). Zebrafish with mutant sam2, ortholog to the
human FAM19A2 gene, were found to have shoaling (Choi et al.,
2018) and social preference (Ariyasiri et al., 2019) deficits. The
human FAM19A2 gene is located in the 12q14.1 locus, home to a
copy-number variation (CNV) associated with intellectual disability Disease Models & Mechanisms
and autism (Autism Genome Project et al., 2007).
Zebrafish also demonstrated its rapid disease-modeling capability
in a recent study in which a novel autism risk gene, CEP41, was
identified by whole-exome sequencing. The zebrafish CEP41
morphant showed deficits in social preference behavior (Patowary
et al., 2019), providing experimental support for this new autism
risk gene. A CRISPR-based targeted mutagenesis study
systematically evaluated 35 autism and schizophrenia risk genes
in an unsupervised machine learning assay for schooling (Tang
et al., 2018). Significant behavioral changes were observed in the
immp2l and scn1lab mutants; immp2l knockout enhanced shoaling,
whereas heterozygous mutation in scn1lab seemed to suppress all
evident social interactions between individuals. Their human
ortholog, IMMP2L, is associated with Tourette syndrome (Petek
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et al., 2001), and SCN1A is associated with autism (Weiss et al.,
2003) and Dravet syndrome (Wolff et al., 2006). Several other
mutations also altered shoaling and schooling, but to a lesser degree.
Intellectual-disability risk genes
Intellectual disability is often comorbid with autism. Zebrafish
knockout of dyrk1aa, an ortholog of the human Down syndrome
gene DYRK1A, induced shoaling and social preference impairments
(Kim et al., 2017b). Fragile X syndrome is a form of human
intellectual disability caused by a loss-of-function mutation of the
fragile X mental retardation 1 (FMR1) gene (Wu et al., 2017).
Interestingly, knocking out of zebrafish fmr1 caused precocious
development of shoaling behavior, a phenomenon interpreted as a
result of hyperactivity and increased anxiety (Wu et al., 2017),
although such a phenomenon does not seem to be present in human
patients with fragile X syndrome (Tranfaglia, 2011).
Schizophrenia risk genes
The zebrafish ortholog of the schizophrenia risk gene DISC1
induced impaired shoaling response to stress when mutated (Eachus
et al., 2017). Acute exposure to alarm substance (Box 2) or osmotic
stress increased shoal cohesion in 5-dpf WT fish but not disc1
mutants, suggesting its role in the development of the
hypothalamic-pituitary-interrenal (HPI) axis, the fish equivalent
of the hypothalamic-pituitary-adrenal (HPA) axis. Knocking out
adra1aa and adra1ab, the two zebrafish orthologs of human
ADRA1A, causes fish to freeze in tight groups for prolonged periods
of time (Tang et al., 2018). Polymorphisms in the promoter region
of the ADRA1A gene have been associated with schizophrenia
(Clark et al., 2005), although not without controversies (Huang
et al., 2008; Clark et al., 2006). While the freezing behavior found in
fish is significant, whether or how this deficit translates to human
disease phenotypes may require further investigation.
Other genetic models that cause social deficits
Researchers serendipitously discovered increased aggression in the
spiegeldanio strain, an fgfr1at3R705H/t3R705H mutant (Norton et al.,
2011), during routine stock maintenance. This mutant showed
increased mirror biting behavior and novel-object exploration,
reminiscent of behavioral phenotypes seen in aggression-boldness
syndrome. However, association of the human FGFR1 with
aggression has not been reported.
Leptin is generally known as an appetite regulator, but recent
evidence has shown that it also plays roles in behavioral regulation
(Morrison, 2009). Knockout of lepa by TALENs resulted in reduced
aggression in a mirror-biting assay and reduced shoaling (Audira
et al., 2018a). The authors argue that a dysregulated HPI/HPA axis
may be responsible for the social deficit phenotype. In humans, an
elevated leptin level has been associated with autism (Ashwood
et al., 2008; Blardi et al., 2010; Raghavan et al., 2018) and Rett
syndrome (Blardi et al., 2007, 2009), whereas a decrease in leptin is
linked to schizophrenia and depression (Kraus et al., 2001; Atmaca
et al., 2003).
Gene expression modulation models
Changes in gene expression levels have been associated with social
disorders. For example, CNV in chromosome region 16p11.2 is
linked to autism (Sebat et al., 2007). Overexpression of the 29 genes
encompassed by the 16p11.2 CNV in zebrafish identified KCTD13
as an inducer of microcephaly (Golzio et al., 2012). Suppression of
the same gene by morpholino resulted in macrocephaly (Golzio
et al., 2012). Zebrafish morphants in several of these genes also
Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446
showed deficits in brain-ventricle and midbrain development
(Blaker-Lee et al., 2012). Although modulation of gene
expression at the larval or adult stages is also possible using
inducible expression systems (Chiu et al., 2016), this has not been
utilized to establish social-deficit models in zebrafish.
Chemically induced models: embryonic and maternal exposure
Both genes and the environment contribute to the development of
social behavior. For example, environmental factors are estimated to
account for 41% of autism risk (Gaugler et al., 2014). In fact, a
number of environmental toxins, such as bisphenol A (BPA) (Stein
et al., 2015), polychlorinated biphenyls (PCBs) (Lyall et al., 2017)
and pesticides (von Ehrenstein et al., 2019), have been associated
with elevated autism risk through epidemiological research, and
were investigated in rodent models (Yu et al., 2011; Jolous-Jamshidi
et al., 2010; Lan et al., 2017; Mullen et al., 2012). The zebrafish
provides a powerful model for studying environmental factors that
affect social development, especially given the simplicity of
compound administration through water immersion. This
subsection summarizes findings on how chemical exposure prior
to or during embryonic development affects social behavior.
Alcohol and other abused drugs
Alcohol consumption during pregnancy can lead to fetal alcohol
spectrum disorders (FASDs; Box 2). Patients with less-severe FASD
can exhibit social deficits without anatomical changes (Seguin and
Gerlai, 2018). Zebrafish embryos that were briefly (2 h) exposed to
low levels (up to 1%) of alcohol develop to adults with no gross
anatomical changes but show dose-dependent reductions in social
preference to virtual (Fernandes and Gerlai, 2009) or live (Buske and
Gerlai, 2011) social stimuli. This effect is likely mediated by
impairments in the dopaminergic and serotoninergic systems
(Fernandes et al., 2015; Buske and Gerlai, 2011). Embryonic
exposure to another commonly abused drug, ketamine, did not
significantly alter shoaling behavior (Félix et al., 2017a,b).
Prescription drugs
When taken during pregnancy, some common prescription drugs
may have side effects or toxicity that affect the development of
sociality in humans. In addition, due to their continuous usage and
emission, pharmaceuticals often accumulate faster than they are
removed from the environment and are considered pseudo-
persistent contaminants (Mackay et al., 2014), making them
accessible to humans through environmental exposure.
The effects of pharmaceuticals on social development can be
conveniently modeled in zebrafish. For example, prenatal exposure
to valproic acid can lead to fetal valproate syndrome (Box 2) in
humans. Embryonic exposure to valproic acid or sodium valproate Disease Models & Mechanisms
induced deficits in social preference behavior (Bailey et al., 2016;
Baronio et al., 2018; Dwivedi et al., 2019; Zimmermann et al.,
2015) but not aggression (Zimmermann et al., 2015). Impairments
in the histaminergic (Baronio et al., 2018) and purinergic
(Zimmermann et al., 2017) systems likely mediate this effect.
Embryonic exposure to 2 nM retinoic acid, an important
signaling mediator in development, decreased social preference to
a video of shoaling fish without inducing neural tube malformations
or elevated death rate (Bailey et al., 2016).
Fluoroquinolones and tetracyclines are β-diketone antibiotics
(DKAs) widely used in humans and animals. A 3-month exposure
to a mixture of six DKA species, starting from birth, increased
shoaling at a low concentration (6.25 mg/l) but inhibited shoal
cohesion at a higher concentration (25 mg/l) (Wang et al., 2016b).
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Environmental chemicals
Expansion of the chemical industry in the past century has greatly
increased the number of environmental chemicals, yet only a
fraction of these have been studied for their effects on the
development of social behavior. Some commonly found
environmental toxins have been studied in the zebrafish social
behavior model. Benzo[α]pyrene often forms during organic-matter
combustion and is found in cigarette smoke, diesel exhaust and
grilled foods. When tested across three generations, benzo[α]pyrene
induced a shoaling deficit in the first but not the subsequent
generations (Knecht et al., 2017).
Chemical flame retardants are added to many household products.
Among these, the brominated flame retardant (BFR) polybrominated
diphenyl ethers (PBDEs) were widely used until the early 2000s.
Although now largely phased out due to toxicity concerns, they persist
in the environment, which can lead to continuous low-level exposure.
When exposed to low doses of either of two prominent PBDEs, BDE-
99 and BDE-47, zebrafish exposed to BDE-99 but not BDE-47
exhibited reduced social preference behavior (Glazer et al., 2018b).
Another study reported elevated shoaling between pairs of zebrafish
larvae following embryonic BDE-47 treatment (Zhang et al., 2017).
Interestingly, the same group also tested two BDE-47 metabolites, 6-
OH-BDE-47 and 6-MeO-BDE-47, using the same experimental
setup, and found that 6-MeO-BDE-47 but not 6-OH-BDE-47
inhibited shoaling (Zhang et al., 2018). Another BFR,
tetrabromobisphenol A, heightened aggression in males but not in
females (Chen et al., 2016a).
BFRs have been largely replaced by a newer class of flame
retardants, the organophosphate flame retardants (OPFRs).
Currently, little is known about the potential developmental
neurotoxicity of these chemicals. Six commonly used OPFRs
showed no negative effect on shoaling behavior through embryonic
exposure (Glazer et al., 2018a; Oliveri et al., 2015). A mixture of
BFRs and OPFRs, FM 550 did, however, induce shoaling deficits
(Bailey and Levin, 2015).
The organophosphorus pesticide dichlorvos (Altenhofen et al.,
2019) and the neonicotinoid pesticide imidacloprid (Crosby et al.,
2015) showed no effect on social behavior.
Endocrine-disrupting chemicals (EDCs) such as xenoestrogen
have been suspected of affecting social behavior. Indeed, embryonic
exposure to 17α-ethinylestradiol enhanced social preference
behavior (Volkova et al., 2015).
BPA increased time spent near a mirror, but reduced male attacks
on the mirror (Weber et al., 2015).
The heavy metals lead and arsenic were also tested, with
lead exposure increasing aggression in a mirror test (Weber and
Ghorai, 2013) and arsenic showing no effect on social behavior
(Dipp et al., 2018).
Maternal exposure
Because humans develop in utero, environmental risk factors for
social-behavior-related disorders must access the fetus through
maternal exposure. Although exposure mechanisms in egg-laying
fish and placental animals are significantly different, it is possible to
model some aspects of this exposure mechanism in zebrafish. For
example, exposing adult female zebrafish to a mixture of the water-
soluble fraction of crude oil and lead was found to suppress shoaling
behavior in their offspring (Wang et al., 2016c).
Chemically induced models: adult exposure
Adult zebrafish can be used for pharmacological and toxicological
studies. Drugs can be easily administered by direct water
Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446
immersion, which enables drug absorption through the skin and
gill, or oral ingestion. Both acute and chronic drug exposure can be
conducted with good temporal control, as drugs can be added and
removed at precise time points. To overcome potential issues in drug
solubility and to enable pharmacokinetic analyses, drugs can also be
applied by oral administration (Kulkarni et al., 2014; Dang et al.,
2016) or intraperitoneal injection (Samaee et al., 2017). Drug
absorption and metabolism can be measured by mass spectrometry
(Villacrez et al., 2018).
Dietary components
Chronic exposure to dietary components can affect a body’s
nutritional and toxicological balance, which in turn modulate the
overall health of an animal through regulation of metabolism and
gene expression. Trace elements such as selenium and zinc are
essential nutrients for mammals but are neurotoxic at excessive
levels and their neurobehavioral effects on social behavior are not
well understood. Chronic (60 days) exposure to selenomethionine, a
naturally occurring selenoamino acid found in cereal grains,
grassland legumes and soybeans (Whanger, 2002), suppressed
shoaling in adult fish, potentially due to alterations of the
serotonergic pathway (Attaran et al., 2019). Chronic (21 days)
exposure to zinc chloride reduced mirror-biting behavior
(Sarasamma et al., 2018). Hyperprolinemia is an inherited
disorder of proline metabolism deficiency and has been associated
with schizoaffective disorders (Jacquet et al., 2005; Orešic et al.,
2011). To examine the effect of excess proline on social behavior,
adult fish were exposed to 1.5 mM proline for 7 days. Impairments
in social preference and other schizophrenia-related behaviors were
found and rescued by the atypical antipsychotic drug sulpiride but
not the typical antipsychotic haloperidol (Savio et al., 2012).
Environmental chemicals
Direct short-term (days) exposure to the herbicides glyphosate
(Bridi et al., 2017) and atrazine (Schmidel et al., 2014) reduced
aggressive behavior and shoaling, respectively, whereas an 18-day
exposure to intraperitoneally injected paraquat did not significantly
affect social interaction (Bortolotto et al., 2014). Acute exposure to
gold resulted in a temporary reduction in social preference behavior
that may be related to elevated oxidative stress; the social inhibition
effect was short lived and the treated fish recovered within several
hours (Strungaru et al., 2018). Chronic exposure to the EDC BPA
reduced courtship behavior in females but increased their
aggression towards mating competitors; females also preferred
control males over BPA-treated males during courtship tests (Li
et al., 2017a). Nonylphenol, another EDC and xenoestrogen
compound, inhibited aggression and social preference behaviors
by chronic exposure (Xia et al., 2010). 17α-ethinylestradiol, a Disease Models & Mechanisms
synthetic estrogen and major component in oral contraceptive pills,
is excreted from the human body in high amounts and accumulates
in the environment. Its impact on zebrafish social behavior were
examined in several studies to assess its influence on aquatic
animals, revealing changes in social hierarchy and courtship in fish
following exposure (Coe et al., 2008, 2009; Colman et al., 2009;
Filby et al., 2012). Another EDC, triclosan, had inconsistent effects
on social preference behavior (Liu et al., 2018b; Zang et al., 2019).
Neuroactive chemicals
Neuroactive chemicals have been applied to adult fish directly to
investigate how different neurotransmitter pathways contribute to
the regulation of social behavior and to examine a drug’s therapeutic
potential in treating social disorders. Oxytocin (OT) and arginine-
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vasopressin (AVP) are neuropeptides known to regulate social
behavior in mammals. Their zebrafish homologs, isotocin (IT) and
vasotocin (AVT), together with the mammalian OT and AVP, were
examined in a social preference assay in which a WT test subject
was placed between WT and nacre fish. Control- and vehicle-treated
fish prefer to stay close to the WT social stimulus, whereas
increasing doses of all four neuropeptides first reversed this
preference, and then returned it to baseline, meaning that, at
medium doses, the treated fish preferred to stay closer to the nacre
than to the WT social stimulus (Braida et al., 2012). A synthetic
oxytocin receptor ligand, dOTK2–C8, elicited a similar preference-
reversal phenotype (Busnelli et al., 2016).
