C H A P T E R

11
The Role of MicroRNAs in Stress-Induced
Psychopathologies
O. Issler1,2,3, A. Chen1,2
1Weizmann Institute of Science, Rehovot, Israel; 2Max-Planck Institute of Psychiatry, Munich, Germany; 3Icahn School
of Medicine at Mount Sinai, New York, NY, United States

O U T L I N E

Introduction117 Circulating miRNAs as Biomarkers for

Stress-Related Psychopathologies 122
microRNAs118
The Role of miRNAs in Stress-Induced Anxiety 120 Open Questions and Future Directions 123
The Role of miRNAs in Fear Conditioning 120 Concluding Remarks 123
The Role of miRNAs in Chronic Stress-Induced
References124
Major Depression 121
Transgenerational Effects of Stress Mediated
by Sperm miRNAs 122

Abstract Stress during embryonic development or early life may

Exposure to stress is a known risk factor for disease develop-
ment, particularly in psychiatric disorders. Such long-lasting
effects of stress on an organism’s physiology are facilitated by
epigenetic processes, and one such mechanism is posttranscrip-
tional regulation by microRNAs (miRNAs). Here, we review
the findings of studies in human, animal, and cellular models
on miRNAs’ involvement in stress-related psychopathologies,
focusing on anxiety and depression. A better understanding of
the complex genetic and environmental interactions that give
rise to the susceptibility to develop psychopathologies, may
promote the needed breakthroughs in diagnostics and thera-
peutics in psychiatry.
INTRODUCTION
Environmental factors, mainly exposure to psycho-
logical or physiological stressors, are associated with
an increased risk of developing psychiatric disorders.
program brain vulnerability, while stress in adolescence
or later in life is associated with triggering the onset of
psychiatric disorders. For example, immunological stress
caused by a viral infection in utero is linked with increased
risk to develop schizophrenia,80 while exposure to acute
stressors in adolescence may trigger the onset of the first
psychotic episode of this disease.13 Most psychiatric dis-
orders display a strong genetic component, but heritabil-
ity alone only partially explains an individual’s risk to
develop mental illness. Only a few specific gene muta-
tions have been directly linked to increased susceptibil-
ity for a psychopathology, such MeCP2 mutations that
are directly linked to Rett syndrome and increased risk of
autism.84 Rather evidence is pointing toward a complex
interaction between genetic predisposition and envi-
ronmental factors being the root of mental illness. For
example, the literature reports an interaction between

Stress: Neuroendocrinology and Neurobiology 117

http://dx.doi.org/10.1016/B978-0-12-802175-0.00011-5 © 2017 Elsevier Inc. All rights reserved.
118 11.  THE ROLE OF MICRORNAs IN STRESS-INDUCED PSYCHOPATHOLOGIES

the Sert gene promoter polymorphism and childhood

stress in predisposing to medication-resistant depres-
sion.9,66 Environmental factors can lead to changes in
gene expression levels via epigenetic mechanisms. These
epigenetic changes may mediate the onset of a disease
without altering the DNA sequence. Such mechanisms
include histone modification, DNA methylation, and
posttranscriptional regulation by noncoding RNAs, such
as microRNAs (miRNAs), which are the focus of this
chapter. Elucidating the role of stress-related processes
mediated by miRNAs may promote a better understand-
ing of the pathophysiology and neurobiology of psychi-
atric disorders. This will potentially promote the highly
needed breakthroughs in the development of new drug
targets and biomarkers for mental illness.

