Research briefing

A battle
that ESR1-expressing neurons of the
The mission
MPOA (MPOAESR1 neurons) and BNSTprESR1
To promote offspring survival, a hardwired neurons reciprocally inhibit each other.

between neural neural circuit in mothers supports

behaviours that are aimed at caring for
Notably, artificial activation and inhibition
of projections of MPOAESR1 neurons in

circuits for the young. However, virgin female animals

often show hostile behaviours towards the
young of their species1. For example, nearly
the BNSTpr and of BNSTprESR1 neuronal
projections in the MPOA demonstrated

infanticide and
that the relative inhibition strength
100% of wild female mice readily kill pups between these two populations determines
that are unrelated to them2. This behaviour behaviour towards the pups. Finally, as

maternal-care is thought to increase the perpetrators’

reproductive success by freeing up
female mice transition from infanticidal
behaviour to maternal care after becoming

behaviours
A previously unknown neural
circuit in the brains of female
mice is activated during
infanticidal behaviour, and
reciprocally inhibits another
circuit that promotes maternal-
care behaviour. These circuits
show opposing changes in
excitability when female mice
become mothers, explaining
the switch in young-directed
behaviours that occurs with
motherhood.
This is a summary of:
Mei, L. et al. Antagonistic circuits mediating
infanticide and maternal care in female mice.
Nature https://doi.org/10.1038/s41586-023-
06147-9 (2023).
Cite this as:
Nature https://doi.org/10.1038/d41586-023-
01513-z (2023).
resources for their own future offspring.
Given the prevalence and innateness
of pup-directed hostile behaviour, a
dedicated and hardwired circuit probably
exists to support its expression; however,
its components are unknown. We set out
to identify the neural circuit responsible
for driving infanticide in female mice,
and to determine its potential interaction
with the circuit supporting maternal-care
behaviours. This is an important problem
because the infanticide circuit, although
perhaps inactive in humans under normal
conditions, could be responsible for child
abuse, a prevalent problem in society.
The discovery
A brain structure called the medial preoptic
area (MPOA) of the hypothalamus is a key
site for maternal behaviour3. Given that
maternal behaviour and infanticide rarely
occur together in individuals, and that
MPOA cells are mostly inhibitory (that
is, they reduce activity in the neurons
they signal to), we hypothesized that the
neural circuits underlying infanticide and
maternal care inhibit each other. To test this
hypothesis, we systematically artificially
activated cells connected with the MPOA.
Stimulating such cells in three sites — the
principal nucleus of the bed nucleus of
the stria terminalis (denoted BNSTpr),
the posterodorsal part of the medial
amygdala (MeApd) and the ventrolateral
part of the ventromedial hypothalamus
(VMHvl) — promoted negative pup-directed
behaviours such as attacks or neglect.
We investigated the BNSTpr further,
because its activation consistently and
specifically led to infanticide, and little
is known about its function in female
animals. We found that expression of the
protein ESR1 was a good marker for BNSTpr
neurons that connect to the MPOA and
that are active during infanticide. Artificial
activation of these BNSTprESR1 cells was
sufficient to promote infanticide, whereas
artificial inactivation of these neurons in
female mice that were prone to attacking
pups reduced attacking behaviour. Using
circuit-mapping techniques, we established
mothers, the excitability of BNSTprESR1
neurons and MPOAESR1 neurons decreases
and increases, respectively. Altogether,
these results support the opposing
relationship between the maternal and
infanticide circuits and provide insights into
the neural mechanisms that support the
drastic switch in young-directed behaviours
upon motherhood in mice (Fig. 1).
The implications
Although child abuse is probably
accompanied by a defective maternal
circuit, it is important to note that a lack of
maternal caring behaviour is not equivalent
to actively hostile actions towards the child.
Our study describes a dedicated circuit that
drives negative young-directed behaviours
and simultaneously opposes the maternal-
care circuit. Inhibiting this ‘hostile’ circuit
could be a strategy to not only prevent
child abuse, but also improve the quality of
maternal care when needed.
Our study focuses on female mice, and
it remains unclear whether these circuits
operate in the same manner in males. Future
research should address this question.
Furthermore, a recent study showed that
BNSTprESR1 cells can be subdivided into
dozens of molecularly distinguishable
clusters4. In males, BNSTprESR1 cells have
roles in adult-directed aggression and sexual
behaviours5. Therefore, it is likely that not all
BNSTprESR1 cells in males, and possibly also in
females, are relevant for infanticide. Future
studies will probably refine the molecular
identities of BNSTpr infanticide-driving
cells.
Lastly, it will be interesting to understand
whether (and if so, how) factors associated
with child abuse, such as stress and
depression, shift the balance between the
activity of the maternal-care and infanticide
circuits.
Long Mei and Dayu Lin are at the New York
University Langone Medical Center, New York
City, New York, USA.