The dopaminergic system has been implicated in reward and
social responses. Not surprisingly, the dopamine D1 receptor
antagonist SCH23390 significantly reduced social preference in the
WT AB zebrafish strain. Interestingly, researchers failed to observe
a similar effect in another WT zebrafish strain, demonstrating
natural variation in behavioral responses to neuroactive chemicals in
different zebrafish strains (Scerbina et al., 2012). The common
prescription drugs fluoxetine (Giacomini et al., 2016) and
benzodiazepines (Giacomini et al., 2016; Schaefer et al., 2015)
both inhibited shoaling. Fluoxetine also inhibited the offensive
aggression behavior in dominant fish while suppressing freezing
behavior in the subordinate fish (Theodoridi et al., 2017).
The glutamatergic N-methyl-d-aspartate receptor antagonist MK-
801, commonly used to inhibit memory formation, has been used to
create fish models with autism- and schizophrenia-like behavioral
deficits. Acute exposure to MK-801 decreases social preference
(Dreosti et al., 2015), shoaling (Maaswinkel et al., 2013a) and
aggression (Zimmermann et al., 2016), an effect rescued by
oxytocin and the oxytocin receptor agonist carbetocin
(Zimmermann et al., 2016). Atypical antipsychotics sulpiride and
olanzapine also reversed MK-801-induced social impairment, yet
the typical antipsychotic haloperidol failed to reverse this
phenotype (Seibt et al., 2011).
Nicotine significantly inhibits shoal cohesion but only mildly
affects polarization, whereas ethanol strongly affects polarization
within a fish school but only modestly inhibits shoal cohesion (Miller
et al., 2013). In a social novelty test (Ariyasiri et al., 2019), control fish
typically prefer to interact with a novel over a familiar fish. Ethanol
exposure significantly suppressed this novelty preference behavior
without affecting sociality in a three-chamber social preference test
(Ariyasiri et al., 2019). Individual fish also respond differently to
ethanol. While ‘shy’ individuals typically spent more time near a
shoal than ‘bold’ fish, ethanol increased shoaling in bold fish but
inhibited shoaling in shy fish (Araujo-Silva et al., 2018). The acute
mild inhibitory effect of ethanol on sociality is enhanced by taurine, a
common supplement in energy drinks (Fontana et al., 2018). Taurine
also prevented alcohol-induced elevated aggression (Fontana et al.,
2016). While acute ethanol exposure mildly inhibits shoaling, chronic
(8 days) exposure to ethanol surprisingly increases shoal cohesion
(Müller et al., 2017b). Chronic ethanol exposure dramatically lowered
fertility when at least one of the mating partners was treated, and this
inhibition was fully reversed by a 9-week withdrawal program
(Dewari et al., 2016).
The psychotropic drug lysergic acid diethylamide (LSD)
inhibited shoaling (Green et al., 2012; Grossman et al., 2010) but
not social preference behavior (Grossman et al., 2010). Similar
to the effects of oxytocin and arginine-vasopressin receptor
agonists, the amphetamine derivatives 2,5-dimethoxy-4-bromo-
amphetamine hydrobromide, para-methoxyamphetamine and 3,4-
methylenedioxymethamphetamine generated an inverted-U-shaped
Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446
curve in the nacre/WT social preference assay, shifting social
preference from WT conspecifics to nacre and then back to WT fish
at progressively increasing doses. Ketamine (Riehl et al., 2011) and
ibogaine (Cachat et al., 2013) both inhibited group cohesion.
Stressor-induced models
External stressors
Unpredictable chronic stress (UCS) and developmental social
isolation (DSI) are often applied to animal models to mimic the
environmental stressors that may contribute to psychiatric disorder
development in humans. Zebrafish UCS assays apply different
combinations of chronic stressors – such as restraint, social isolation,
overcrowding, tank or water change, cold/heat, being chased by a net,
dorsal body exposure in shallow water, exposure to air in a net,
predator presence, and alarm substance – for varying durations (days
to weeks). Stressors are often randomized on different days to ensure
unpredictability. UCS assays with different stress protocols have
generated inconsistent results, including increased (Chakravarty et al.,
2013), first increased and then decreased (Piato et al., 2011), or
unaltered (Fulcher et al., 2017) shoaling behavior after UCS. Acute
stress by harassing the fish with a pen net prior to a behavioral test
decreased social preference behavior but increased aggression
(Giacomini et al., 2016). The effect of DSI on shoaling also
remains controversial, as different reports have found it decreased
(Shams et al., 2018) or did not alter (Fulcher et al., 2017) shoaling.
Physiological stressors
An induced inflammatory response by inoculating fish with formalin-
inactivated Aeromonas hydrophila reduced social preference behavior
(Kirsten et al., 2018), consistent with a previous report linking the
immune system with social behavior in mice (Filiano et al., 2016).
Traumatic brain injury (TBI) by pulsed, high-intensity focused
ultrasound to the adult zebrafish brain increased shoaling cohesion
(McCutcheon et al., 2017), although it may be difficult to determine
the exact location and degree of brain damage caused by such a
diffusive injury method. Hunger reduced aggression in females but
not in males, possibly due to the females’ stronger need to conserve
energy compared to males (Ariyomo and Watt, 2015).
Circuit manipulation models
Different parts of the subcortical social brain (SSB) play different
roles in social behavior. Manipulating these brain regions and neural
circuits through targeted neuronal inhibition, ablation and activation
using genetic, optogenetic and chemogenetic (Box 2) approaches
can help improve our understanding of the mechanisms regulating
different aspects of social behavior. For example, targeted
expression of tetanus neurotoxin to silence the lateral or medial
subregion of the dorsal habenula (Table 1; Fig. 2) resulted in Disease Models & Mechanisms
predispositions to lose or win a fight, respectively, revealing a dual
control system for conflict resolution (Chou et al., 2016). In another
study, manual (by inserting a 27½ G needle) and genetic ablations
of a population of neurons in the ventral telencephalon inhibited
social interactions, as quantified by failure to adjust orientation
against a social stimulus fish (Stednitz et al., 2018). The ablated
region is believed to be homologous to the mammalian lateral
septum (Table 1; Fig. 2), a region implicated in social behavior in
mammals (Clarke and File, 1982; Shin et al., 2018).
Emerging technologies for modeling social behavior
disorders in zebrafish: opportunities and challenges
In this section, we discuss emerging technologies that can
potentially improve modeling of social behavior disorders in
11
REVIEW Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446

Table 1. Anatomical and functional conservation of the subcortical social brain between mammals and zebrafish
Mammalian structures
Anterior hypothalamus (AH)
Basolateral amygdala (BLA)
Cerebellum (CB)
Dorsal raphe (DR)
Hippocampus (HIP)
Lateral habenula (LHb)
Lateral septum (LS)
Medial amygdala (MeA)
Medial bed nucleus of the stria
terminalis (BNSTm)
Medial preoptic area (MPOA)
Nucleus accumbens (NAc)
Periaqueductal gray/central gray
(PAG/CG)
Striatum (STR)
Ventral tegmental area (VTA)
Ventral pallidum (VP)
Ventromedial hypothalamus (VMH)
Recent experimental evidence of SSB conservation between zebrafish and mammals are referenced in column 3. Additional references covering earlier research
can be found in the review by O’Connell and Hofmann (2011b). Structures are listed in alphabetical order.
Mammalian functions
Aggression (Falkner and Lin, 2014)
Social fear (Qi et al., 2018)
Social reward (Carta et al., 2019)
Social isolation (Matthews et al., 2016)
Social memory (Hitti and Siegelbaum, 2014; Okuyama
et al., 2016; Meira et al., 2018)
Aggression (Flanigan et al., 2017), social play (van Kerkhof
et al., 2013), social defeat (Wang et al., 2017a)
Aggression (Leroy et al., 2018), early-life stress-induced
social dysfunction (Shin et al., 2018)
Sexual behavior (Ferrero et al., 2013), sex discrimination of
social cues (Yao et al., 2017), social information
processing (Li et al., 2017b), social recognition
(Takayanagi et al., 2017), aggression and parenting
(Tachikawa et al., 2013)
Stress response (Lebow and Chen, 2016), sexual behavior
and parenting (Tsuneoka et al., 2015)
Sexually dimorphic behaviors (Wei et al., 2018), social
reward (McHenry et al., 2017), parenting (Fang et al.,
2018; Wu et al., 2014; Brown et al., 2017)
Social reward (Dölen et al., 2013)
Defensive behavior (Deng et al., 2016)
Pair bonding (Báez-Mendoza and Schultz, 2013)
Social reward (Hung et al., 2017)
Sexual behavior, social affiliation (Smith et al., 2009)
Aggression (Hashikawa et al., 2017), defensive behavior
(Wang et al., 2019), sexual behavior (Nomoto and
Lima, 2015)
Homologous zebrafish structures
Ventral tuberal nucleus (VTN) (Xie and Dorsky, 2017)
Medial dorsal telencephalon (Dm) (von Trotha et al.,
2014, Perathoner et al., 2016)
CB (Bae et al., 2009)
DR (Yokogawa et al., 2012)
Lateral dorsal telencephalon (Dl) (von Trotha et al., 2014)
Ventral habenula (VHb) (Amo et al., 2010)
Ventral nucleus of the ventral telencephalon (Vv)
Supracommissural nucleus of the ventral telencephalon
(Vs) (Perathoner et al., 2016)
Supracommissural nucleus of the ventral
telencephalon (Vs)
Preoptic area (POA) (Xie and Dorsky, 2017)
Dorsal ventral telencephalon (Vd)
PAG/CG
Dorsal (Vd) and central (Vc) ventral telencephalon
Posterior tuberculum (PT)
N.A.
Anterior tuberal nucleus (ATN) (Xie and Dorsky, 2017)

zebrafish. These can be broadly categorized as the ‘next generation’
methods for high-throughput model generation and drug testing,
high-resolution functional brain imaging, and high-precision circuit
manipulation for studying the circuit-level mechanisms of
behavioral deficits. These research goals, limitations of current
methodologies and potential solutions to overcome these limitations
are summarized in Table 2.
High-throughput genome editing for disease modeling
Many neuropsychiatric disorders with social deficits have a strong
genetic basis. Advanced genetic and genomic technologies have
enabled researchers to find hundreds of genes that contribute to risks
of developing neurological diseases. Given that the zebrafish is
relatively inexpensive and easy to manipulate genetically compared
to rodents, it has great potential as an experimental model to study
these disease risk genes.
CRISPR is a popular technology for genome editing in zebrafish
due to its simplicity and speed (Hwang et al., 2013; Prykhozhij
et al., 2017; Prykhozhij and Berman, 2018). Researchers have
attempted to improve throughput by developing more scalable
methods. Current approaches are based on pooled CRISPR
targeting followed by individual genotyping and separation, but
have yet to provide a truly high-throughput output (Varshney et al.,
2015; Shah et al., 2015). Several possible approaches may improve
the current methods. Pooled CRISPR followed by early genotyping
of live larvae using a recently developed approach (Lambert et al.,
2018) can significantly speed up the turnover for each round of
genotyping. Robotically controlled and fully automated embryonic
injection methods (Zhao et al., 2018) also have the potential to
increase the throughput of CRISPR delivery. Automated feeding
systems such as Tritone (Aquatic Solutions) may facilitate the
husbandry of large numbers of mutant lines generated by high-
throughput CRISPR editing. Finally, if large numbers of disease-
related mutants are generated, expanding the capacity of zebrafish
stock centers may be needed (Table 2).
High-throughput chemical screening for disease modeling and drug
discovery
Both genes and the environment contribute to the development of
social behavior. The development of some social-related disorders
is also believed to be affected by environmental factors such as
prenatal exposure to certain chemicals. The zebrafish has been a
popular model for in vivo chemical screening (Rennekamp and
Peterson, 2015). Its ex utero development allows embryos to be Disease Models & Mechanisms
exposed to potentially toxic chemicals during early embryogenesis.
The zebrafish larva is small, and a large number of larvae can fit into
a compact imaging arena, enabling high-throughput behavioral
profiling and phenotype-based drug discovery (Jordi et al., 2018;
Bruni et al., 2016; Kokel et al., 2010, 2012; Rihel et al., 2010).
These features make zebrafish an attractive model for systematically
identifying potential environmental risk factors that contribute to
disease etiology by high-throughput chemical and behavioral
screening. Although technologies are readily available to expose
zebrafish embryos, larvae or adults to chemicals in a high-
throughput or scalable manner, a social behavior testing system
capable of operating in a high-throughput or scalable fashion has yet
to be developed (Table 2). The establishment of such a high-
throughput social behavior assay in zebrafish would enable

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Table 2. Potential applications of emerging technologies to improve social disorder modeling in zebrafish.
Research goals Limitations of current methods
High-throughput genome editing for • Mutagenesis methods are low throughput
disease modeling • Labor-intensive husbandry
• Limited resources for husbandry of mutant lines
High-throughput behavioral • Current social behavior assays are low throughput
screening for disease modeling or
drug discovery
Investigating circuit-level • Lack of real-time imaging capability for older or freely
mechanisms underlying deficits of moving fish
social disease models • Lack of whole-brain activity imaging methods
• Lack of circuit activation methods
• Low temporal resolution in circuit manipulation
approaches
researchers to systematically screen chemicals for their disease-
inducing risks and discover new drugs for treating social behavior
deficits in humans.
Neural activity imaging and circuit manipulation technologies for
social disorder models
The circuit-level mechanisms underlying social behavior and
disorders are not well understood. The zebrafish is a promising
model for elucidating these mechanisms because, compared to
rodents, it is relatively easy to image due to its small size and
transparent nature. Furthermore, it is amenable to facile circuit
manipulations through genetically targeted ablation, or optical and
chemical activation or inhibition. Although many of these
technologies are already established in zebrafish, they have rarely
been used to investigate social behavior. Here, we discuss the potential
to use imaging and circuit manipulation techniques to study brain
activities in social behavior and disease models (Table 2).
Real-time calcium imaging has long been applied to larval
zebrafish less than a week old. Researchers recently developed a
two-photon calcium imaging approach that enables real-time brain
imaging of 3-week-old zebrafish (Jetti et al., 2014; Vendrell-Llopis
and Yaksi, 2015), a stage when robust social preference behavior is
developed. Although, in the current methods, the fish must be
restrained for imaging, combining this method with VR technology
may allow brain activity imaging during a virtual social interaction.
In addition, with the recent advancements in real-time brain imaging
of freely moving larvae (Kim et al., 2017a; Cong et al., 2017; Muto
and Kawakami, 2016), it may one day be possible to develop
calcium imaging methods for freely moving 3-week-old fish during
physical social interactions. Alternatively, whole-brain or whole-
body tissue clearing methods such as CLARITY and PACT have
been successfully applied to adult zebrafish (Cronan et al., 2015),
and could enable post-hoc analysis of whole-brain activity patterns
during social interactions by examining the expression of immediate
early genes (Box 2).