KEY POINTS
• D  ysregulation of epigenetic mechanisms often
mediates the adverse effects of stress on anxiety
and depression susceptibility.
• miRNAs are modulators of normal stress
response and stress-induced anxiety, and are
important for fear learning.
• Chronic stress-induced depression alters
miRNAs expression profiles, and the effects of
antidepressants are induced in part by miRNAs.
• Sperm miRNAs are mediators of
transgenerational effects of stress on the offspring
behavior and metabolism.
• Circulating miRNAs’ fingerprint reflects the
anxiety and depression state of the individual
and may be used as a diagnostic biomarker.
MICRORNAs
Since their recent discovery, descriptions of novel
miRNAs and their widespread role in biological pro-
cesses are accumulating, and position miRNAs as a
prevalent mode of posttranscriptional regulation of
gene expression.1 Each miRNA may regulate hundreds
of downstream targets, and collectively miRNAs are
predicted to regulate more than half of the protein-cod-
ing genes and by that affect many cellular processes in
health and disease.21 Much is already known regarding
miRNA biogenesis38 and function1,8,41 (Fig. 11.1). Briefly,
the mature single-stranded miRNA, of about 22 nucleo-
tides, is incorporated into a miRNA-induced silencing
complex and induces translational repression or mRNA
destabilization of target mRNAs. MiRNAs can act as an
“expression switch” that blocks the expression of their
FIGURE 11.1  miRNA biogenesis and molecular activity. miRNA
genes are transcribed by RNA polymerase II and RNA polymerase III
into primary miRNA transcripts (pri-miRNA) and form a distinctive
secondary hairpin structure.5 Pri-miRNAs are transcribed either from
dedicated genes or processed from introns of other genes, as individ-
ual miRNAs or as miRNAs clusters. This pri-miRNA is then cleaved
by a microprocessor complex that contains the RNase III enzyme
ribonuclease 3 (called DROSHA) and microprocessor complex sub-
unit DGCR8.45 Following nuclear processing and cleavage of the RNA
molecule, its size is reduced to 70–110 nucleotides. Now referred to
as precursor miRNA (pre-miRNA), it is exported to the cytoplasm by
Exportin-5 (XPO5) in a complex with Ran-GTP.81 Here, the pre-miRNA
is cleaved by DICER to generate a roughly 22-nucleotide miRNA
duplex. Next, DICER and its interaction domain protein Tar RNA-
binding protein (TRBP) dissociate from the miRNA duplex to form
the active RNA-induced silencing complex (RISC) that performs gene
silencing. The double-stranded duplex needs to be separated into the
functional guide strand, which is complementary to the target mRNA
and the passenger strand, which is subsequently degraded. The func-
tional strand of the mature miRNA binds to form the RISC complex
together with Argonaute (AGO2) proteins11 and guides the complex
to target the 3′ untranslated region (3′ UTR) of mRNAs. This inhibits
mRNA translation or promotes its degradation. miRNA specificity to
their target mRNAs is canonically determined by Watson and Crick
base-pairing of a six to eight nucleotide sequence in the 5′ end of the
mature miRNA named seed sequence to a complementary seed match
sequence in the target gene 3′ UTR.1,31

I.  NEUROENDOCRINE CONTROL OF THE STRESS RESPONSE

 MICRORNAs
target genes.1 In such cases, a mutually exclusive expres-
sion pattern of the silencing miRNA and its target genes
are often observed, as commonly reported in develop-
mental studies.34 Alternatively, miRNAs can act as “fine
tuners” of the expression levels of their target genes,
evident by their coexpression with target genes, as often
reported in adult tissues.1,70
Accumulating evidence suggests that adult brain
miRNAs function as endogenous hubs for fine-tuning
target gene expression levels, thereby affecting the struc-
ture and function of neuronal networks. In the healthy
brain, miRNAs play a role in synaptic plasticity,64,73,78
119
and neurodegenerative diseases.7,17,63 With respect to
stress, miRNAs were demonstrated to be involved in the
cellular response to stress18,46,53 and to have a role in an
organism’s central response to stress. In this chapter we
will highlight studies providing evidence for the role of
central or circulating miRNAs in stress-related psycho-
pathologies, with a spotlight on depression and anxiety
disorders due to the large amount of data on these two
disorders that have been accumulated to date. To this
end, human samples, animal models, and cellular sys-
tems are utilized in a variety of methodical and technical
approaches (Fig. 11.2).

FIGURE 11.2  Experimental approaches for studying miRNAs in psychopathologies. In order to reveal the role of miRNAs in stress-related
psychopathologies, data is collected from human patients and animal models of mental disorders in a variety of approaches. Several types of
studies utilize human samples: genetic association studies, linking chromosomal variation to risk for mental disorder, postmortem studies exam-
ining the miRNAs expression profile in specific brain areas of patients, and evaluation of the levels of blood miRNAs for diagnostic purposes. In
rodent models for mental disorders, the effects of different paradigms of stress on the miRNome are often tested, along with direct manipulation
of groups of specific miRNAs levels. Technically, some approaches are unique to the study of miRNAs and others are modifications of research
techniques used to study protein-coding genes. The miRNAs’ expression profile is often analyzed using high throughput methods. Bioinformatic
analysis is used to identify specific miRNA–target gene interaction. In vitro assays are often carried out to confirm the predicted interactions and
for in-depth understanding of miRNA-related molecular mechanisms. Furthermore, mouse models are used to test causal effects of alteration of
specific miRNA expression levels on mouse behavior, physiology, and gene expression. By and large, studies combining several approaches and
using different models are of the greatest validity.

