Intermale aggression is used to establish social rank. Several neuronal populations have been implicated in aggression, but the circuit mechanisms that shape this innate behavior and coordinate its different components (including attack execution and reward) remain elusive. We show that dopamine transporter-expressing neurons in the hypothalamic ventral premammillary nucleus (PMv neurons) organize goal-oriented aggression in male mice. Activation of PMv neurons triggers attack behavior; silencing these neurons interrupts attacks. Regenerative PMv membrane conductances interacting with recurrent and reciprocal excitation explain how a brief trigger can elicit a long-lasting response (hysteresis). PMv projections to the ventrolateral part of the ventromedial hypothalamic and the supramammillary nuclei control attack execution and aggression reward, respectively. Brief manipulation of PMv activity switched the dominance relationship between males, an effect persisting for weeks. These results identify a network structure anchored in PMv neurons that organizes aggressive behavior and, as a consequence, determines intermale hierarchy.

Striatal activity is dynamically modulated by acetylcholine and dopamine, both of which are essential for basal ganglia function. Synchronized pauses in the activity of striatal cholinergic interneurons (ChINs) are correlated with elevated activity of midbrain dopaminergic neurons, whereas synchronous firing of ChINs induces local release of dopamine. The mechanisms underlying ChIN synchronization and its interplay with dopamine release are not fully understood. Here we show that polysynaptic inhibition between ChINs is a robust network motif and instrumental in shaping the network activity of ChINs. Action potentials in ChINs evoke large inhibitory responses in multiple neighboring ChINs, strong enough to suppress their tonic activity. Using a combination of optogenetics and chemogenetics we show the involvement of striatal tyrosine hydroxylase-expressing interneurons in mediating this inhibition. Inhibition between ChINs is attenuated by dopaminergic midbrain afferents acting presynaptically on D2 receptors. Our results present a novel form of interaction between striatal dopamine and acetylcholine dynamics.

Summary Persistent neural activity has been described in cortical, hippocampal, and motor networks as mediating working memory of transiently encountered stimuli 1 , 2 . Internal emotion states such as fear also exhibit persistence following exposure to an inciting stimulus 3 , but whether slow neural dynamics are involved is not well-studied. SF1 + /Nr5a1 + neurons in the dorsomedial and central subdivisions of the ventromedial hypothalamus (VMHdm/c) are necessary for defensive responses to predators 4 – 7 . Optogenetic activation of VMHdm SF1 neurons elicits defensive behaviours that outlast stimulation 5 , 8 , suggesting the induction of a persistent internal state of fear or anxiety. Here we show that in response to naturalistic threatening stimuli, VMHdm SF1 neurons exhibit persistent activity lasting many tens of seconds. This persistent activity was correlated with, and required for, persistent defensive behavior in an open-field assay, and was dependent on neurotransmitter release from VMHdm SF1 neurons. Stimulation and calcium imaging experiments in acute slices revealed local excitatory connectivity between VMHdm SF1 neurons. Microendoscopic calcium imaging of VMHdm SF1 neurons revealed that persistent activity at the population level reflects heterogeneous dynamics among individual cells. Unexpectedly, distinct but overlapping VMHdm SF1 subpopulations were persistently activated by different modalities of threatening stimuli. Computational modeling suggests that neither recurrent excitation nor slow-acting neuromodulators alone can account for persistent activity that maintains stimulus identity. Our results identify stimulus-specific slow neural dynamics in the hypothalamus, on a time scale orders of magnitude longer than that supporting working memory in the cortex 9 , 10 , as a contributing mechanism underlying a persistent emotion state. (238 words)

Reward-related behavior is complex and its dysfunction correlated with neuropsychiatric illness. Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been associated with different aspects of reward function, but it remains to be disentangled how distinct VTA DA neurons contribute to the full range of behaviors ascribed to the VTA. Here, a recently identified subtype of VTA neurons molecularly defined by NeuroD6 (NEX1M) was addressed. Among all VTA DA neurons, less than 15% were identified as positive for NeuroD6. In addition to dopaminergic markers, sparse NeuroD6 neurons expressed the vesicular glutamate transporter 2 (Vglut2) gene. To achieve manipulation of NeuroD6 VTA neurons, NeuroD6(NEX)-Cre-driven mouse genetics and optogenetics were implemented. First, expression of vesicular monoamine transporter 2 (VMAT2) was ablated to disrupt dopaminergic function in NeuroD6 VTA neurons. Comparing Vmat2 lox/lox;NEX-Cre conditional knockout (cKO) mice with littermate controls, it was evident that baseline locomotion, preference for sugar and ethanol, and place preference upon amphetamine-induced and cocaine-induced conditioning were similar between genotypes. However, locomotion upon repeated psychostimulant administration was significantly elevated above control levels in cKO mice. Second, optogenetic activation of NEX-Cre VTA neurons was shown to induce DA release and glutamatergic postsynaptic currents within the nucleus accumbens. Third, optogenetic stimulation of NEX-Cre VTA neurons in vivo induced significant place preference behavior, while stimulation of VTA neurons defined by Calretinin failed to cause a similar response. The results show that NeuroD6 VTA neurons exert distinct regulation over specific aspects of reward-related behavior, findings that contribute to the current understanding of VTA neurocircuitry.