Conventional methods in zebrafish manipulate circuit activity by
inhibiting neuronal activity through expression of neurotoxins such
as tetanus or botulinum toxins, or ablation of targeted neurons by
expressing nitroreductase (Curado et al., 2008). Newer technologies
such as optogenetics (Förster et al., 2017) and chemogenetics (Chen
et al., 2016b) (Box 2) can be applied to zebrafish to activate or
inhibit certain brain regions. It is also possible to combine both
methods by applying an optically switchable compound to activate
certain neurons (Lam et al., 2017). These newer methods can
activate specific neurons with reversible temporal control.
Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446
Possible solutions
• Rapid genotyping for fast turnaround
• Automated microinjection
• Automated fish husbandry
• Expansion of fish husbandry capacity
• High-throughput or scalable social behavior assays
• Adopt recent advances in real-time brain imaging, whole-
body hydrogel tissue chemistry methods, and
optogenetic- and chemogenetic-based circuit
manipulation approaches
Conclusions
Animal models for behavioral disorders are inevitably confronted
with questions about their validity. This is true for emerging model
organisms such as the zebrafish as well as for established ones such
as rodents. Care must be taken when interpreting results acquired
from animal models that attempt to mimic symptoms of human
conditions. This is especially true for complex traits such as social
behaviors. Nevertheless, behavioral assays often provide readouts
that are more relevant to the core symptoms of human behavior
disorders than other assays that examine changes in anatomy,
physiology or endophenotypes. Therefore, efforts in advancing the
current assay and analysis methods of social behavior are necessary
to facilitate progress in disease research.
The extensive data discussed in this Review support the idea that
many of the most fundamental elements of social behavior – e.g.
conspecific association, communication, establishment of hierarchies,
social eavesdropping, aggression and mating – are conserved in social
vertebrates from teleosts to mammals. Vertebrates as evolutionarily
distant as zebrafish and rodents share numerous genetic,
pharmacological, neuroanatomical and behavioral similarities
relevant to social behavior. Common structures in the SSB may
provide a biological foundation for social behavior conservation
among vertebrates. We argue that the more complex, higher-order
social behaviors in humans must be understood as layered on top of
the SSB, and studying the zebrafish SSB can therefore have direct
implications for understanding sociality in humans. Given the
numerous methods currently available for studying various aspects
of social behavior in zebrafish, the existing zebrafish models of social
deficits and the technologies (established and emergent) for high-
throughput experimentation, we anticipate that the zebrafish SSB will
become an increasingly important model for understanding the Disease Models & Mechanisms
biology of sociality in health and disease.
Competing interests
The authors declare no competing or financial interests.
Funding
This research received no specific grant from any funding agency in the public,
commercial or not-for-profit sectors.
References
Abril-de-Abreu, R., Cruz, A. S. and Oliveira, R. F. (2015a). Social dominance
modulates eavesdropping in zebrafish. R. Soc. Open Sci. 2, 150220. doi:10.1098/
rsos.150220
Abril-de-Abreu, R., Cruz, J. and Oliveira, R. F. (2015b). Social eavesdropping in
zebrafish: tuning of attention to social interactions. Sci. Rep. 5, 12678. doi:10.
1038/srep12678
13
REVIEW
Adolphs, R. (2003). Cognitive neuroscience of human social behaviour. Nat. Rev.
Neurosci. 4, 165-178. doi:10.1038/nrn1056
Adolphs, R. (2009). The social brain: neural basis of social knowledge. Annu. Rev.
Psychol. 60, 693-716. doi:10.1146/annurev.psych.60.110707.163514
Al-Jubouri, Q., Al-Nuaimy, W., Al-Taee, M. A. and Young, I. (2017). Computer
Stereovision System for 3D Tracking of Free-Swimming Zebrafish. 2017 10th
International Conference on Developments in eSystems Engineering (DeSE).
doi:10.1109/DeSE.2017.31
Altenhofen, S., Nabinger, D. D., Bitencourt, P. E. R. and Bonan, C. D. (2019).
Dichlorvos alters morphology and behavior in zebrafish (Danio rerio) larvae.
Environ. Pollut. 245, 1117-1123. doi:10.1016/j.envpol.2018.11.095
Amo, R., Aizawa, H., Takahoko, M., Kobayashi, M., Takahashi, R., Aoki, T. and
Okamoto, H. (2010). Identification of the zebrafish ventral habenula as a homolog
of the mammalian lateral habenula. J. Neurosci. 30, 1566-1574. doi:10.1523/
JNEUROSCI.3690-09.2010
Araujo-Silva, H., Pinheiro-da-Silva, J., Silva, P. F. and Luchiari, A. C. (2018).
Individual differences in response to alcohol exposure in zebrafish (Danio rerio).
PLoS ONE 13, e0198856. doi:10.1371/journal.pone.0198856
Arganda, S., Perez-Escudero, A. and de Polavieja, G. G. (2012). A common rule
for decision making in animal collectives across species. Proc. Natl. Acad. Sci.
USA 109, 20508-20513. doi:10.1073/pnas.1210664109
Ariyasiri, K., Choi, T.-I., Kim, O.-H., Hong, T. I., Gerlai, R. and Kim, C.-H. (2019).
Pharmacological (ethanol) and mutation (sam2 KO) induced impairment of
novelty preference in zebrafish quantified using a new three-chamber social
choice task. Prog. Neuropsychopharmacol. Biol. Psychiatry 88, 53-65. doi:10.
1016/j.pnpbp.2018.06.009
Ariyomo, T. O. and Watt, P. J. (2015). Effect of hunger level and time of day on
boldness and aggression in the zebrafish Danio rerio. J. Fish Biol. 86, 1852-1859.
doi:10.1111/jfb.12674
Armbruster, B. N., Li, X., Pausch, M. H., Herlitze, S. and Roth, B. L. (2007).
Evolving the lock to fit the key to create a family of G protein-coupled receptors
potently activated by an inert ligand. Proc. Natl. Acad. Sci. USA 104, 5163-5168.
doi:10.1073/pnas.0700293104
Ashwood, P., Kwong, C., Hansen, R., Hertz-Picciotto, I., Croen, L., Krakowiak,
P., Walker, W., Pessah, I. N. and van de Water, J. (2008). Brief report: plasma
leptin levels are elevated in autism: association with early onset phenotype?
J. Autism Dev. Disord. 38, 169-175. doi:10.1007/s10803-006-0353-1
Atmaca, M., Kuloglu, M., Tezcan, E. and Ustundag, B. (2003). Serum leptin and
cholesterol levels in schizophrenic patients with and without suicide attempts.
Acta Psychiatr. Scand. 108, 208-214. doi:10.1034/j.1600-0447.2003.00145.x
Attaran, A., Salahinejad, A., Crane, A. L., Niyogi, S. and Chivers, D. P. (2019).
Chronic exposure to dietary selenomethionine dysregulates the genes involved in
serotonergic neurotransmission and alters social and antipredator behaviours in
zebrafish (Danio rerio). Environ. Pollut. 246, 837-844. doi:10.1016/j.envpol.2018.
12.090
Audira, G., Sarasamma, S., Chen, J.-R., Juniardi, S., Sampurna, B. P., Liang, S.-
T., Lai, Y.-H., Lin, G.-M., Hsieh, M.-C. and Hsiao, C.-D. (2018a). Zebrafish
mutants carrying leptin a (lepa) gene deficiency display obesity, anxiety, less
aggression and fear, and circadian rhythm and color preference dysregulation.
Int. J. Mol. Sci. 19, E4038. doi:10.3390/ijms19124038
Audira, G., Sampurna, B. P., Juniardi, S., Liang, S.-T., Lai, Y.-H. and Hsiao, C.-D.
(2018b). A simple setup to perform 3D locomotion tracking in zebrafish by using a
single camera. Inventions 3, 11. doi:10.3390/inventions3010011
Autism Genome Project Consortium, Szatmari, P., Paterson, A. D.,
Zwaigenbaum, L., Roberts, W., Brian, J., Liu, X. Q., Vincent, J. B., Skaug,
J. L., Thompson, A. P., Senman, L., et al. (2007). Mapping autism risk loci using
genetic linkage and chromosomal rearrangements. Nat. Genet. 39, 319-328.
doi:10.1038/ng1985
Bae, Y.-K., Kani, S., Shimizu, T., Tanabe, K., Nojima, H., Kimura, Y.,
Higashijima, S.-I. and Hibi, M. (2009). Anatomy of zebrafish cerebellum and
screen for mutations affecting its development. Dev. Biol. 330, 406-426. doi:10.
1016/j.ydbio.2009.04.013
Bá ez-Mendoza, R. and Schultz, W. (2013). The role of the striatum in social
behavior. Front. Neurosci. 7, 233. doi:10.3389/fnins.2013.00233
Bai, Y.-X., Zhang, S.-H., Fan, Z., Liu, X.-Y., Zhao, X., Feng, X.-Z. and Sun, M.-Z.
(2018). Automatic multiple zebrafish tracking based on improved HOG features.
Sci. Rep. 8, 10884. doi:10.1038/s41598-018-29185-0
Bailey, J. M. and Levin, E. D. (2015). Neurotoxicity of FireMaster 550® in zebrafish
(Danio rerio): chronic developmental and acute adolescent exposures.
Neurotoxicol. Teratol. 52, 210-219. doi:10.1016/j.ntt.2015.07.001
Bailey, J. M., Oliveri, A. N., Karbhari, N., Brooks, R. A., De La Rocha, A. J.,
Janardhan, S. and Levin, E. D. (2016). Persistent behavioral effects following
early life exposure to retinoic acid or valproic acid in zebrafish. Neurotoxicology
52, 23-33. doi:10.1016/j.neuro.2015.10.001
Baronio, D., Puttonen, H. A. J., Sundvik, M., Semenova, S., Lehtonen, E. and
Panula, P. (2018). Embryonic exposure to valproic acid affects the histaminergic
system and the social behaviour of adult zebrafish (Danio rerio). Br. J. Pharmacol.
175, 797-809. doi:10.1111/bph.14124
Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446
Bartolini, T., Mwaffo, V., Showler, A., Macrì, S., Butail, S. and Porfiri, M. (2016).
Zebrafish response to 3D printed shoals of conspecifics: the effect of body size.
Bioinspir. Biomim. 11, 026003. doi:10.1088/1748-3190/11/2/026003
Berman, G. J., Choi, D. M., Bialek, W. and Shaevitz, J. W. (2014). Mapping the
stereotyped behaviour of freely moving fruit flies. J. R Soc. Interface 11,
20140672. doi:10.1098/rsif.2014.0672
Bernier, R., Golzio, C., Xiong, B., Stessman, H. A., Coe, B. P., Penn, O.,
Witherspoon, K., Gerdts, J., Baker, C., Vulto-van Silfhout, A. T., et al. (2014).
Disruptive CHD8 mutations define a subtype of autism early in development. Cell
158, 263-276. doi:10.1016/j.cell.2014.06.017
Biechl, D., Tietje, K., Gerlach, G. and Wullimann, M. F. (2016). Crypt cells are
involved in kin recognition in larval zebrafish. Sci. Rep. 6, 24590. doi:10.1038/
srep24590
Bishop, B. H., Spence-Chorman, N. and Gahtan, E. (2016). Three-dimensional
motion tracking reveals a diving component to visual and auditory escape swims
in zebrafish larvae. J. Exp. Biol. 219, 3981-3987. doi:10.1242/jeb.147124
Blakemore, S.-J. (2008). The social brain in adolescence. Nat. Rev. Neurosci. 9,
267-277. doi:10.1038/nrn2353
Blakemore, S.-J. (2012). Development of the social brain in adolescence. J. R Soc.
Med. 105, 111-116. doi:10.1258/jrsm.2011.110221
Blaker-Lee, A., Gupta, S., Mccammon, J. M., de Rienzo, G. and Sive, H. (2012).
Zebrafish homologs of genes within 16p11.2, a genomic region associated with
brain disorders, are active during brain development, and include two deletion
dosage sensor genes. Dis. Model. Mech. 5, 834-851. doi:10.1242/dmm.009944
Blardi, P., de Lalla, A., D’ambrogio, T., Zappella, M., Cevenini, G., Ceccatelli, L.,
Auteri, A. and Hayek, J. (2007). Rett syndrome and plasma leptin levels.
J. Pediatr. 150, 37-39. doi:10.1016/j.jpeds.2006.10.061
Blardi, P., de Lalla, A., D’ambrogio, T., Vonella, G., Ceccatelli, L., Auteri, A. and
Hayek, J. (2009). Long-term plasma levels of leptin and adiponectin in Rett
syndrome. Clin. Endocrinol. 70, 706-709. doi:10.1111/j.1365-2265.2008.03386.x
Blardi, P., de Lalla, A., Ceccatelli, L., Vanessa, G., Auteri, A. and Hayek, J.
(2010). Variations of plasma leptin and adiponectin levels in autistic patients.
Neurosci. Lett. 479, 54-57. doi:10.1016/j.neulet.2010.05.027
Bortolotto, J. W., Cognato, G. P., Christoff, R. R., Roesler, L. N., Leite, C. E., Kist,
L. W., Bogo, M. R., Vianna, M. R. and Bonan, C. D. (2014). Long-term exposure
to paraquat alters behavioral parameters and dopamine levels in adult zebrafish
(Danio rerio). Zebrafish 11, 142-153. doi:10.1089/zeb.2013.0923
Braida, D., Donzelli, A., Martucci, R., Capurro, V., Busnelli, M., Chini, B. and
Sala, M. (2012). Neurohypophyseal hormones manipulation modulate social and
anxiety-related behavior in zebrafish. Psychopharmacology (Berl.) 220, 319-330.
doi:10.1007/s00213-011-2482-2
Bridi, D., Altenhofen, S., Gonzalez, J. B., Reolon, G. K. and Bonan, C. D. (2017).
Glyphosate and Roundup® alter morphology and behavior in zebrafish.
Toxicology 392, 32-39. doi:10.1016/j.tox.2017.10.007
Brown, A. E. X., Yemini, E. I., Grundy, L. J., Jucikas, T. and Schafer, W. R.
(2013). A dictionary of behavioral motifs reveals clusters of genes affecting
Caenorhabditis elegans locomotion. Proc. Natl. Acad. Sci. USA 110, 791-796.
doi:10.1073/pnas.1211447110
Brown, R. S. E., Aoki, M., Ladyman, S. R., Phillipps, H. R., Wyatt, A., Boehm, U.
and Grattan, D. R. (2017). Prolactin action in the medial preoptic area is
necessary for postpartum maternal nursing behavior. Proc. Natl. Acad. Sci. USA
114, 10779-10784. doi:10.1073/pnas.1708025114
Bruni, G., Rennekamp, A. J., Velenich, A., Mccarroll, M., Gendelev, L., Fertsch,
E., Taylor, J., Lakhani, P., Lensen, D., Evron, T. et al. (2016). Zebrafish
behavioral profiling identifies multitarget antipsychotic-like compounds. Nat.