I.  NEUROENDOCRINE CONTROL OF THE STRESS RESPONSE

120 11.  THE ROLE OF MICRORNAs IN STRESS-INDUCED PSYCHOPATHOLOGIES
The Role of miRNAs in Stress-Induced Anxiety
Along with a synchronized neuroendocrine and
sympathetic system’s activity, the normal response to
stress includes increased arousal, fear, and anxiety. After
the termination of the stress response, the physiologi-
cal, endocrine, and behavioral arms of the response to
stress normalize the homeostatic balance. However, in
some pathological cases, often following chronic stress
or robust stressors, the anxiety remains and stabilizes in
a form of a psychiatric disorder. There is evidence that
miRNAs take part in regulating both the stress-induced
anxiety that is part of the physiological response to
homeostatic challenge and in psychopathological anxi-
ety conditions.
There are reports from rodent studies on miRNAs’
involvement in the central stress response. For example,
the expression profile of miRNAs is altered by acute
stress in the prefrontal cortex (PFC),60 the hippocam-
pus,52 and the amygdala.30,50,52 Haramati et al. reported
an increase in anxiety-like behaviors when ablating the
miRNA population by conditionally knocking out the
miRNAs’ processing gene, Dicer. In addition, a screen
of amygdala miRNAs’ profile following stress high-
lighted the interaction between miR-34c and a key gene
in the central stress response, corticotropin-releasing
factor receptor type 1 (Crfr1).30 Furthermore, virally
mediated overexpression of miR-34 in the adult mouse
amygdala protected the mice from stress-induced
anxiety as measured behaviorally. Moreover, overex-
pressing miR-34 in vitro blunted the response of Crfr1
to its endogenous ligand Crf, suggesting that miR-34
functionally regulates the molecular machinery of the
response to stress.30 Taken together, evidence suggests
that brain miRNAs take part in the natural, stress-
induced anxiety, and potentially also in pathological
anxiety.
THE ROLE OF miRNAs IN FEAR
CONDITIONING
Based on learning theories, it is hypothesized that
the origin of anxiety disorders is from overgener-
alization or incorrect associations between neutral
signs and fearful stimuli. A common paradigm used
to model anxiety-like behaviors in rodents is fear
conditioning (FC), where neutral cues and contexts
are experimentally associated with instinctive fear
responses. Abnormalities in the conditioning itself,
cue and content tests, or in extinction can be inter-
preted as potential models for anxiety disorders. There
are several studies that investigate the role of miRNAs
in the FC paradigm. The starting point of many of
I.  NEUROENDOCRINE CONTROL OF THE STRESS RESPONSE
these studies is a high throughput examination of the
miRNAs’ profile in a certain brain area after the FC
paradigm. Some studies followed up the research by
an in-depth analysis of the role of a specific miRNA
identified in the screen.
Broad evidence for the role of miRNAs in FC comes
from a study showing that hippocampal CA1 miR-
NAs’ expression patterns and the expression levels
of genes in the miRNAs’ biogenesis pathway were
changed following contextual FC paradigm.42 Another
study showed, more specifically, that miR-134’s inter-
action with Sirt1 in the hippocampus plays a role in
FC.22 Lentiviral-induced miR-134 knockdown in the
hippocampus restored fear learning hampered by the
knockout of the transcription regulator of miR-134,
Sirt1.22 Another study showed that miR-128b plays an
important role in fear extinction in the infralimbic PFC
