Integration of hunger and hormonal state gates infant-directed aggression
Summary
This Nature paper shows how two internal states — hunger and reproductive (oestrous) state — are integrated in the medial preoptic area (MPOA) of the hypothalamus to switch virgin female mice from ignoring or caring for pups to attacking them. Food deprivation activates Agouti-related peptide (Arc AgRP) neurons in the arcuate nucleus; their projections to MPOA release neuropeptide Y (NPY), which inhibits MPOA neuron excitability by reducing HCN channel function. The reproductive state (tracked by the progesterone/oestradiol ratio) sets the baseline HCN expression in MPOA neurons: a high P4/E2 ratio (metestrus) lowers HCN abundance and makes NPY inhibition more effective, producing a quiescent MPOA and higher probability of pup-directed aggression. Microendoscopic calcium imaging confirms MPOA population activity encodes a persistent ‘aggression’ state. The work combines behaviour, opto/chemogenetics, electrophysiology, molecular knockdowns and in vivo imaging to define a circuit and molecular mechanism for state integration that flexibly gates social behaviour.
Key Points
- Hunger (food deprivation or chemogenetic AgRP activation) shifts many virgin females to pup-directed aggression; refeeding reverses this.
- Arc AgRP→MPOA projections mediate the effect; prolonged stimulation (≈30 min) is required to trigger aggression.
- NPY release from Arc AgRP terminals — not AgRP peptide — inhibits MPOA neurons, reducing HCN-mediated voltage sag and excitability.
- Oestrous state determines switching probability: the P4/E2 ratio (not absolute hormone levels) predicts how likely hunger is to evoke aggression (metestrus high, oestrus low).
- HCN channels are the molecular integrator: hormone-driven changes in HCN expression set baseline excitability; NPY acutely inhibits HCN function to silence MPOA neurons.
- Blocking HCN channels in MPOA is sufficient to induce pup-directed aggression in sated females without altering feeding.
- Cellular-resolution calcium imaging shows MPOA population activity forms a low-dimensional, persistent aggression state that is decodable and self-reinforcing across attacks.
- Projection-specific knockdown of Npy in Arc AgRP→MPOA delays aggression onset and restores HCN function, confirming causal role of NPY release.
Context and relevance
This study addresses a central question in behavioural neuroscience: how multiple, orthogonal internal states are combined by brain circuits to produce adaptive social decisions. It identifies a concrete molecular locus (HCN channels in MPOA neurons) where reproductive hormones and a neuromodulator from hunger circuits converge. That mechanistic clarity — from peptide release to ion-channel modulation to population dynamics and behaviour — makes the work widely relevant to researchers studying motivation, parenting, aggression and hypothalamic state control. The results also illustrate how need states (hunger) can re-prioritise social behaviours depending on hormonal context, a principle likely conserved across species and relevant for understanding state-dependent risk/defence trade-offs.
Why should I read this?
Want the short version: hunger can flip maternal-like behaviour into aggression, but only if the hormone balance in the MPOA lets it. This paper walks you through the actual circuit and molecule doing the gating — AgRP neurons release NPY that knocks down HCN channels in MPOA neurones, and the P4/E2 ratio sets how many HCN channels are around. It’s clean, multi-level neuroscience that explains a surprising behavioural switch. Saves you the slog of reading pages of methods — and gives you a neat model you can riff on.
Author style
Punchy and mechanistic: the authors combine behaviour, projection-specific manipulations, slice electrophysiology, single-molecule in situ, targeted knockdowns and microendoscopic imaging to make a tight causal story. If you care about how internal states are integrated at the neuron and circuit level, this is high-impact, well-controlled work that points to HCN channels as a hub for state gating.