Chem. Biol. 12, 559-566. doi:10.1038/nchembio.2097
Buske, C. and Gerlai, R. (2011). Early embryonic ethanol exposure impairs
shoaling and the dopaminergic and serotoninergic systems in adult zebrafish.
Neurotoxicol. Teratol. 33, 698-707. doi:10.1016/j.ntt.2011.05.009
Disease Models & Mechanisms
Busnelli, M., Kleinau, G., Muttenthaler, M., Stoev, S., Manning, M., Bibic, L.,
Howell, L. A., Mccormick, P. J., di Lascio, S., Braida, D. et al. (2016). Design
and characterization of superpotent bivalent ligands targeting oxytocin receptor
dimers via a channel-like structure. J. Med. Chem. 59, 7152-7166. doi:10.1021/
acs.jmedchem.6b00564
Butail, S. and Paley, D. A. (2012). Three-dimensional reconstruction of the fast-start
swimming kinematics of densely schooling fish. J. R Soc. Interface 9, 77-88.
doi:10.1098/rsif.2011.0113
Butail, S., Bartolini, T. and Porfiri, M. (2013a). Collective response of zebrafish
shoals to a free-swimming robotic fish. PLoS ONE 8, e76123. doi:10.1371/journal.
pone.0076123
Butail, S., Bollt, E. M. and Porfiri, M. (2013b). Analysis and classification of
collective behavior using generative modeling and nonlinear manifold learning.
J. Theor. Biol. 336, 185-199. doi:10.1016/j.jtbi.2013.07.029
Butail, S., Mwaffo, V. and Porfiri, M. (2016). Model-free information-theoretic
approach to infer leadership in pairs of zebrafish. Phys. Rev. E 93, 042411. doi:10.
1103/PhysRevE.93.042411
Cachat, J., Kyzar, E. J., Collins, C., Gaikwad, S., Green, J., Roth, A., El-Ounsi,
M., Davis, A., Pham, M., Landsman, S. et al. (2013). Unique and potent effects of
acute ibogaine on zebrafish: the developing utility of novel aquatic models for
14
REVIEW
hallucinogenic drug research. Behav. Brain Res. 236, 258-269. doi:10.1016/j.bbr.
2012.08.041
Carta, I., Chen, C. H., Schott, A. L., Dorizan, S. and Khodakhah, K. (2019).
Cerebellar modulation of the reward circuitry and social behavior. Science 363,
eaav0581. doi:10.1126/science.aav0581
Cazenille, L., Collignon, B., Chemtob, Y., Bonnet, F., Gribovskiy, A., Mondada,
F., Bredeche, N. and Halloy, J. (2018). How mimetic should a robotic fish be to
socially integrate into zebrafish groups? Bioinspir. Biomim. 13, 025001. doi:10.
1088/1748-3190/aa8f6a
Chakravarty, S., Reddy, B. R., Sudhakar, S. R., Saxena, S., Das, T., Meghah, V.,
Brahmendra Swamy, C. V., Kumar, A. and Idris, M. M. (2013). Chronic
unpredictable stress (CUS)-induced anxiety and related mood disorders in a
zebrafish model: altered brain proteome profile implicates mitochondrial
dysfunction. PLoS ONE 8, e63302. doi:10.1371/journal.pone.0063302
Chen, J., Tanguay, R. L., Simonich, M., Nie, S., Zhao, Y., Li, L., Bai, C., Dong, Q.,
Huang, C. and Lin, K. (2016a). TBBPA chronic exposure produces sex-specific
neurobehavioral and social interaction changes in adult zebrafish. Neurotoxicol.
Teratol. 56, 9-15. doi:10.1016/j.ntt.2016.05.008
Chen, S., Chiu, C. N., Mcarthur, K. L., Fetcho, J. R. and Prober, D. A. (2016b).
TRP channel mediated neuronal activation and ablation in freely behaving
zebrafish. Nat. Methods 13, 147-150. doi:10.1038/nmeth.3691
Chiu, C. N., Rihel, J., Lee, D. A., Singh, C., Mosser, E. A., Chen, S., Sapin, V.,
Pham, U., Engle, J., Niles, B. J. et al. (2016). A zebrafish genetic screen
identifies neuromedin U as a regulator of sleep/wake states. Neuron 89, 842-856.
doi:10.1016/j.neuron.2016.01.007
Choi, J.-H., Jeong, Y.-M., Kim, S., Lee, B., Ariyasiri, K., Kim, H.-T., Jung, S.-H.,
Hwang, K.-S., Choi, T.-I., Park, C. O. et al. (2018). Targeted knockout of a
chemokine-like gene increases anxiety and fear responses. Proc. Natl. Acad. Sci.
USA 115, E1041-E1050. doi:10.1073/pnas.1707663115
Chou, M.-Y., Amo, R., Kinoshita, M., Cherng, B.-W., Shimazaki, H., Agetsuma,
M., Shiraki, T., Aoki, T., Takahoko, M., Yamazaki, M. et al. (2016). Social conflict
resolution regulated by two dorsal habenular subregions in zebrafish. Science
352, 87-90. doi:10.1126/science.aac9508
Clark, D. A., Arranz, M. J., Mata, I., Lopé z-Ilundain, J., Pé rez-Nievas, F. and
Kerwin, R. W. (2005). Polymorphisms in the promoter region of the alpha1A-
adrenoceptor gene are associated with schizophrenia/schizoaffective disorder in
a Spanish isolate population. Biol. Psychiatry 58, 435-439. doi:10.1016/j.
biopsych.2005.04.051
Clark, D. A., Mancama, D., Kerwin, R. W. and Arranz, M. J. (2006). Expression of
the alpha1A-adrenergic receptor in schizophrenia. Neurosci. Lett. 401, 248-251.
doi:10.1016/j.neulet.2006.03.025
Clarke, A. and File, S. E. (1982). Selective neurotoxin lesions of the lateral septum:
changes in social and aggressive behaviours. Pharmacol. Biochem. Behav. 17,
623-628. doi:10.1016/0091-3057(82)90334-3
Clements, K. N., Miller, T. H., Keever, J. M., Hall, A. M. and Issa, F. A. (2018).
Social status-related differences in motor activity between wild-type and mutant
zebrafish. Biol. Bull. 235, 71-82. doi:10.1086/699514
Coe, T. S., Hamilton, P. B., Hodgson, D., Paull, G. C., Stevens, J. R., Sumner, K.
and Tyler, C. R. (2008). An environmental estrogen alters reproductive
hierarchies, disrupting sexual selection in group-spawning fish. Environ. Sci.
Technol. 42, 5020-5025. doi:10.1021/es800277q
Coe, T. S., Hamilton, P. B., Hodgson, D., Paull, G. C. and Tyler, C. R. (2009).
Parentage outcomes in response to estrogen exposure are modified by social
grouping in zebrafish. Environ. Sci. Technol. 43, 8400-8405. doi:10.1021/
es902302u
Colman, J. R., Baldwin, D., Johnson, L. L. and Scholz, N. L. (2009). Effects of the
synthetic estrogen, 17alpha-ethinylestradiol, on aggression and courtship
behavior in male zebrafish (Danio rerio). Aquat. Toxicol. 91, 346-354. doi:10.
1016/j.aquatox.2008.12.001
Cong, L., Wang, Z., Chai, Y., Hang, W., Shang, C., Yang, W., Bai, L., Du, J., Wang,
K. and Wen, Q. (2017). Rapid whole brain imaging of neural activity in freely
behaving larval zebrafish (Danio rerio). eLife 6, e28158. doi:10.7554/eLife.28158
Cronan, M. R., Rosenberg, A. F., Oehlers, S. H., Saelens, J. W., Sisk, D. M.,
Jurcic Smith, K. L., Lee, S. and Tobin, D. M. (2015). CLARITY and PACT-based
imaging of adult zebrafish and mouse for whole-animal analysis of infections. Dis.
Model. Mech. 8, 1643-1650. doi:10.1242/dmm.021394
Crosby, E. B., Bailey, J. M., Oliveri, A. N. and Levin, E. D. (2015). Neurobehavioral
impairments caused by developmental imidacloprid exposure in zebrafish.
Neurotoxicol. Teratol. 49, 81-90. doi:10.1016/j.ntt.2015.04.006
Curado, S., Stainier, D. Y. R. and Anderson, R. M. (2008). Nitroreductase-
mediated cell/tissue ablation in zebrafish: a spatially and temporally controlled
ablation method with applications in developmental and regeneration studies. Nat.
Protoc. 3, 948-954. doi:10.1038/nprot.2008.58
Dang, M., Henderson, R. E., Garraway, L. A. and Zon, L. I. (2016). Long-term drug
administration in the adult zebrafish using oral gavage for cancer preclinical
studies. Dis. Model. Mech. 9, 811-820. doi:10.1242/dmm.024166
Darrow, K. O. and Harris, W. A. (2004). Characterization and development of
courtship in zebrafish, Danio rerio. Zebrafish 1, 40-45. doi:10.1089/
154585404774101662
Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446
Deng, H., Xiao, X. and Wang, Z. (2016). Periaqueductal gray neuronal activities
underlie different aspects of defensive behaviors. J. Neurosci. 36, 7580-7588.
doi:10.1523/JNEUROSCI.4425-15.2016
Dewari, P. S., Ajani, F., Kushawah, G., Kumar, D. S. and Mishra, R. K. (2016).
Reversible loss of reproductive fitness in zebrafish on chronic alcohol exposure.
Alcohol 50, 83-89. doi:10.1016/j.alcohol.2015.11.006
Dipp, V. R., Valles, S., Ortiz-Kerbertt, H., Suarez, J. V. and Bardullas, U. (2018).
Neurobehavioral alterations in zebrafish due to long-term exposure to low doses of
inorganic arsenic. Zebrafish 15, 575-585. doi:10.1089/zeb.2018.1627
Dö len, G., Darvishzadeh, A., Huang, K. W. and Malenka, R. C. (2013). Social
reward requires coordinated activity of nucleus accumbens oxytocin and
serotonin. Nature 501, 179-184. doi:10.1038/nature12518
Dreosti, E., Lopes, G., Kampff, A. R. and Wilson, S. W. (2015). Development of
social behavior in young zebrafish. Front. Neural Circuits 9, 39. doi:10.3389/fncir.
2015.00039
Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P.,
Fauchereau, F., Nygren, G., Rastam, M., Gillberg, I. C., Anckarsä ter, H. et al.
(2007). Mutations in the gene encoding the synaptic scaffolding protein SHANK3
are associated with autism spectrum disorders. Nat. Genet. 39, 25-27. doi:10.
1038/ng1933
Dwivedi, S., Medishetti, R., Rani, R., Sevilimedu, A., Kulkarni, P. and
Yogeeswari, P. (2019). Larval zebrafish model for studying the effects of
valproic acid on neurodevelopment: An approach towards modeling autism.
J. Pharmacol. Toxicol. Methods 95, 56-65. doi:10.1016/j.vascn.2018.11.006
Eachus, H., Bright, C., Cunliffe, V. T., Placzek, M., Wood, J. D. and Watt, P. J.
(2017). Disrupted-in-Schizophrenia-1 is essential for normal hypothalamic-
pituitary-interrenal (HPI) axis function. Hum. Mol. Genet. 26, 1992-2005. doi:10.
1093/hmg/ddx076
Eguiraun, H., Casquero, O., Sørensen, A. J. and Martinez, I. (2018). Reducing the
number of individuals to monitor shoaling fish systems - application of the shannon
entropy to construct a biological warning system model. Front. Physiol. 9, 493.
doi:10.3389/fphys.2018.00493
Engeszer, R. E., Ryan, M. J. and Parichy, D. M. (2004). Learned social preference
in zebrafish. Curr. Biol. 14, 881-884. doi:10.1016/j.cub.2004.04.042
Falkner, A. L. and Lin, D. (2014). Recent advances in understanding the role of the
hypothalamic circuit during aggression. Front. Syst. Neurosci. 8, 168. doi:10.
3389/fnsys.2014.00168
Fang, Y. Y., Yamaguchi, T., Song, S. C., Tritsch, N. X. and Lin, D. (2018). A
hypothalamic midbrain pathway essential for driving maternal behaviors. Neuron
98, 192-207.e10. doi:10.1016/j.neuron.2018.02.019
Fantz, R. L. (1963). Pattern vision in newborn infants. Science 140, 296-297. doi:10.
1126/science.140.3564.296
Fé lix, L. M., Antunes, L. M., Coimbra, A. M. and Valentim, A. M. (2017a).
Behavioral alterations of zebrafish larvae after early embryonic exposure to
ketamine. Psychopharmacology (Berl.) 234, 549-558. doi:10.1007/s00213-016-
4491-7
Fé lix, L. M., Serafim, C., Martins, M. J., Valentim, A. M., Antunes, L. M., Matos, M.
and Coimbra, A. M. (2017b). Morphological and behavioral responses of
zebrafish after 24h of ketamine embryonic exposure. Toxicol. Appl. Pharmacol.
321, 27-36. doi:10.1016/j.taap.2017.02.013
Fernandes, Y. and Gerlai, R. (2009). Long-term behavioral changes in response to
early developmental exposure to ethanol in zebrafish. Alcohol. Clin. Exp. Res. 33,
601-609. doi:10.1111/j.1530-0277.2008.00874.x
Fernandes, Y., Rampersad, M. and Gerlai, R. (2015). Embryonic alcohol exposure
impairs the dopaminergic system and social behavioral responses in adult
zebrafish. Int. J. Neuropsychopharmacol. 18, pyu089. doi:10.1093/ijnp/pyu089
Ferrero, D. M., Moeller, L. M., Osakada, T., Horio, N., Li, Q., Roy, D. S., Cichy, A.,
Spehr, M., Touhara, K. and Liberles, S. D. (2013). A juvenile mouse pheromone
inhibits sexual behaviour through the vomeronasal system. Nature 502, 368-371.
doi:10.1038/nature12579
Disease Models & Mechanisms
Filby, A. L., Paull, G. C., Bartlett, E. J., van Look, K. J. W. and Tyler, C. R. (2010a).
Physiological and health consequences of social status in zebrafish (Danio rerio).
Physiol. Behav. 101, 576-587. doi:10.1016/j.physbeh.2010.09.004
Filby, A. L., Paull, G. C., Hickmore, T. F. A. and Tyler, C. R. (2010b). Unravelling
the neurophysiological basis of aggression in a fish model. BMC Genomics 11,
498. doi:10.1186/1471-2164-11-498
Filby, A. L., Paull, G. C., Searle, F., Ortiz-Zarragoitia, M. and Tyler, C. R. (2012).
Environmental estrogen-induced alterations of male aggression and dominance
hierarchies in fish: a mechanistic analysis. Environ. Sci. Technol. 46, 3472-3479.
doi:10.1021/es204023d
Filiano, A. J., Xu, Y., Tustison, N. J., Marsh, R. L., Baker, W., Smirnov, I., Overall,
C. C., Gadani, S. P., Turner, S. D., Weng, Z. et al. (2016). Unexpected role of
interferon-gamma in regulating neuronal connectivity and social behaviour.