(ILPFC).47 MiR-128b is upregulated in mice following
fear extinction in the ILPFC and lentiviral-mediated
overexpression or knockdown of miR-128b in this
brain area facilitates or inhibits fear extinction, respec-
tively. A few potential target genes of miR-128b that can
mediate this effect were identified. The authors focus
on the Rcs/Arpp21 gene and identify its downregula-
tion after fear extinction. Indeed, knocking down Rcs
facilitates fear extinction. Interestingly, miR-128b’s pre-
cursor is imbedded within an intron of the Rcs gene;
therefore, the genes are coregulated and take part in
modulating fear extinction.47 Analyzing the effects of
FC on miRNA expression in the rat lateral amygdala
demonstrated that downregulation of miR-182 occurs
in conjunction with upregulation of its actin-related
target genes.28 These genes are known to be involved
in synaptic plasticity, a structural process associated
with learning. Blocking miR-182 downregulation by
virally overexpressing miR-182 in the lateral amyg-
dala, interfered with the fear memory, suggesting that
miR-182 downregulation is essential for this process.28
An increase in miR-132 levels in mouse hippocam-
pus after FC was also reported, while site specifically
reducing miR-132 levels by lentiviruses inhibited the
learned freezing behavior.77 In addition, a study screen-
ing for the miRNA’s profile in the amygdala shortly
after FC-identified upregulation of miR-34a.15 Next,
the authors showed that lentivirally knocking down
miR-34a in the amygdala led to decreased freezing in
the context test, suggesting that miR-34a is necessary
for normal fear consolidation.15 Subsequently, genes
within the Notch signaling pathway were bioinformati-
cally identified to be targets of miR-34a, as confirmed
in vitro. Furthermore, Notch1 and its ligand Jag1 are
downregulated in the amygdala after FC. Inhibiting
Notch1 facilitates and increases Notch signaling,
which impairs consolidation. Collectively, decreased
 THE ROLE OF miRNAs IN FEAR CONDITIONING 121
TABLE 11.1  Specific miRNAs Regulating Fear Conditioning induce depression-like behaviors. For example, maternal
separation early life stress,56,71 chronic restraint stress,52,61
Effect
miRNA on Fear Relevant Associated and repeated inescapable shocks,68 all altered miRNAs’
Number Learning Target Genes Brain Area References expression profiles in brain areas associated with MDD,
47
such as the PFC, amygdala, and hippocampus. Similarly,
miR-128 Facilitation Rcs ILPFC
postmortem studies analyzing the miRNome of depressed
miR-132 Facilitation ? HC 77
patients identified modified expression patterns in the
miR-134 Inhibition Creb HC 22 PFC49,51,67,69 and hippocampus.39 Meta-analysis and com-
28
putational efforts to combine the results from rodent and
miR-182 Inhibition Cortactin and LA
Rac1
human studies is required. In addition, extending the
screens to other brain areas associated with MDD, such as
miR-19b Inhibition Adbr1 BLA 74
the raphe nucleus, may be informative.
miR-33 Inhibition Gabra4, Kcc2 HC 36 A few in-depth studies have focused on specific
Gabrb2, Syn2 miRNAs highlighted by screens and bioinformatic
miR-34a Facilitation Notch1 BLA 15 analysis, and associated with exposure to chronic stress,
MDD, and antidepressant treatment. For example, a
BLA, basolateral amygdala; HC, hippocampus; ILPFC, infralimbic prefrontal
cortex; LA, lateral amygdala.
study showed that miR-16 facilitated antidepressant
activity by reducing serotonin reuptake and inducing
serotonergic characteristics in noradrenergic neurons.2
