The neural control of infanticide and parental behaviors in male mice

This study identifies a conserved mutually inhibitory circuit between MPOA and BNST Esr1 neurons that governs the switch between infanticide and parental care in male mice, revealing that while the circuit motif is shared with females, intrinsic cellular differences and activity balance adjustments during fatherhood underlie the distinct behavioral tendencies between sexes.

The Gist

The Big Picture: The "Good Dad" vs. "Bad Dad" Switch in Mice

Imagine a male mouse living a normal life. If you put a baby mouse (a pup) in his cage, he might see it as a threat or an annoyance and kill it. This is called infanticide. But, if that same male mouse becomes a father, his behavior flips completely. He starts grooming, protecting, and carrying the babies. He becomes a good dad.

Scientists have long wondered: What happens inside the mouse's brain to make this switch? Is it a completely different set of brain parts for "killing" and "caring," or is it the same parts just turned up or down?

This study found that it's the same brain circuit, acting like a seesaw, but the "weight" on each side changes depending on whether the mouse is a virgin or a father.

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The Two Key Players: The "Kill Switch" and the "Love Switch"

The researchers focused on two specific neighborhoods in the mouse brain:

1. The BNSTp (The "Kill Switch"): A small area that, when active, makes the mouse want to attack the baby.
2. The MPOA (The "Love Switch"): A nearby area that, when active, makes the mouse want to care for the baby.

The Seesaw Analogy:
Think of these two brain areas as a playground seesaw.

• When the BNSTp (Kill Switch) is heavy and going down, the MPOA (Love Switch) is light and stuck in the air. The mouse attacks.
• When the MPOA (Love Switch) gets heavy and goes down, the BNSTp is lifted up. The mouse cares for the baby.
• They are connected by a direct wire: when one turns on, it actively shuts off the other. They cannot both be "on" at the same time.

What the Scientists Did (The Experiments)

The team used advanced tools to peek inside the brains of male mice to see what was happening.

1. Watching the Brain in Real-Time (The "CCTV Camera")
They gave mice a special "glow-in-the-dark" sensor in their brains that lit up when brain cells were active.

• Virgin Mice: When they saw a baby, the "Kill Switch" (BNSTp) lit up like a firework, while the "Love Switch" stayed dark.
• Fathers: When they saw their own babies, the "Love Switch" (MPOA) lit up brightly, and the "Kill Switch" went dark.

2. Flipping the Switches (The "Remote Control")

• Turning on the Kill Switch: They used light to zap the BNSTp in mice that were not naturally killers. Result: Even gentle mice suddenly attacked the babies.
• Turning off the Kill Switch: They used a "chemical brake" to silence the BNSTp in aggressive mice. Result: The killers stopped attacking and started grooming the babies instead.
• Turning on the Love Switch: They zapped the MPOA in aggressive mice. Result: The aggression stopped, and they started caring for the pups.

3. The "Fatherhood Transformation" (The "Software Update")
The most fascinating part was looking at the wiring of the brain cells themselves.

• Before Fatherhood: The "Kill Switch" cells were naturally very energetic and loud. The "Love Switch" cells were sluggish and quiet.
• After Fatherhood: Something changed! The "Kill Switch" cells became tired and quiet (less excitable), while the "Love Switch" cells became super-charged and energetic.

It's as if becoming a father triggers a software update in the brain. The "Kill" program gets downgraded to run slower, and the "Care" program gets an upgrade to run faster.

Why Do Males Kill More Than Females?

You might ask, "If the circuit is the same, why do male mice kill babies more often than female mice?"

The answer lies in the factory settings.

• Male Mice: Their "Kill Switch" is built with a stronger engine (more excitable cells), and their "Love Switch" has a weaker engine. It takes a lot of effort to flip the switch to "Care."
• Female Mice: Their "Kill Switch" is naturally weaker, and their "Love Switch" is naturally stronger. They are biologically primed to be moms, so the switch flips much easier.

The Takeaway

This study reveals that nature doesn't build two separate brains for "killing" and "loving." Instead, it builds one shared circuit that acts like a seesaw.

• Virgin Males: The seesaw is stuck on the "Kill" side because the engine is too strong.
• Fathers: The experience of fatherhood (likely triggered by mating and hormones) re-wires the engine. It weakens the "Kill" side and strengthens the "Love" side, allowing the seesaw to flip.

It's a beautiful example of how the brain is plastic—it can physically change its own "settings" to allow an animal to switch from being a threat to being a protector.

Technical Summary

1. Problem Statement

Infanticide (killing conspecific young) and parental care are mutually exclusive behaviors critical for offspring survival. While the neural circuitry controlling these behaviors has been extensively studied in female mice, the mechanisms in males remain less understood.

• Previous Knowledge: In females, a mutually inhibitory circuit between MPOA$^{Esr1}$ (medial preoptic area, estrogen receptor alpha-expressing cells) and BNSTp$^{Esr1}$ (posterior bed nucleus of the stria terminalis, Esr1-expressing cells) was identified. MPOA$^{Esr1}$ drives maternal care, while BNSTp$^{Esr1}$ drives infanticide.
• The Gap: It was unclear if this specific circuit motif exists in males. Previous studies suggested sex-specific differences, identifying different brain regions (e.g., BNSTrh, MeApd) for male infanticide. Furthermore, the physiological mechanisms underlying the transition from infanticide (in virgins) to paternal care (in fathers) were unknown.
• Core Question: Does the MPOA$^{Esr1}$–BNSTp$^{Esr1}$ antagonistic circuit control pup-directed behaviors in males, and how do the intrinsic properties of these neurons change during the transition to fatherhood?