Nature 535, 425-429. doi:10.1038/nature18626
Flanigan, M., Aleyasin, H., Takahashi, A., Golden, S. A. and Russo, S. J. (2017).
An emerging role for the lateral habenula in aggressive behavior. Pharmacol.
Biochem. Behav. 162, 79-86. doi:10.1016/j.pbb.2017.05.003
Fontana, B. D., Meinerz, D. L., Rosa, L. V. C., Mezzomo, N. J., Silveira, A.,
Giuliani, G. S., Quadros, V. A., Filho, G. L. B., Blaser, R. E. and Rosemberg,
D. B. (2016). Modulatory action of taurine on ethanol-induced aggressive
15
REVIEW
behavior in zebrafish. Pharmacol. Biochem. Behav. 141, 18-27. doi:10.1016/j.
pbb.2015.11.011
Fontana, B. D., Stefanello, F. V., Mezzomo, N. J., Mü ller, T. E., Quadros, V. A.,
Parker, M. O., Rico, E. P. and Rosemberg, D. B. (2018). Taurine modulates
acute ethanol-induced social behavioral deficits and fear responses in adult
zebrafish. J. Psychiatr. Res. 104, 176-182. doi:10.1016/j.jpsychires.2018.08.008
Fö rster, D., Dal Maschio, M., Laurell, E. and Baier, H. (2017). An optogenetic
toolbox for unbiased discovery of functionally connected cells in neural circuits.
Nat. Commun. 8, 116. doi:10.1038/s41467-017-00160-z
Franco-Restrepo, J. E., Forero, D. A. and Vargas, R. A. (2019). A review of freely
available, open-source software for the automated analysis of the behavior of
adult zebrafish. Zebrafish 16, 223-232. doi:10.1089/zeb.2018.1662
Frith, C. D. (2007). The social brain? Philos. Trans. R. Soc. Lond. B Biol. Sci. 362,
671-678. doi:10.1098/rstb.2006.2003
Fulcher, N., Tran, S., Shams, S., Chatterjee, D. and Gerlai, R. (2017).
Neurochemical and behavioral responses to unpredictable chronic mild stress
following developmental isolation: the zebrafish as a model for major depression.
Zebrafish 14, 23-34. doi:10.1089/zeb.2016.1295
Gaugler, T., Klei, L., Sanders, S. J., Bodea, C. A., Goldberg, A. P., Lee, A. B.,
Mahajan, M., Manaa, D., Pawitan, Y., Reichert, J. et al. (2014). Most genetic risk
for autism resides with common variation. Nat. Genet. 46, 881-885. doi:10.1038/
ng.3039
Gerlach, G., Hodgins-Davis, A., Avolio, C. and Schunter, C. (2008). Kin
recognition in zebrafish: a 24-hour window for olfactory imprinting. Proc. Biol.
Sci. 275, 2165-2170. doi:10.1098/rspb.2008.0647
Gerlach, G., Tietje, K., Biechl, D., Namekawa, I., Schalm, G. and Sulmann, A.
(2019). Behavioural and neuronal basis of olfactory imprinting and kin recognition
in larval fish. J. Exp. Biol. 222, Suppl. 1, jeb189746. doi:10.1242/jeb.189746
Gerlai, R. (2017). Animated images in the analysis of zebrafish behavior. Curr Zool
63, 35-44. doi:10.1093/cz/zow077
Giacomini, A. C. V. V., Abreu, M. S., Giacomini, L. V., Siebel, A. M., Zimerman,
F. F., Rambo, C. L., Mocelin, R., Bonan, C. D., Piato, A. L. and Barcellos,
L. J. G. (2016). Fluoxetine and diazepam acutely modulate stress induced-
behavior. Behav. Brain Res. 296, 301-310. doi:10.1016/j.bbr.2015.09.027
Gierszewski, S., Mü ller, K., Smielik, I., Hü twohl, J.-M., Kuhnert, K.-D. and Witte,
K. (2017). The virtual lover: variable and easily guided 3D fish animations as an
innovative tool in mate-choice experiments with sailfin mollies-II. Validation. Curr.
Zool. 63, 65-74. doi:10.1093/cz/zow108
Gierszewski, S., Baker, D., Mü ller, K., Hü twohl, J. M., Kuhnert, K.-D. and Witte,
K. (2018). Using the FishSim animation toolchain to investigate fish behavior: a
case study on mate-choice copying in Sailfin Mollies. J. Vis. Exp. 141, e58435.
doi:10.3791/58435
Glazer, L., Hawkey, A. B., Wells, C. N., Drastal, M., Odamah, K.-A., Behl, M. and
Levin, E. D. (2018a). Developmental exposure to low concentrations of
organophosphate flame retardants causes life-long behavioral alterations in
zebrafish. Toxicol. Sci. 165, 487-498. doi:10.1093/toxsci/kfy173
Glazer, L., Wells, C. N., Drastal, M., Odamah, K.-A., Galat, R. E., Behl, M. and
Levin, E. D. (2018b). Developmental exposure to low concentrations of two
brominated flame retardants, BDE-47 and BDE-99, causes life-long behavioral
alterations in zebrafish. Neurotoxicology 66, 221-232. doi:10.1016/j.neuro.2017.
09.007
Golden, S. A., Heshmati, M., Flanigan, M., Christoffel, D. J., Guise, K., Pfau,
M. L., Aleyasin, H., Menard, C., Zhang, H., Hodes, G. E. et al. (2016). Basal
forebrain projections to the lateral habenula modulate aggression reward. Nature
534, 688-692. doi:10.1038/nature18601
Golzio, C., Willer, J., Talkowski, M. E., Oh, E. C., Taniguchi, Y., Jacquemont, S.,
Reymond, A., Sun, M., Sawa, A., Gusella, J. F. et al. (2012). KCTD13 is a major
driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number
variant. Nature 485, 363-367. doi:10.1038/nature11091
Green, J., Collins, C., Kyzar, E. J., Pham, M., Roth, A., Gaikwad, S., Cachat, J.,
Stewart, A. M., Landsman, S., Grieco, F. et al. (2012). Automated high-
throughput neurophenotyping of zebrafish social behavior. J. Neurosci. Methods
210, 266-271. doi:10.1016/j.jneumeth.2012.07.017
Grossman, L., Utterback, E., Stewart, A., Gaikwad, S., Chung, K. M., Suciu, C.,
Wong, K., Elegante, M., Elkhayat, S., Tan, J. et al. (2010). Characterization of
behavioral and endocrine effects of LSD on zebrafish. Behav. Brain Res. 214,
277-284. doi:10.1016/j.bbr.2010.05.039
Guayasamin, O. L., Couzin, I. D. and Miller, N. Y. (2017). Behavioural plasticity
across social contexts is regulated by the directionality of inter-individual
differences. Behav. Processes 141, 196-204. doi:10.1016/j.beproc.2016.10.004
Halloy, J., Sempo, G., Caprari, G., Rivault, C., Asadpour, M., Tache, F., Said, I.,
Durier, V., Canonge, S., Ame, J. M. et al. (2007). Social integration of robots into
groups of cockroaches to control self-organized choices. Science 318,
1155-1158. doi:10.1126/science.1144259
Hanell, A. and Marklund, N. (2014). Structured evaluation of rodent behavioral
tests used in drug discovery research. Front. Behav. Neurosci. 8, 252. doi:10.
3389/fnbeh.2014.00252
Harpaz, R., Tkac ik, G. and Schneidman, E. (2017). Discrete modes of social
information processing predict individual behavior of fish in a group. Proc. Natl.
Acad. Sci. USA 114, 10149-10154. doi:10.1073/pnas.1703817114
Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446
Hashikawa, K., Hashikawa, Y., Tremblay, R., Zhang, J., Feng, J. E., Sabol, A.,
Piper, W. T., Lee, H., Rudy, B. and Lin, D. (2017). Esr1(+) cells in the
ventromedial hypothalamus control female aggression. Nat. Neurosci. 20,
1580-1590. doi:10.1038/nn.4644
Heap, L. A., Goh, C. C., Kassahn, K. S. and Scott, E. K. (2013). Cerebellar output
in zebrafish: an analysis of spatial patterns and topography in eurydendroid cell
projections. Front. Neural Circuits 7, 53. doi:10.3389/fncir.2013.00053
Heras, F. J. H., Romero-Ferrero, F., Hinz, R. C. and de Polavieja, G. G. (2018).
Deep attention networks reveal the rules of collective motion in zebrafish. bioRxiv.
doi:10.1101/400747
Hinz, R. C. and de Polavieja, G. G. (2017). Ontogeny of collective behavior reveals
a simple attraction rule. Proc. Natl. Acad. Sci. USA 114, 2295-2300. doi:10.1073/
pnas.1616926114
Hinz, C., Kobbenbring, S., Kress, S., Sigman, L., Mü ller, A. and Gerlach, G.
(2013). Kin recognition in zebrafish, Danio rerio, is based on imprinting on
olfactory and visual stimuli. Anim. Behav. 85, 925-930. doi:10.1016/j.anbehav.
2013.02.010
Hitti, F. L. and Siegelbaum, S. A. (2014). The hippocampal CA2 region is essential
for social memory. Nature 508, 88-92. doi:10.1038/nature13028
Hoffman, E. J., Turner, K. J., Fernandez, J. M., Cifuentes, D., Ghosh, M., Ijaz, S.,
Jain, R. A., Kubo, F., Bill, B. R., Baier, H. et al. (2016). Estrogens suppress a
behavioral phenotype in zebrafish mutants of the autism risk gene, CNTNAP2.
Neuron 89, 725-733. doi:10.1016/j.neuron.2015.12.039
Huang, K., Shi, Y., Tang, W., Tang, R., Guo, S., Xu, Y., Meng, J., Li, X., Feng, G.
and He, L. (2008). No association found between the promoter variants of
ADRA1A and schizophrenia in the Chinese population. J. Psychiatr. Res. 42,
384-388. doi:10.1016/j.jpsychires.2007.02.008
Hung, L. W., Neuner, S., Polepalli, J. S., Beier, K. T., Wright, M., Walsh, J. J.,
Lewis, E. M., Luo, L., Deisseroth, K., Dö len, G. and et al. (2017). Gating of social
reward by oxytocin in the ventral tegmental area. Science 357, 1406-1411. doi:10.
1126/science.aan4994
Huntingford, F. and Turner, A. K. (1987). Animal conflict. London; New York:
Chapman and Hall.
Hwang, W. Y., Fu, Y., Reyon, D., Maeder, M. L., Tsai, S. Q., Sander, J. D.,
Peterson, R. T., Yeh, J.-R. J. and Joung, J. K. (2013). Efficient genome editing in
zebrafish using a CRISPR-Cas system. Nat. Biotechnol. 31, 227-229. doi:10.
1038/nbt.2501
Jacquet, H., Demily, C., Houy, E., Hecketsweiler, B., Bou, J., Raux, G., Lerond,
J., Allio, G., Haouzir, S., Tillaux, A. et al. (2005). Hyperprolinemia is a risk factor
for schizoaffective disorder. Mol. Psychiatry 10, 479-485. doi:10.1038/sj.mp.
4001597
Jetti, S. K., Vendrell-Llopis, N. and Yaksi, E. (2014). Spontaneous activity governs
olfactory representations in spatially organized habenular microcircuits. Curr. Biol.
24, 434-439. doi:10.1016/j.cub.2014.01.015
Jolous-Jamshidi, B., Cromwell, H. C., Mcfarland, A. M. and Meserve, L. A.
(2010). Perinatal exposure to polychlorinated biphenyls alters social behaviors in
rats. Toxicol. Lett. 199, 136-143. doi:10.1016/j.toxlet.2010.08.015
Jordi, J., Guggiana-Nilo, D., Bolton, A. D., Prabha, S., Ballotti, K., Herrera, K.,
Rennekamp, A. J., Peterson, R. T., Lutz, T. A. and Engert, F. (2018). High-
throughput screening for selective appetite modulators: a multibehavioral and
translational drug discovery strategy. Sci. Adv. 4, eaav1966. doi:10.1126/sciadv.
aav1966
Katz, Y., Tunstrom, K., Ioannou, C. C., Huepe, C. and Couzin, I. D. (2011).
Inferring the structure and dynamics of interactions in schooling fish. Proc. Natl.
Acad. Sci. USA 108, 18720-18725. doi:10.1073/pnas.1107583108
Kim, D. H., Kim, J., Marques, J. C., Grama, A., Hildebrand, D. G. C., Gu, W., Li,
J. M. and Robson, D. N. (2017a). Pan-neuronal calcium imaging with cellular
resolution in freely swimming zebrafish. Nat. Methods 14, 1107-1114. doi:10.
1038/nmeth.4429
Disease Models & Mechanisms
Kim, O.-H., Cho, H.-J., Han, E., Hong, T. I., Ariyasiri, K., Choi, J.-H., Hwang, K.-
S., Jeong, Y.-M., Yang, S.-Y., Yu, K. et al. (2017b). Zebrafish knockout of Down
syndrome gene, DYRK1a, shows social impairments relevant to autism. Mol.
Autism 8, 50. doi:10.1186/s13229-017-0168-2
Kirsten, K., Soares, S. M., Koakoski, G., Carlos Kreutz, L. and Barcellos, L. J. G.
(2018). Characterization of sickness behavior in zebrafish. Brain Behav. Immun.
73, 596-602. doi:10.1016/j.bbi.2018.07.004
Knecht, A. L., Truong, L., Marvel, S. W., Reif, D. M., Garcia, A., Lu, C., Simonich,
M. T., Teeguarden, J. G. and Tanguay, R. L. (2017). Transgenerational
inheritance of neurobehavioral and physiological deficits from developmental
exposure to benzo[a]pyrene in zebrafish. Toxicol. Appl. Pharmacol. 329, 148-157.
doi:10.1016/j.taap.2017.05.033
Kokel, D., Bryan, J., Laggner, C., White, R., Cheung, C. Y. J., Mateus, R., Healey,
D., Kim, S., Werdich, A. A., Haggarty, S. J. et al. (2010). Rapid behavior-based
identification of neuroactive small molecules in the zebrafish. Nat. Chem. Biol. 6,
231-237. doi:10.1038/nchembio.307
Kokel, D., Rennekamp, A. J., Shah, A. H., Liebel, U. and Peterson, R. T. (2012).
Behavioral barcoding in the cloud: embracing data-intensive digital phenotyping in
neuropharmacology. Trends Biotechnol. 30, 421-425. doi:10.1016/j.tibtech.2012.
05.001
16
REVIEW
Kopman, V., Laut, J., Polverino, G. and Porfiri, M. (2013). Closed-loop control of
zebrafish response using a bioinspired robotic-fish in a preference test. J. R Soc.
Interface 10, 20120540. doi:10.1098/rsif.2012.0540
Kraus, T., Haack, M., Schuld, A., Hinze-Selch, D. and Pollmä cher, T. (2001). Low
leptin levels but normal body mass indices in patients with depression or
schizophrenia. Neuroendocrinology 73, 243-247. doi:10.1159/000054641
Krause, J. and Ruxton, G. D. (2002). Living in Groups. Oxford, New York: Oxford
University Press.