Notch signaling enabled partly by increased miR-34a Specifically, miR-16 targets the serotonin reuptake
facilitated fear learning consolidation.15 Recently, Volk transporter (SERT) in normal conditions. MiR-16 is
et al. identified an upregulation in miR-19b levels in upregulated in the serotonergic raphe nucleus and
the amygdala of mice exposed to chronic social defeat downregulated in the noradrenergic locus coeruleus
stress, a model for inducing anxiety and depression-like by selective serotonin reuptake inhibitor (SSRI) anti-
behaviors. Bioinformatics, in vitro and in vivo studies, depressants. Apart from reducing serotonin reuptake
showed that miR-19b targets a key gene in the stress- in serotonergic neurons, Braudry et al. showed that
related neuroadrenergic circuit, the adrenergic receptor miR-16 induces a serotonergic profile of neuroadrener-
beta 1 (Adbr1).74 Lentiviral overexpression of miR-19b gic neurons mediated by the neurotropic factor S100β.
in mouse amygdala led to decreased cued freezing Finally, depression-like behaviors, induced by expo-
behavior, while knockdown of miR-19b led to the mir- sure to chronic stress, were reduced by infusion of miR-
ror phenotype, suggesting that miR-19-Adbr1 interac- 16 into the raphe nucleus or anti-miR-16 into the locus
tion regulates the circuits controlling learned fear.74 coeruleus, to the same extent as SSRI infusion to the
Finally, it was elegantly shown that downregulation of raphe nucleus. These results offer a mechanistic under-
miR-33 mediates the anxiolytic effects of a GABA ago- standing to the mode of action of serotonin-related anti-
nist as measured in the contextual FC test. Viral hip- depressant drugs.2 Moreover, in a follow-up study, an
pocampal overexpression of miR-33 blocked the effects additional role was assigned to miR-16 in the response
of the agonist, while using locked nucleic acid oligos to SSRI, molecularly mediating increased adult neu-
to inhibit miR-33 mimicked the anxiolytic effects. The rons neurogenesis in the hippocampus.44
authors suggest these effects are mediated by several Another study that examined the serotonergic cir-
GABA-related genes that are regulated in vivo by miR- cuitry identified an interaction between miR-135,
33.36 Taken together, a large amount of data demon- the SERT, and the serotonin receptor 1a (HTR1A) in
strates the role of miRNAs in normal fear processing mediating stress-induced anxiety and depression and
and dysregulation in pathological FC behavior (sum- in the response to SSRIs.35 In this study, miR-135 was
marized in Table 11.1). identified in a screen, profiling the miRNA fingerprint
of serotonergic neurons and bioinformatics. Further
experimental work demonstrated that miR-135 regu-
The Role of miRNAs in Chronic Stress-Induced
lates two key genes in the serotonergic system, SERT
Major Depression and HTR1A. Furthermore, it was shown that miR-135
Exposure to chronic psychological mild stress often levels increased in the serotonergic raphe nucleus of
precedes the onset of major depression disorder (MDD) mice following SSRI administration. Mimicking this
episodes. This phenomenon is partially mediated by miR- by increasing miR-135 level specifically in serotoner-
NAs. Screen studies using rodent models demonstrated an gic neurons using transgenic mice induced behavioral
altered miRNAs’ expression pattern in several brain sites resiliency to chronic stress along with adaption of the
following exposure to chronic stress paradigms aimed to serotonergic tone. Furthermore, in human studies’