Nature | Published online 7 June 2023

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EXPERT OPINION
Infanticide is a behaviour that has
been predominantly investigated
in males. In their data-rich paper,
Mei et al. show that activating or inhibiting
BNSTprESR1 neurons in female mice can drive or
suppress infanticide, respectively, establishing
a role for these neurons in infant-directed
aggression in female mice. The authors also
conclude that mutual inhibition between
BNSTprESR1 neurons and MPOAESR1 neurons
is responsible for switching between infant-
directed attack and pup retrieval.” (CC BY 4.0)
Xiao-Hong Xu is at the Chinese Academy of
Sciences, Shanghai, China.
REFERENCES
1. Lukas, D. & Huchard, E. Phil. Trans. R. Soc. B
374, 20180075 (2019).
2. Soroker, V. & Terkel, J. Animal Behav. 36,
1275–1281 (1988).
3. Fang, Y.-Y., Yamaguchi, T., Song, S. C.,
Tritsch, N. X. & Lin, D. Neuron 98, 192–207
(2018).

FIGURE 4. Knoedler, J. R. et al. Cell 185, 654–671,

(2022).

a b
Hostile virgin female mice Mothers 5. Yang, B., Karigo, T. & Anderson, D. J.
Nature 608, 741–749 (2022).
BNSTprESR1 Infanticide BNSTprESR1

No infanticide
Inhibit

Inhibit
Inhibit

Inhibit

No maternal
behaviour

MPOAESR1 MPOAESR1 Maternal care

Figure 1 | Neural circuits promoting infanticide and maternal care in female mice oppose each other. a,
In hostile virgin female mice, a group of neuronal cells termed BNSTprESR1 cells exhibit high excitability (the
red circle shows their response to an injection of current), respond highly towards pups (the cells’ response
is shown above the thick arrow) and strongly inhibit another group of cells called MPOAESR1 cells, leading to
infanticidal behaviours. b, By contrast, in mothers, MPOAESR1 cells exhibit high excitability (red circle) and
high responses towards pups (as shown above the thin arrow), and strongly inhibit BNSTprESR1 cells, leading
to the expression of maternal behaviours.

BEHIND THE PAPER FROM THE EDITOR

Science can be a long and challenging
journey, but those first glimmers of finding
something new make it all worthwhile. I recall
one afternoon, after months of trying to find
the infanticide centre in the mouse brain
by activating MPOA-connected regions, I
finally saw a female mouse show aggressive
behaviour towards a pup on activating the
BNSTpr. I could not contain my excitement,
and a “yes” burst out of my mouth. I was
thrilled to share my discovery with my mentor
D.L., who happened to be passing by; she too
was exuberant, cheering, “You found it!” As I
delved deeper, more evidence confirmed
the central role of BNSTprESR1 cells in female
infanticide. Most strikingly, when I artificially
activated BNSTprESR1 cells, mother mice
quickly turned from angels into devils,
repeatedly attacking their own pups. The
moment I first witnessed this shocking change
will probably stick in my mind for a long time.
L.M.
Female mice are known to care and nurture
their young but, at the opposite extreme, can
also engage in infanticide. This paper explores
and unpacks the brain circuits involved in
these divergent behaviours and finds that the
two circuits are not separate, but rather are in
competition with one another.
David Rowland, Associate Editor, Nature

Nature | Published online 7 June 2023

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