Kulkarni, P., Chaudhari, G. H., Sripuram, V., Banote, R. K., Kirla, K. T., Sultana,
R., Rao, P., Oruganti, S. and Chatti, K. (2014). Oral dosing in adult zebrafish:
proof-of-concept using pharmacokinetics and pharmacological evaluation of
carbamazepine. Pharmacol. Rep. 66, 179-183. doi:10.1016/j.pharep.2013.06.
012
Kuroda, T. (2018). A system for the real-time tracking of operant behavior as an
application of 3D camera. J. Exp. Anal. Behav. 110, 522-544. doi:10.1002/jeab.
471
Laan, A., Gil de Sagredo, R. and de Polavieja, G. G. (2017). Signatures of optimal
control in pairs of schooling zebrafish. Proc. Biol. Sci. 284, 20170224. doi:10.
1098/rspb.2017.0224
Laan, A., Iglesias-Julios, M. and de Polavieja, G. G. (2018). Zebrafish aggression
on the sub-second time scale: evidence for mutual motor coordination and multi-
functional attack manoeuvres. R. Soc. Open Sci. 5, 180679. doi:10.1098/rsos.
180679
Lam, P.-Y., Mendu, S. K., Mills, R. W., Zheng, B., Padilla, H., Milan, D. J., Desai,
B. N. and Peterson, R. T. (2017). A high-conductance chemo-optogenetic
system based on the vertebrate channel Trpa1b. Sci. Rep. 7, 11839. doi:10.1038/
s41598-017-11791-z
Lambert, C. J., Freshner, B. C., Chung, A., Stevenson, T. J., Bowles, D. M.,
Samuel, R., Gale, B. K. and Bonkowsky, J. L. (2018). An automated system for
rapid cellular extraction from live zebrafish embryos and larvae: development and
application to genotyping. PLoS ONE 13, e0193180. doi:10.1371/journal.pone.
0193180
Lan, A., Kalimian, M., Amram, B. and Kofman, O. (2017). Prenatal chlorpyrifos
leads to autism-like deficits in C57Bl6/J mice. Environ. Health 16, 43. doi:10.1186/
s12940-017-0251-3
Larsch, J. and Baier, H. (2018). Biological motion as an innate perceptual
mechanism driving social affiliation. Curr. Biol. 28, 3523-3532.e4. doi:10.1016/j.
cub.2018.09.014
Larson, E. T., O’Malley, D. M. and Melloni, R. H.Jr. (2006). Aggression and
vasotocin are associated with dominant-subordinate relationships in zebrafish.
Behav. Brain Res. 167, 94-102. doi:10.1016/j.bbr.2005.08.020
Lebow, M. A. and Chen, A. (2016). Overshadowed by the amygdala: the bed
nucleus of the stria terminalis emerges as key to psychiatric disorders. Mol.
Psychiatry 21, 450-463. doi:10.1038/mp.2016.1
Leroy, F., Park, J., Asok, A., Brann, D. H., Meira, T., Boyle, L. M., Buss, E. W.,
Kandel, E. R. and Siegelbaum, S. A. (2018). A circuit from hippocampal CA2 to
lateral septum disinhibits social aggression. Nature 564, 213-218. doi:10.1038/
s41586-018-0772-0
Li, X., Guo, J.-Y., Li, X., Zhou, H.-J., Zhang, S.-H., Liu, X.-D., Chen, D.-Y., Fang,
Y.-C. and Feng, X.-Z. (2017a). Behavioural effect of low-dose BPA on male
zebrafish: Tuning of male mating competition and female mating preference
during courtship process. Chemosphere 169, 40-52. doi:10.1016/j.chemosphere.
2016.11.053
Li, Y., Mathis, A., Grewe, B. F., Osterhout, J. A., Ahanonu, B., Schnitzer, M. J.,
Murthy, V. N. and Dulac, C. (2017b). Neuronal representation of social
information in the medial amygdala of awake behaving mice. Cell 171,
1176-1190.e17. doi:10.1016/j.cell.2017.10.015
Lindeyer, C. M. and Reader, S. M. (2010). Social learning of escape routes in
zebrafish and the stability of behavioural traditions. Anim. Behav. 79, 827-834.
doi:10.1016/j.anbehav.2009.12.024
Lister, J. A., Robertson, C. P., Lepage, T., Johnson, S. L. and Raible, D. W.
(1999). nacre encodes a zebrafish microphthalmia-related protein that regulates
neural-crest-derived pigment cell fate. Development 126, 3757-3767.
Liu, C.-X., Li, C.-Y., Hu, C.-C., Wang, Y., Lin, J., Jiang, Y.-H., Li, Q. and Xu, X.
(2018a). CRISPR/Cas9-induced shank3b mutant zebrafish display autism-like
behaviors. Mol. Autism 9, 23. doi:10.1186/s13229-018-0204-x
Liu, J., Sun, L., Zhang, H., Shi, M., Dahlgren, R. A., Wang, X. and Wang, H.
(2018b). Response mechanisms to joint exposure of triclosan and its chlorinated
derivatives on zebrafish (Danio rerio) behavior. Chemosphere 193, 820-832.
doi:10.1016/j.chemosphere.2017.11.106
Lopes, J. S., Abril-de-Abreu, R. and Oliveira, R. F. (2015). Brain transcriptomic
response to social eavesdropping in zebrafish (Danio rerio). PLoS ONE 10,
e0145801. doi:10.1371/journal.pone.0145801
Lord, C., Cook, E. H., Leventhal, B. L. and Amaral, D. G. (2000). Autism spectrum
disorders. Neuron 28, 355-363. doi:10.1016/S0896-6273(00)00115-X
Lyall, K., Croen, L. A., Sjö din, A., Yoshida, C. K., Zerbo, O., Kharrazi, M. and
Windham, G. C. (2017). Polychlorinated biphenyl and organochlorine pesticide
concentrations in maternal mid-pregnancy serum samples: association with
autism spectrum disorder and intellectual disability. Environ. Health Perspect.
125, 474-480. doi:10.1289/EHP277
Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446
Maaswinkel, H., Zhu, L. and Weng, W. (2013a). Assessing social engagement in
heterogeneous groups of zebrafish: a new paradigm for autism-like behavioral
responses. PLoS ONE 8, e75955. doi:10.1371/journal.pone.0075955
Maaswinkel, H., Zhu, L. and Weng, W. (2013b). Using an automated 3D-tracking
system to record individual and shoals of adult zebrafish. J. Vis. Exp. 82, e50681.
doi:10.3791/50681
Mackay, D., Hughes, D. M., Romano, M. L. and Bonnell, M. (2014). The role of
persistence in chemical evaluations. Integr. Environ. Assess. Manag. 10,
588-594. doi:10.1002/ieam.1545
Macrì, S., Neri, D., Ruberto, T., Mwaffo, V., Butail, S. and Porfiri, M. (2017). Three-
dimensional scoring of zebrafish behavior unveils biological phenomena hidden by
two-dimensional analyses. Sci. Rep. 7, 1962. doi:10.1038/s41598-017-01990-z
Madeira, N. and Oliveira, R. F. (2017). Long-term social recognition memory in
zebrafish. Zebrafish 14, 305-310. doi:10.1089/zeb.2017.1430
Madirolas, G. and de Polavieja, G. G. (2015). Improving collective estimations
using resistance to social influence. PLoS Comput. Biol. 11, e1004594. doi:10.
1371/journal.pcbi.1004594
Malki, K., du Rietz, E., Crusio, W. E., Pain, O., Paya-Cano, J., Karadaghi, R. L.,
Sluyter, F., DE Boer, S. F., Sandnabba, K., Schalkwyk, L. C. et al. (2016).
Transcriptome analysis of genes and gene networks involved in aggressive
behavior in mouse and zebrafish. Am. J. Med. Genet. B Neuropsychiatr. Genet.
171, 827-838. doi:10.1002/ajmg.b.32451
Marques, J. C., Lackner, S., Fé lix, R. and Orger, M. B. (2018). Structure of the
zebrafish locomotor repertoire revealed with unsupervised behavioral clustering.
Curr. Biol. 28, 181-195.e5. doi:10.1016/j.cub.2017.12.002
Maruska, K., Soares, M. C., Lima-Maximino, M., Henrique de Siqueira-Silva, D.
and Maximino, C. (2019). Social plasticity in the fish brain: neuroscientific and
ethological aspects. Brain Res. 1711, 156-172. doi:10.20944/preprints201809.
0279.v2
Matthews, G. A., Nieh, E. H., Vander Weele, C. M., Halbert, S. A., Pradhan, R. V.,
Yosafat, A. S., Glober, G. F., Izadmehr, E. M., Thomas, R. E., Lacy, G. D. et al.
(2016). Dorsal Raphe dopamine neurons represent the experience of social
isolation. Cell 164, 617-631. doi:10.1016/j.cell.2015.12.040
Mccutcheon, V., Park, E., Liu, E., Sobhebidari, P., Tavakkoli, J., Wen, X.-Y. and
Baker, A. J. (2017). A novel model of traumatic brain injury in adult zebrafish
demonstrates response to injury and treatment comparable with mammalian
models. J. Neurotrauma 34, 1382-1393. doi:10.1089/neu.2016.4497
Mchenry, J. A., Otis, J. M., Rossi, M. A., Robinson, J. E., Kosyk, O., Miller, N. W.,
Mcelligott, Z. A., Budygin, E. A., Rubinow, D. R. and Stuber, G. D. (2017).
Hormonal gain control of a medial preoptic area social reward circuit. Nat.
Neurosci. 20, 449-458. doi:10.1038/nn.4487
Meira, T., Leroy, F., Buss, E. W., Oliva, A., Park, J. and Siegelbaum, S. A. (2018).
A hippocampal circuit linking dorsal CA2 to ventral CA1 critical for social memory
dynamics. Nat. Commun. 9, 4163. doi:10.1038/s41467-018-06501-w
Miller, N. and Gerlai, R. (2007). Quantification of shoaling behaviour in zebrafish
(Danio rerio). Behav. Brain Res. 184, 157-166. doi:10.1016/j.bbr.2007.07.007
Miller, N., Greene, K., Dydinski, A. and Gerlai, R. (2013). Effects of nicotine and
alcohol on zebrafish (Danio rerio) shoaling. Behav. Brain Res. 240, 192-196.
doi:10.1016/j.bbr.2012.11.033
Morrison, C. D. (2009). Leptin signaling in brain: a link between nutrition and
cognition? Biochim. Biophys. Acta 1792, 401-408. doi:10.1016/j.bbadis.2008.12.
004
Mullen, B. R., Khialeeva, E., Hoffman, D. B., Ghiani, C. A. and Carpenter, E. M.
(2012). Decreased reelin expression and organophosphate pesticide exposure
alters mouse behaviour and brain morphology. ASN Neuro 5, e00106. doi:10.
1042/AN20120060
Mü ller, K., Smielik, I., Hü twohl, J.-M., Gierszewski, S., Witte, K. and Kuhnert, K.-
D. (2017a). The virtual lover: variable and easily guided 3D fish animations as an
innovative tool in mate-choice experiments with sailfin mollies-I. Design and
Disease Models & Mechanisms
implementation. Curr. Zool. 63, 55-64. doi:10.1093/cz/zow106
Mü ller, T. E., Nunes, S. Z., Silveira, A., Loro, V. L. and Rosemberg, D. B. (2017b).
Repeated ethanol exposure alters social behavior and oxidative stress
parameters of zebrafish. Prog. Neuropsychopharmacol. Biol. Psychiatry 79,
105-111. doi:10.1016/j.pnpbp.2017.05.026
Muto, A. and Kawakami, K. (2016). Calcium imaging of neuronal activity in free-
swimming larval zebrafish. Methods Mol. Biol. 1451, 333-341. doi:10.1007/978-1-
4939-3771-4_23
Mwaffo, V., Butail, S. and Porfiri, M. (2017). In-silico experiments of zebrafish
behaviour: modeling swimming in three dimensions. Sci. Rep. 7, 39877. doi:10.
1038/srep39877
Newman, S. W. (1999). The medial extended amygdala in male reproductive
behavior a node in the mammalian social behavior network. Ann. N. Y. Acad. Sci.
877, 242-257. doi:10.1111/j.1749-6632.1999.tb09271.x
Nomoto, K. and Lima, S. Q. (2015). Enhanced male-evoked responses in the
ventromedial hypothalamus of sexually receptive female mice. Curr. Biol. 25,
589-594. doi:10.1016/j.cub.2014.12.048
Norton, W. H. J., Stumpenhorst, K., Faus-Kessler, T., Folchert, A., Rohner, N.,
Harris, M. P., Callebert, J. and Bally-Cuif, L. (2011). Modulation of Fgfr1a
signaling in zebrafish reveals a genetic basis for the aggression-boldness
17
REVIEW
syndrome. J. Neurosci. 31, 13796-13807. doi:10.1523/JNEUROSCI.2892-11.
2011
O’Connell, L. A. and Hofmann, H. A. (2011a). Genes, hormones, and circuits: an
integrative approach to study the evolution of social behavior. Front.
Neuroendocrinol. 32, 320-335. doi:10.1016/j.yfrne.2010.12.004
O’Connell, L. A. and Hofmann, H. A. (2011b). The vertebrate mesolimbic reward
system and social behavior network: a comparative synthesis. J. Comp. Neurol.
519, 3599-3639. doi:10.1002/cne.22735
O’Connell, L. A. and Hofmann, H. A. (2012). Evolution of a vertebrate social
decision-making network. Science 336, 1154-1157. doi:10.1126/science.
1218889
Okuyama, T., Kitamura, T., Roy, D. S., Itohara, S. and Tonegawa, S. (2016).
Ventral CA1 neurons store social memory. Science 353, 1536-1541. doi:10.1126/
science.aaf7003
Oliveira, R. F., Simões, J. M., Teles, M. C., Oliveira, C. R., Becker, J. D. and
Lopes, J. S. (2016). Assessment of fight outcome is needed to activate socially
driven transcriptional changes in the zebrafish brain. Proc. Natl. Acad. Sci. USA
113, E654-E661. doi:10.1073/pnas.1514292113
Oliveri, A. N., Bailey, J. M. and Levin, E. D. (2015). Developmental exposure to
organophosphate flame retardants causes behavioral effects in larval and adult
zebrafish. Neurotoxicol. Teratol. 52, 220-227. doi:10.1016/j.ntt.2015.08.008
, M., Tang, J., Seppä nen-Laakso, T., Mattila, I., Saarni, S. E., Saarni, S. I.,
Oreš ic
Lö nnqvist, J., Sysi-Aho, M., Hyö tylä inen, T., Perä lä , J. and et al. (2011).
Metabolome in schizophrenia and other psychotic disorders: a general
population-based study. Genome Med. 3, 19. doi:10.1186/gm233
Patowary, A., Won, S. Y., Oh, S. J., Nesbitt, R. R., Archer, M., Nickerson, D.,
Raskind, W. H., Bernier, R., Lee, J. E. and Brkanac, Z. (2019). Family-based
exome sequencing and case-control analysis implicate CEP41 as an ASD gene.