I.  NEUROENDOCRINE CONTROL OF THE STRESS RESPONSE

122 11.  THE ROLE OF MICRORNAs IN STRESS-INDUCED PSYCHOPATHOLOGIES
samples it was reported that miR-135 levels are down-
regulated in the serotonergic raphe nucleus of suicide
victims with MDD and circulating levels of miR-135
were suggested as a potential biomarker for depres-
sion and response to treatment.35 In summary, along
with screening studies reporting an alternation in the
miRNA’s expression profile by antidepressant treat-
ment in animal models56 and human lymphoblastoid
cell lines,57,58 there are causal reports on a role for both
miR-16 and miR-135 in regulating the serotonergic tone
and mediating the response to antidepressants.
TRANSGENERATIONAL EFFECTS OF
STRESS MEDIATED BY SPERM miRNAs
Recent studies reported intriguing results regarding
altered behavioral, physiological, and epigenetic modi-
fications in offspring of a stressed parent that were not
directly exposed to stress themselves (reviewed in Ref.
24). There is evidence that this phenomenon is modulated
by sperm miRNAs. Initially, a study by Rodgers et al.62
showed that parental exposure to chronic variable stress
altered the nonstressed offspring’s HPA axis function,
and the transcriptome in the paraventricular nucleus of
the hypothalamus (PVN) and bed nucleus of the stria ter-
minalis (BNST). In parallel, sperm miRNAs’ expression
pattern was altered in stressed mice and the authors sug-
gested that this potentially mediated the modified phe-
notype observed in their offspring.62 Similarly, a study
by Gapp et al.23 showed that parental exposure to early
life stress altered anxiety, depression, and metabolism
of the offspring, along with modifying their brain and
sperm transcriptome, including the miRNAs’ expres-
sion profiles. Furthermore, directly manipulating the
oocytes by injecting RNA from sperm of stressed mice
to embryos of naïve parents passed the stress-induced
phenotype transgenerationally.23 These findings demon-
strate inheritance of acquired stress-induced traits and
by that can be considered as evidence for Lamarckism.
Epigenetic regulation by miRNAs emerges as a mecha-
nistic molecular mediator of this phenomenon.
CIRCULATING miRNAs AS
BIOMARKERS FOR STRESS-RELATED
PSYCHOPATHOLOGIES
Blood levels of miRNAs can be utilized as potential
biomarkers for diagnosis of stress-related psychiatric
disorders and as a means to evaluate the response of
patients to treatment. In the circulation, miRNAs are
detectable in blood cells, plasma, or serum, either in
particular membrane vesicles, exosomes, or bound
to protein. Primarily, correlations have been reported
I.  NEUROENDOCRINE CONTROL OF THE STRESS RESPONSE
between levels of circulating miRNAs and disease
states, such as different types of cancers65 and diabe-
tes.29 Recently, there is increasing evidence of altered
pattern of circulating miRNAs associated with mental
disorders.59 The mechanism by which miRNAs enter
the circulation is only partially understood; there is
evidence that miRNAs are released from cells that
undergo apoptosis, or may be actively secreted from
living cells, via lipid structures, such as exosomes
or in high-density lipoproteins (e.g., Refs. 40, 72, 76;
reviewed in Ref. 14).
Two studies focused on the effects of stress-induced
anxiety on the circulating miRNA’s profile in healthy
controls and characterized the blood miRNome at
several time points before and after a stressful exam,
and both highlighted upregulation of miR-16.33,37 The
circulating miRNA’s profile of psychiatric patients
was also tested, for example in patients with PTSD,82
MDD,3,4,20,75,79 schizophrenia,27,43 and autism.55 More
specifically, one study suggests that miR-1202 levels
in the circulation could be potentially used for assign-
ing patients to different treatments.49 Initially it was
found that miR-1202 levels are downregulated in PFC
postmortem brain tissue from depressed subjects.
Next, in a prospective study of depressed patients
treated with SSRIs, miR-1202 circulation levels could
distinguish between responders and nonresponders,
as the miR-1202 level is initially lower and upregu-
lated upon drug administration, only in responders.49
Furthermore, to complete the mouse and in vitro
studies described above, we reported that miR-135a
levels are lower in the blood of depressed subjects.
In another cohort, miR-135 levels were increased by
treatment.35 Replication studies using bigger cohorts
are needed to further validate these findings and iden-
tify additional relevant miRNAs. Taken together, psy-
chiatric diagnosis and response to treatment might be
reflected in fingerprints of circulating miRNAs that
can potentially be used in the clinic for diagnosis and
treatment assignment.
Alternately, patient-derived stable cell lines can be
generated from noninvasive samples collected from
psychiatric patients, for example, lymphoblast lines
generated from blood lymphocytes or dermal-derived
fibroblasts. These cells would represent the genetic
landscape of the patient’s disorder, and studying their
miRNA expression profile at baseline or in response
to treatment may indicate potential miRNAs that are
relevant to the disorder of interest. Furthermore, cell
lines derived from patients may serve as tools for
screening response to drugs as part of a personalized
medicinal approach. For example, the miRNAs’ expres-
sion pattern was analyzed in human lymphoblastoid
cell lines derived from healthy subjects treated with
SSRIs58 and in fibroblasts derived from MDD patients
 Concluding Remarks
and controls.25,26 Such studies highlighted a panel of
miRNAs potentially associated either with MDD or
the response to antidepressants that should be further
tested for use as biomarkers.
OPEN QUESTIONS AND FUTURE
DIRECTIONS
Reviewing the first era of research on the role of
stress-related miRNAs in mental disorders raises novel
questions requiring further study:
  