2. Methodology

The study utilized a combination of viral tracing, optogenetics, chemogenetics, fiber photometry, and in vitro electrophysiology in male mice (primarily Swiss Webster [SW] and C57BL/6 strains).

• Animal Models: Esr1-2A-Cre mice (SW and C57 backgrounds) were used to target Esr1-expressing neurons. Mice were screened for spontaneous infanticide or parental behavior before experiments.
• Viral Manipulations:
  • Fiber Photometry: GCaMP6f expression to record in vivo Ca$^{2+}$ activity in BNSTp$^{Esr1}$ and MPOA$^{Esr1}$ during pup interactions in virgins and fathers.
  • Optogenetics: ChR2 (activation) and ChrimsonR (activation) to stimulate specific cell populations.
  • Chemogenetics: hM3Dq (activation) and hM4Di (inhibition) to modulate neuronal activity via CNO injection.
  • Ablation: Diphtheria Toxin Receptor (DTR) expression to selectively ablate BNSTp$^{Esr1}$ cells using Diphtheria Toxin (DT).
• Electrophysiology: In vitro whole-cell patch-clamp recordings (current-clamp and voltage-clamp) to measure intrinsic excitability (F-I curves) and synaptic connectivity between BNSTp$^{Esr1}$ and MPOA$^{Esr1}$ in virgins vs. fathers.
• Behavioral Assays: Standardized tests involving the introduction of P1–P4 pups or adult male intruders to quantify latency to attack, investigation, retrieval, and grooming.

3. Key Contributions & Results

A. BNSTp$^{Esr1}$ Drives Male Infanticide

• Activity Correlation: Fiber photometry showed that BNSTp$^{Esr1}$ activity sharply increases during pup approach, investigation, and attack in infanticidal virgin males. In contrast, fathers showed minimal BNSTp$^{Esr1}$ activation during paternal behaviors.
• Necessity:
  • Ablation: Selective ablation of BNSTp$^{Esr1}$ cells in infanticidal virgins converted 5/8 mice from attackers to retrievers.
  • Inhibition: Chemogenetic inhibition (hM4Di) of BNSTp$^{Esr1}$ significantly reduced pup attack latency and duration in C57 and SW males.
• Sufficiency: Optogenetic or chemogenetic activation of BNSTp$^{Esr1}$ in non-infanticidal virgin males robustly induced pup attack (latency < 2s). Remarkably, activating these cells in fathers (who normally care for pups) immediately triggered pup attack, overriding the paternal state.
• Specificity: Activation induced pup-specific aggression; it did not induce attack toward adult males but instead increased allogrooming of adult intruders.

B. MPOA$^{Esr1}$ Drives Paternal Care and Suppresses Infanticide

• Activity Correlation: MPOA$^{Esr1}$ activity increased during pup approach and retrieval in fathers but was suppressed or showed a declining trend during pup attacks in virgins.
• Modulation:
  • Inhibition: Chemogenetic inhibition of MPOA$^{Esr1}$ in non-infanticidal virgins induced infanticide (6/9 mice attacked).
  • Activation: Chemogenetic activation of MPOA$^{Esr1}$ in infanticidal virgins suppressed infanticide (only 1/6 attacked).
• Conclusion: MPOA$^{Esr1}$ and BNSTp$^{Esr1}$ function as a "seesaw" mechanism; they are mutually antagonistic, with MPOA$^{Esr1}$ suppressing infanticide and promoting care.

C. Physiological Plasticity During Fatherhood

• Excitability Switch: In vitro recordings revealed a state-dependent reversal in excitability:
  • MPOA$^{Esr1}$: Virgin males showed a tendency toward depolarization block (firing rate peaked then dropped). Fathers showed sustained, high-frequency firing with increased current injection.
  • BNSTp$^{Esr1}$: Virgin males were highly excitable (sustained high firing). Fathers showed reduced excitability (firing rate declined after 80 pA).
• Balance Shift: In virgins, BNSTp$^{Esr1}$ is more excitable than MPOA$^{Esr1}$. In fathers, MPOA$^{Esr1}$ becomes significantly more excitable than BNSTp$^{Esr1}$. This shift in the excitability balance underlies the behavioral switch from infanticide to care.

D. Sex Differences in Circuit Properties

• Intrinsic Properties: Despite the shared circuit motif, there are fundamental sex differences:
  • BNSTp$^{Esr1}$: More excitable in males than females (regardless of reproductive state).
  • MPOA$^{Esr1}$: More excitable in females than males.
• Implication: The higher baseline excitability of the infanticide-promoting BNSTp$^{Esr1}$ in males explains their higher tendency for infanticide compared to females. The circuit architecture is conserved, but the "set point" of cellular properties differs.

4. Significance

• Unified Circuit Model: The study establishes that the MPOA$^{Esr1}$–BNSTp$^{Esr1}$ antagonistic circuit is a conserved, sex-common motif for controlling pup-directed behaviors in both male and female mice. This challenges the notion that male and female infanticide circuits are entirely distinct.
• Mechanism of Behavioral Switch: It identifies cellular plasticity (changes in intrinsic excitability) rather than just synaptic rewiring as a key mechanism for the transition from infanticide to paternal care.
• Sexual Dimorphism: The research clarifies that sex differences in behavior arise from quantitative differences in the intrinsic properties of conserved circuits (e.g., males have a "higher set point" for infanticide due to more excitable BNSTp$^{Esr1}$ cells), rather than qualitative differences in circuit topology.
• Clinical Relevance: Understanding the neural basis of parental aggression and its suppression provides insights into postpartum aggression, infanticide, and the neural mechanisms of parental bonding, which may have implications for treating psychiatric conditions involving aggression or lack of parental care.