Transl. Psychiatry 9, 4. doi:10.1038/s41398-018-0343-z
Paull, G. C., Filby, A. L., Giddins, H. G., Coe, T. S., Hamilton, P. B. and Tyler,
C. R. (2010). Dominance hierarchies in zebrafish (Danio rerio) and their
relationship with reproductive success. Zebrafish 7, 109-117. doi:10.1089/zeb.
2009.0618
Pavlidis, M., Sundvik, M., Chen, Y.-C. and Panula, P. (2011). Adaptive changes in
zebrafish brain in dominant-subordinate behavioral context. Behav. Brain Res.
225, 529-537. doi:10.1016/j.bbr.2011.08.022
Perathoner, S., Cordero-Maldonado, M. L. and Crawford, A. D. (2016). Potential
of zebrafish as a model for exploring the role of the amygdala in emotional memory
and motivational behavior. J. Neurosci. Res. 94, 445-462. doi:10.1002/jnr.23712
Pé rez-Escudero, A., Vicente-Page, J., Hinz, R. C., Arganda, S. and de Polavieja,
G. G. (2014). idTracker: tracking individuals in a group by automatic identification
of unmarked animals. Nat. Methods 11, 743-748. doi:10.1038/nmeth.2994
Petek, E., Windpassinger, C., Vincent, J. B., Cheung, J., Boright, A. P., Scherer,
S. W., Kroisel, P. M. and Wagner, K. (2001). Disruption of a novel gene (IMMP2L)
by a breakpoint in 7q31 associated with Tourette syndrome. Am. J. Hum. Genet.
68, 848-858. doi:10.1086/319523
Piato, Â. L., Capiotti, K. M., Tamborski, A. R., Oses, J. P., Barcellos, L. J. G.,
Bogo, M. R., Lara, D. R., Vianna, M. R. and Bonan, C. D. (2011). Unpredictable
chronic stress model in zebrafish (Danio rerio): behavioral and physiological
responses. Prog. Neuropsychopharmacol. Biol. Psychiatry 35, 561-567. doi:10.
1016/j.pnpbp.2010.12.018
Polverino, G., Abaid, N., Kopman, V., Macrì, S. and Porfiri, M. (2012). Zebrafish
response to robotic fish: preference experiments on isolated individuals and small
shoals. Bioinspir. Biomim. 7, 036019. doi:10.1088/1748-3182/7/3/036019
Ponzoni, L., Sala, M. and Braida, D. (2016). Ritanserin-sensitive receptors
modulate the prosocial and the anxiolytic effect of MDMA derivatives, DOB and
Pma, in zebrafish. Behav. Brain Res. 314, 181-189. doi:10.1016/j.bbr.2016.08.
009
Porfiri, M. and Ruiz Marı́n, M. (2017). Symbolic dynamics of animal interaction.
J. Theor. Biol. 435, 145-156. doi:10.1016/j.jtbi.2017.09.005
Prykhozhij, S. V. and Berman, J. N. (2018). Zebrafish knock-ins swim into the
mainstream. Dis. Model. Mech. 11, dmm037515. doi:10.1242/dmm.037515
Prykhozhij, S. V., Steele, S. L., Razaghi, B. and Berman, J. N. (2017). A rapid and
effective method for screening, sequencing and reporter verification of engineered
frameshift mutations in zebrafish. Dis. Model. Mech. 10, 811-822. doi:10.1242/
dmm.026765
Qi, C.-C., Wang, Q.-J., Ma, X.-Z., Chen, H.-C., Gao, L.-P., Yin, J. and Jing, Y.-H.
(2018). Interaction of basolateral amygdala, ventral hippocampus and medial
prefrontal cortex regulates the consolidation and extinction of social fear. Behav.
Brain. Funct. 14, 7. doi:10.1186/s12993-018-0139-6
Qian, Z.-M. and Chen, Y. Q. (2017). Feature point based 3D tracking of multiple fish
from multi-view images. PLoS ONE 12, e0180254. doi:10.1371/journal.pone.
0180254
Qian, Z.-M., Cheng, X. E. and Chen, Y. Q. (2014). Automatically detect and track
multiple fish swimming in shallow water with frequent occlusion. PLoS ONE 9,
e106506. doi:10.1371/journal.pone.0106506
Qian, Z.-M., Wang, S. H., Cheng, X. E. and Chen, Y. Q. (2016). An effective and
robust method for tracking multiple fish in video image based on fish head
detection. BMC Bioinformatics 17, 251. doi:10.1186/s12859-016-1138-y
Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446
Raghavan, R., Zuckerman, B., Hong, X., Wang, G., Ji, Y., Paige, D., Dibari, J.,
Zhang, C., Fallin, M. D. and Wang, X. (2018). Fetal and infancy growth pattern,
cord and early childhood plasma leptin, and development of autism spectrum
disorder in the Boston birth cohort. Autism Res. 11, 1416-1431. doi:10.1002/aur.
2011
Rennekamp, A. J. and Peterson, R. T. (2015). 15 years of zebrafish chemical
screening. Curr. Opin. Chem. Biol. 24, 58-70. doi:10.1016/j.cbpa.2014.10.025
Riehl, R., Kyzar, E., Allain, A., Green, J., Hook, M., Monnig, L., Rhymes, K.,
Roth, A., Pham, M., Razavi, R. et al. (2011). Behavioral and physiological effects
of acute ketamine exposure in adult zebrafish. Neurotoxicol. Teratol. 33, 658-667.
doi:10.1016/j.ntt.2011.05.011
Rihel, J., Prober, D. A., Arvanites, A., Lam, K., Zimmerman, S., Jang, S.,
Haggarty, S. J., Kokel, D., Rubin, L. L., Peterson, R. T. and et al. (2010).
Zebrafish behavioral profiling links drugs to biological targets and rest/wake
regulation. Science 327, 348-351. doi:10.1126/science.1183090
Romero-Ferrero, F., Bergomi, M. G., Hinz, R. C., Heras, F. J. H. and de Polavieja,
G. G. (2019). idtracker.ai: tracking all individuals in small or large collectives of
unmarked animals. Nat. Methods 16, 179-182. doi:10.1038/s41592-018-0295-5
Rosenthal, S. B., Twomey, C. R., Hartnett, A. T., Wu, H. S. and Couzin, I. D.
(2015). Revealing the hidden networks of interaction in mobile animal groups
allows prediction of complex behavioral contagion. Proc. Natl. Acad. Sci. USA
112, 4690-4695. doi:10.1073/pnas.1420068112
Roy, T. and Bhat, A. (2017). Social learning in a maze? Contrasting individual
performance among wild zebrafish when associated with trained and naïve
conspecifics. Behav. Processes 144, 51-57. doi:10.1016/j.beproc.2017.09.004
Ruberto, T., Mwaffo, V., Singh, S., Neri, D. and Porfiri, M. (2016). Zebrafish
response to a robotic replica in three dimensions. R Soc Open Sci 3, 160505.
doi:10.1098/rsos.160505
Ruberto, T., Polverino, G. and Porfiri, M. (2017). How different is a 3D-printed
replica from a conspecific in the eyes of a zebrafish?. J. Exp. Anal. Behav. 107,
279-293. doi:10.1002/jeab.247
Samaee, S.-M., Seyedin, S. and Varga, Z. M. (2017). An affordable intraperitoneal
injection setup for juvenile and adult zebrafish. Zebrafish 14, 77-79. doi:10.1089/
zeb.2016.1322
Sarasamma, S., Audira, G., Juniardi, S., Sampurna, B. P., Liang, S.-T., Hao, E.,
Lai, Y.-H. and Hsiao, C.-D. (2018). Zinc chloride exposure inhibits brain
acetylcholine levels, produces neurotoxic signatures, and diminishes memory
and motor activities in adult zebrafish. Int. J. Mol. Sci. 19, 3195. doi:10.3390/
ijms19103195
Savio, L. E. B., Vuaden, F. C., Piato, A. L., Bonan, C. D. and Wyse, A. T. S. (2012).
Behavioral changes induced by long-term proline exposure are reversed by
antipsychotics in zebrafish. Prog. Neuropsychopharmacol. Biol. Psychiatry 36,
258-263. doi:10.1016/j.pnpbp.2011.10.002
Scerbina, T., Chatterjee, D. and Gerlai, R. (2012). Dopamine receptor antagonism
disrupts social preference in zebrafish: a strain comparison study. Amino Acids
43, 2059-2072. doi:10.1007/s00726-012-1284-0
Schaefer, I. C., Siebel, A. M., Piato, A. L., Bonan, C. D., Vianna, M. R. and Lara,
D. R. (2015). The side-by-side exploratory test: a simple automated protocol for
the evaluation of adult zebrafish behavior simultaneously with social interaction.
Behav. Pharmacol. 26, 691-696. doi:10.1097/FBP.0000000000000145
Schirmer, A., Jesuthasan, S. and Mathuru, A. S. (2013). Tactile stimulation
reduces fear in fish. Front. Behav. Neurosci. 7, 167. doi:10.3389/fnbeh.2013.
00167
Schmidel, A. J., Assmann, K. L., Werlang, C. C., Bertoncello, K. T., Francescon,
F., Rambo, C. L., Beltrame, G. M., Calegari, D., Batista, C. B., Blaser, R. E.
et al. (2014). Subchronic atrazine exposure changes defensive behaviour profile
and disrupts brain acetylcholinesterase activity of zebrafish. Neurotoxicol. Teratol.
44, 62-69. doi:10.1016/j.ntt.2014.05.006
Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T.,
Disease Models & Mechanisms
Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J. et al. (2007). Strong association
of de novo copy number mutations with autism. Science 316, 445-449. doi:10.
1126/science.1138659
Seguin, D. and Gerlai, R. (2018). Fetal alcohol spectrum disorders: zebrafish in the
analysis of the milder and more prevalent form of the disease. Behav. Brain Res.
352, 125-132. doi:10.1016/j.bbr.2017.10.005
Seibt, K. J., Piato, A. L., da Luz Oliveira, R., Capiotti, K. M., Vianna, M. R. and
Bonan, C. D. (2011). Antipsychotic drugs reverse MK-801-induced cognitive and
social interaction deficits in zebrafish (Danio rerio). Behav. Brain Res. 224,
135-139. doi:10.1016/j.bbr.2011.05.034
Shah, A. N., Davey, C. F., Whitebirch, A. C., Miller, A. C. and Moens, C. B. (2015).
Rapid reverse genetic screening using CRISPR in zebrafish. Nat. Methods 12,
535-540. doi:10.1038/nmeth.3360
Shams, S., Amlani, S., Buske, C., Chatterjee, D. and Gerlai, R. (2018).
Developmental social isolation affects adult behavior, social interaction, and
dopamine metabolite levels in zebrafish. Dev. Psychobiol. 60, 43-56. doi:10.1002/
dev.21581
Shelton, D. S., Price, B. C., Ocasio, K. M. and Martins, E. P. (2015). Density and
group size influence shoal cohesion, but not coordination in zebrafish (Danio
rerio). J. Comp. Psychol. 129, 72-77. doi:10.1037/a0038382
18
REVIEW
Shin, S., Pribiag, H., Lilascharoen, V., Knowland, D., Wang, X.-Y. and Lim, B. K.
(2018). Drd3 signaling in the lateral septum mediates early life stress-induced
social dysfunction. Neuron 97, 195-208.e6. doi:10.1016/j.neuron.2017.11.040
Smith, K. S., Tindell, A. J., Aldridge, J. W. and Berridge, K. C. (2009). Ventral
pallidum roles in reward and motivation. Behav. Brain Res. 196, 155-167. doi:10.
1016/j.bbr.2008.09.038
Sneddon, L. U., Schmidt, R., Fang, Y. and Cossins, A. R. (2011). Molecular
correlates of social dominance: a novel role for ependymin in aggression. PLoS
ONE 6, e18181. doi:10.1371/journal.pone.0018181
Stednitz, S. J., Mcdermott, E. M., Ncube, D., Tallafuss, A., Eisen, J. S. and
Washbourne, P. (2018). Forebrain control of behaviorally driven social orienting
in zebrafish. Curr. Biol. 28, 2445-2451.e3. doi:10.1016/j.cub.2018.06.016
Stein, T. P., Schluter, M. D., Steer, R. A., Guo, L. and Ming, X. (2015). Bisphenol a
exposure in children with autism spectrum disorders. Autism Res. 8, 272-283.
doi:10.1002/aur.1444
Stephens, G. J., Johnson-Kerner, B., Bialek, W. and Ryu, W. S. (2008).
Dimensionality and dynamics in the behavior of C. elegans. PLoS Comput. Biol. 4,
e1000028. doi:10.1371/journal.pcbi.1000028
Stowers, J. R., Hofbauer, M., Bastien, R., Griessner, J., Higgins, P., Farooqui,
S., Fischer, R. M., Nowikovsky, K., Haubensak, W., Couzin, I. D. et al. (2017).
Virtual reality for freely moving animals. Nat. Methods 14, 995-1002. doi:10.1038/
nmeth.4399
Strungaru, S.-A., Plavan, G., Ciobica, A., Nicoara, M., Robea, M. A., Solcan, C.,
Todirascu-Ciornea, E. and Petrovici, A. (2018). Acute exposure to gold induces
fast changes in social behavior and oxidative stress of zebrafish (Danio rerio).
J. Trace Elem. Med. Biol. 50, 249-256. doi:10.1016/j.jtemb.2018.07.013
Sugathan, A., Biagioli, M., Golzio, C., Erdin, S., Blumenthal, I., Manavalan, P.,
Ragavendran, A., Brand, H., Lucente, D., Miles, J. et al. (2014). CHD8
regulates neurodevelopmental pathways associated with autism spectrum
disorder in neural progenitors. Proc. Natl. Acad. Sci. USA 111, E4468-E4477.
doi:10.1073/pnas.1405266111
Sykes, D. J., Suriyampola, P. S. and Martins, E. P. (2018). Recent experience
impacts social behavior in a novel context by adult zebrafish (Danio rerio). PLoS
ONE 13, e0204994. doi:10.1371/journal.pone.0204994
Tachikawa, K. S., Yoshihara, Y. and Kuroda, K. O. (2013). Behavioral transition
from attack to parenting in male mice: a crucial role of the vomeronasal system.
J. Neurosci. 33, 5120-5126. doi:10.1523/JNEUROSCI.2364-12.2013
Takayanagi, Y., Yoshida, M., Takashima, A., Takanami, K., Yoshida, S.,
Nishimori, K., Nishijima, I., Sakamoto, H., Yamagata, T. and Onaka, T.