1. N  ot much is known regarding the molecular
mechanism mediating the observed changes in
miRNAs’ levels in models of psychopathologies.
This is not the case for all miRNA domains. In cancer
research, for example, altered miRNA promoter
methylation patterns can explain some of the
modified expression patterns of miRNAs associated
with the disease (reviewed in Ref. 19).
2. Comprehensively mapping of the spatial and
temporal expression profile of endogenous miRNAs
in the developing and adult brain, in specific
neuronal cell types, in subcellular fractions (such
as the synaptosomes), in health, and in different
psychopathological conditions is greatly needed.
Such knowledge is crucial for the understanding of
the possible behavioral and physiological functions
of these miRNAs, as there are reports of great cell
type/organism specificity for the miRNome.48 Some
systematic efforts were made to profile miRNAs’
expression patterns in human, mouse, and other
organisms across different tissue types (http://
www.mirz.unibas.ch/smiRNAdb), in the developing
human83 or zebra fish brain,10 and in part of the adult
mouse brain.32 In addition, the interaction between
miRNAs and their target genes has been tested in
young mouse brain12 and in a couple of human
brain sites6 using high-throughput sequencing of
RNAs isolated by cross-linking immunoprecipitation
(HITS-CLIP) in several brain regions. Extending
such studies and mapping mouse and human
miRNA’s expression profiles equivalently to the
mRNA Allen brain atlas (http://www.brain-map.
org.) and miRNA–RNA interactions would be very
informative.
3. The response to stress and the risk to develop
stress-related psychopathologies varies between
the sexes; particularly the increased risk of
developing anxiety and depression in women.
There is evidence that miRNAs can mediate the
effects of prenatal stress on brain sexual dimorphic
organization,54 suggesting that more research
is needed to explore the role of miRNAs in sex
I.  NEUROENDOCRINE CONTROL OF THE STRESS RESPONSE
123
differences in the normal and the pathological
response to stress.
4 . Another field of interest that is relatively unexplored
concerns the possible involvement of miRNAs
in mediating individual differences related to
resiliency or susceptibility to psychiatric disorders.
Meaning, upon exposure to an abnormal stressor,
some individuals will display susceptibility and
develop psychopathologies while others will
remain healthy and are defined as resilient. Such
individual differences are mediated both by genetic
and epigenetic mechanisms, and indeed there is
first evidence from mouse models that miRNA can
mediate this phenomena,16 yet further studies are
needed.
CONCLUDING REMARKS
miRNAs are emerging as pivotal modulators of
normal and pathological responses to stress. The fact
that more than half of the protein-coding genes are
predicted to be regulated by miRNAs and that each
miRNA can regulate hundreds of different genes posi-
tions these molecules as possible master regulators of
many cellular processes. Furthermore, an miRNA may
regulate the expression of several genes within a spe-
cific biological or cellular pathway. These unique fea-
tures, together with rapidly increasing experimental
data, encourage scientists to study the role of miRNAs
in the regulation of stress-related psychopathologies.
miRNAs have an established role in brain develop-
ment, this, taken together with the fact that responses
to stress have a neurodevelopmental origin and that
most psychopathologies are considered to be diseases
of multiple genes, provides further support to the pos-
sible involvement of miRNAs in different psychiatric
disorders.
The accumulating evidence presented in this review
suggests that miRNAs may function through several
mechanisms to direct stress-related behavior. Some
miRNAs’ expression levels change following acute and
chronic stress challenges, thus facilitating a subsequent
change in the expression of target genes, which are
putatively needed in order to direct certain behavioral
outcomes. On the other hand, miRNAs may serve as
“buffers” for keeping protein targets stable and avoid
being upregulated to a pathological level following
challenge and contribute to restoration of homeostasis.
Shedding light on the role of miRNAs in stress-related
psychopathologies may potentially enable a better
understanding of the molecular pathways of these dis-
orders and possibly promote the much needed devel-
opment of new therapeutic and diagnostic approaches
(Fig. 11.3).
124 11.  THE ROLE OF MICRORNAs IN STRESS-INDUCED PSYCHOPATHOLOGIES

FIGURE 11.3  Utilizing miRNA biology in psychiatry for diagnostics and therapeutics. miRNA-related analysis can be used as noninvasive
biomarkers in psychiatry for diagnostic purposes. Association studies linking genetic variation with susceptibility for a psychiatric disorder can
potentially be used for diagnostics. Single nucleotide polymorphisms (SNPs) or chromosomal modifications, such as DNA duplication or deletion
in miRNA genes are examples of such genetic markers. Similarly, the levels of specific miRNAs in, for example, different fractions of the blood,
can be used for diagnosis and monitoring of response to treatment. Manipulating specific miRNA levels can potentially be used for therapeutics
of psychiatric disorders. Viral vectors such as adeno-associated virus (AAV) can be used as part of gene therapy to overexpress or knockdown
specific miRNA. Alternatively, drugs could be developed containing synthetic miRNA mimics or oligos designed to reduce a specific miRNA
level, such as anti-miRNA or “miRNA sponges.”

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