(2017). Activation of supraoptic oxytocin neurons by secretin facilitates social
recognition. Biol. Psychiatry 81, 243-251. doi:10.1016/j.biopsych.2015.11.021
Tang, W., Zhang, G., Serluca, F., Li, J., Xiong, X., Coble, M., Tsai, T., Li, Z.,
Molind, G., Zhu, P. and et al. (2018). Genetic architecture of collective behaviors
in zebrafish. bioRxiv. doi:10.1101/350314
Teles, M. C. and Oliveira, R. F. (2016a). Androgen response to social competition in
a shoaling fish. Horm. Behav. 78, 8-12. doi:10.1016/j.yhbeh.2015.10.009
Teles, M. C. and Oliveira, R. F. (2016b). Quantifying Aggressive Behavior
in Zebrafish. Methods Mol. Biol. 1451, 293-305. doi:10.1007/978-1-4939-3771-
4_20
Teles, M. C., Almeida, O., Lopes, J. S. and Oliveira, R. F. (2015). Social
interactions elicit rapid shifts in functional connectivity in the social decision-
making network of zebrafish. Proc. Biol. Sci. 282, 20151099. doi:10.1098/rspb.
2015.1099
Teles, M. C., Cardoso, S. D. and Oliveira, R. F. (2016a). Social plasticity relies on
different neuroplasticity mechanisms across the brain social decision-making
network in zebrafish. Front. Behav. Neurosci. 10, 16. doi:10.3389/fnbeh.2016.
00016
Teles, M. C., Gozdowska, M., Kalamarz-Kubiak, H., Kulczykowska, E. and
Oliveira, R. F. (2016b). Agonistic interactions elicit rapid changes in brain
nonapeptide levels in zebrafish. Horm. Behav. 84, 57-63. doi:10.1016/j.yhbeh.
2016.05.020
Theodoridi, A., Tsalafouta, A. and Pavlidis, M. (2017). Acute exposure to
fluoxetine alters aggressive behavior of zebrafish and expression of genes
involved in serotonergic system regulation. Front. Neurosci. 11, 223. doi:10.3389/
fnins.2017.00223
Tranfaglia, M. R. (2011). The psychiatric presentation of fragile x: evolution of the
diagnosis and treatment of the psychiatric comorbidities of fragile X syndrome.
Dev. Neurosci. 33, 337-348. doi:10.1159/000329421
Tsuneoka, Y., Tokita, K., Yoshihara, C., Amano, T., Esposito, G., Huang, A. J.,
Yu, L. M., Odaka, Y., Shinozuka, K., Mchugh, T. J. and et al. (2015). Distinct
preoptic-BST nuclei dissociate paternal and infanticidal behavior in mice. EMBO
J. 34, 2652-2670. doi:10.15252/embj.201591942
van Kerkhof, L. W. M., Damsteegt, R., Trezza, V., Voorn, P. and Vanderschuren,
L. J. M. J. (2013). Functional integrity of the habenula is necessary for social play
behaviour in rats. Eur. J. Neurosci. 38, 3465-3475. doi:10.1111/ejn.12353
Varshney, G. K., Pei, W., LaFave, M. C., Idol, J., Xu, L., Gallardo, V., Carrington,
B., Bishop, K., Jones, M. P., Li, M. et al. (2015). High-throughput gene targeting
and phenotyping in zebrafish using CRISPR/Cas9. Genome Res. 25, 1030-1042.
doi:10.1101/gr.186379.114
Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446
Vendrell-Llopis, N. and Yaksi, E. (2015). Evolutionary conserved brainstem
circuits encode category, concentration and mixtures of taste. Sci. Rep. 5, 17825.
doi:10.1038/srep17825
Villacrez, M., Hellman, K., Ono, T., Sugihara, Y., Rezeli, M., Ek, F., Marko-Varga,
G. and Olsson, R. (2018). Evaluation of drug exposure and metabolism in locust
and zebrafish brains using mass spectrometry imaging. ACS Chem. Neurosci. 9,
1994-2000. doi:10.1021/acschemneuro.7b00459
Volkova, K., Reyhanian Caspillo, N., Porseryd, T., Hallgren, S., Dinné tz, P. and
Porsch-Hä llströ m, I. (2015). Developmental exposure of zebrafish (Danio rerio)
to 17alpha-ethinylestradiol affects non-reproductive behavior and fertility as
adults, and increases anxiety in unexposed progeny. Horm. Behav. 73, 30-38.
doi:10.1016/j.yhbeh.2015.05.014
von Ehrenstein, O. S., Ling, C., Cui, X., Cockburn, M., Park, A. S., Yu, F., Wu, J.
and Ritz, B. (2019). Prenatal and infant exposure to ambient pesticides and
autism spectrum disorder in children: population based case-control study. BMJ
364, l962. doi:10.1136/bmj.l962
von Trotha, J. W., Vernier, P. and Bally-Cuif, L. (2014). Emotions and motivated
behavior converge on an amygdala-like structure in the zebrafish.
Eur. J. Neurosci. 40, 3302-3315. doi:10.1111/ejn.12692
Wang, S. H., Cheng, X. E., Qian, Z.-M., Liu, Y. and Chen, Y. Q. (2016a). Automated
planar tracking the waving bodies of multiple zebrafish swimming in shallow water.
PLoS ONE 11, e0154714. doi:10.1371/journal.pone.0154714
Wang, X., Zheng, Y., Zhang, Y., Li, J., Zhang, H. and Wang, H. (2016b). Effects of
β-diketone antibiotic mixtures on behavior of zebrafish (Danio rerio).
Chemosphere 144, 2195-2205. doi:10.1016/j.chemosphere.2015.10.120
Wang, Y., Zhong, H., Wang, C., Gao, D., Zhou, Y. and Zuo, Z. (2016c). Maternal
exposure to the water soluble fraction of crude oil, lead and their mixture induces
autism-like behavioral deficits in zebrafish (Danio rerio) larvae. Ecotoxicol.
Environ. Saf. 134, 23-30. doi:10.1016/j.ecoenv.2016.08.009
Wang, D., Li, Y., Feng, Q., Guo, Q., Zhou, J. and Luo, M. (2017a). Learning shapes
the aversion and reward responses of lateral habenula neurons. eLife 6, e23045.
doi:10.7554/eLife.23045
Wang, S. H., Zhao, J., Liu, X., Qian, Z.-M., Liu, Y. and Chen, Y. Q. (2017b). 3D
tracking swimming fish school with learned kinematic model using LSTM network.
IEEE International Conference on Acoustics Speech and Signal Processing
(ICASSP).
Wang, L., Talwar, V., Osakada, T., Kuang, A., Guo, Z., Yamaguchi, T. and Lin, D.
(2019). Hypothalamic control of conspecific self-defense. Cell Reports 26,
1747-1758.e5. doi:10.1016/j.celrep.2019.01.078
Way, G. P., Ruhl, N., Snekser, J. L., Kiesel, A. L. and Mcrobert, S. P. (2015). A
comparison of methodologies to test aggression in zebrafish. Zebrafish 12,
144-151. doi:10.1089/zeb.2014.1025
Weber, D. N. and Ghorai, J. K. (2013). Experimental design affects social behavior
outcomes in adult zebrafish developmentally exposed to lead. Zebrafish 10,
294-302. doi:10.1089/zeb.2012.0780
Weber, D. N., Hoffmann, R. G., Hoke, E. S. and Tanguay, R. L. (2015). Bisphenol
A exposure during early development induces sex-specific changes in adult
zebrafish social interactions. J. Toxicol. Environ. Health A 78, 50-66. doi:10.1080/
15287394.2015.958419
Wei, Y.-C., Wang, S.-R., Jiao, Z.-L., Zhang, W., Lin, J.-K., Li, X.-Y., Li, S.-S.,
Zhang, X. and Xu, X.-H. (2018). Medial preoptic area in mice is capable of
mediating sexually dimorphic behaviors regardless of gender. Nat. Commun. 9,
279. doi:10.1038/s41467-017-02648-0
Weiss, L. A., Escayg, A., Kearney, J. A., Trudeau, M., Macdonald, B. T., Mori, M.,
Reichert, J., Buxbaum, J. D. and Meisler, M. H. (2003). Sodium channels
SCN1a, SCN2A and SCN3A in familial autism. Mol. Psychiatry 8, 186-194. doi:10.
1038/sj.mp.4001241
Whanger, P. D. (2002). Selenocompounds in plants and animals and their biological
significance. J. Am. Coll. Nutr. 21, 223-232. doi:10.1080/07315724.2002.
10719214
Disease Models & Mechanisms
Wiltschko, A. B., Johnson, M. J., Iurilli, G., Peterson, R. E., Katon, J. M.,
Pashkovski, S. L., Abraira, V. E., Adams, R. P. and Datta, S. R. (2015). Mapping
Sub-Second Structure in Mouse Behavior. Neuron 88, 1121-1135. doi:10.1016/j.
neuron.2015.11.031
Wolff, M., Cassé -Perrot, C. and Dravet, C. (2006). Severe myoclonic epilepsy of
infants (Dravet syndrome): natural history and neuropsychological findings.
Epilepsia 47 Suppl. 2, 45-48. doi:10.1111/j.1528-1167.2006.00688.x
Wu, Z., Autry, A. E., Bergan, J. F., Watabe-Uchida, M. and Dulac, C. G. (2014).
Galanin neurons in the medial preoptic area govern parental behaviour. Nature
509, 325-330. doi:10.1038/nature13307
Wu, Y.-J., Hsu, M.-T., Ng, M.-C., Amstislavskaya, T. G., Tikhonova, M. A., Yang,
Y.-L. and Lu, K.-T. (2017). Fragile X mental retardation-1 knockout zebrafish
shows precocious development in social behavior. Zebrafish 14, 438-443. doi:10.
1089/zeb.2017.1446
Xia, J., Niu, C. and Pei, X. (2010). Effects of chronic exposure to nonylphenol on
locomotor activity and social behavior in zebrafish (Danio rerio). J. Environ. Sci.
(China) 22, 1435-1440. doi:10.1016/S1001-0742(09)60272-2
Xiao, G., Cheng, Z.-B., Huang, S.-S., Li, Y., Mao, J.-F. and Zhao, M.-R. (2015). A
delaunay triangle network based model of fish shoaling behavior for water quality
monitor. J. Environ. Anal. Toxicol. S7, 001. doi:10.4172/2161-0525.S7-001
19
REVIEW
Xie, Y. and Dorsky, R. I. (2017). Development of the hypothalamus: conservation,
modification and innovation. Development 144, 1588-1599. doi:10.1242/dev.
139055
Yao, S., Bergan, J., Lanjuin, A. and Dulac, C. (2017). Oxytocin signaling in the
medial amygdala is required for sex discrimination of social cues. eLife 6, e31373.
doi:10.7554/eLife.31373
Yokogawa, T., Hannan, M. C. and Burgess, H. A. (2012). The dorsal raphe
modulates sensory responsiveness during arousal in zebrafish. J. Neurosci. 32,
15205-15215. doi:10.1523/JNEUROSCI.1019-12.2012
Yu, C., Tai, F., Song, Z., Wu, R., Zhang, X. and He, F. (2011). Pubertal exposure to
bisphenol A disrupts behavior in adult C57BL/6J mice. Environ. Toxicol.
Pharmacol. 31, 88-99. doi:10.1016/j.etap.2010.09.009
Zabala, F., Polidoro, P., Robie, A., Branson, K., Perona, P. and Dickinson, M. H.
(2012). A simple strategy for detecting moving objects during locomotion revealed
by animal-robot interactions. Curr. Biol. 22, 1344-1350. doi:10.1016/j.cub.2012.
05.024
Zabegalov, K. N., Kolesnikova, T. O., Khatsko, S. L., Volgin, A. D., Yakovlev,
O. A., Amstislavskaya, T. G., Friend, A. J., Bao, W., Alekseeva, P. A.,
Lakstygal, A. M. et al. (2019). Understanding zebrafish aggressive behavior.
Behav. Processes 158, 200-210. doi:10.1016/j.beproc.2018.11.010
Zala, S. M. and Mä ä ttä nen, I. (2013). Social learning of an associative foraging task
in zebrafish. Naturwissenschaften 100, 469-472. doi:10.1007/s00114-013-
1017-6
Zala, S. M., Mä ä ttä nen, I. and Penn, D. J. (2012). Different social-learning
strategies in wild and domesticated zebrafish, Danio rerio. Anim. Behav. 83,
1519-1525. doi:10.1016/j.anbehav.2012.03.029
Zang, L., Ma, Y., Huang, W., Ling, Y., Sun, L., Wang, X., Zeng, A., Dahlgren, R. A.,
Wang, C. and Wang, H. (2019). Dietary Lactobacillus plantarum ST-III alleviates
the toxic effects of triclosan on zebrafish (Danio rerio) via gut microbiota
Disease Models & Mechanisms (2019) 12, dmm039446. doi:10.1242/dmm.039446
modulation. Fish Shellfish Immunol. 84, 1157-1169. doi:10.1016/j.fsi.2018.
11.007
Zhang, B., Chen, X., Pan, R., Xu, T., Zhao, J., Huang, W., Liu, Y. and Yin, D.
(2017). Effects of three different embryonic exposure modes of 2, 2′, 4, 4′-
tetrabromodiphenyl ether on the path angle and social activity of zebrafish larvae.
Chemosphere 169, 542-549. doi:10.1016/j.chemosphere.2016.11.098
Zhang, B., Xu, T., Huang, G., Yin, D., Zhang, Q. and Yang, X. (2018).
Neurobehavioral effects of two metabolites of BDE-47 (6-OH-BDE-47 and 6-
MeO-BDE-47) on zebrafish larvae. Chemosphere 200, 30-35. doi:10.1016/j.
chemosphere.2018.02.064
Zhao, Y., Sun, H., Sha, X., Gu, L., Zhan, Z. and Li, W. J. (2018). A review of
automated microinjection of zebrafish embryos. Micromachines (Basel) 10, 7.
doi:10.3390/mi10010007
Zienkiewicz, A., Barton, D. A. W., Porfiri, M. and di Bernardo, M. (2015). Data-
driven stochastic modelling of zebrafish locomotion. J. Math. Biol. 71, 1081-1105.
doi:10.1007/s00285-014-0843-2
Zienkiewicz, A. K., Ladu, F., Barton, D. A. W., Porfiri, M. and Bernardo, M. D.
(2018). Data-driven modelling of social forces and collective behaviour in
zebrafish. J. Theor. Biol. 443, 39-51. doi:10.1016/j.jtbi.2018.01.011
Zimmermann, F. F., Gaspary, K. V., Leite, C. E., de Paula Cognato, G. and
Bonan, C. D. (2015). Embryological exposure to valproic acid induces social
interaction deficits in zebrafish (Danio rerio): a developmental behavior analysis.
Neurotoxicol. Teratol. 52, 36-41. doi:10.1016/j.ntt.2015.10.002
Zimmermann, F. F., Gaspary, K. V., Siebel, A. M. and Bonan, C. D. (2016).
Oxytocin reversed MK-801-induced social interaction and aggression deficits in
zebrafish. Behav. Brain Res. 311, 368-374. doi:10.1016/j.bbr.2016.05.059
Zimmermann, F. F., Gaspary, K. V., Siebel, A. M., Leite, C. E., Kist, L. W., Bogo,
M. R. and Bonan, C. D. (2017). Analysis of extracellular nucleotide metabolism in
adult zebrafish after embryological exposure to valproic acid. Mol. Neurobiol. 54,
3542-3553. doi:10.1007/s12035-016-9917-z
Disease Models & Mechanisms
20