How do we know our social rank? Most social species, from insects to humans, self-organize into social dominance hierarchies (1-4). The establishment of social ranks serves to decrease aggression, conserve energy, and maximize survival for the entire group (5-8). Despite dominance behaviors being critical for successful interactions and ultimately, survival, we have only begun to learn how the brain represents social rank (9-12) and guides behavior based on this representation. The medial prefrontal cortex (mPFC) has been implicated in the expression of social dominance in rodents (10,11), and in social rank learning in humans (13,14). Yet precisely how the mPFC encodes rank and which circuits mediate this computation is not known. We developed a trial-based social competition assay in which mice compete for rewards, as well as a computer vision tool to track multiple, unmarked animals. With the development of a deep learning computer vision tool (AlphaTracker) and wireless electrophysiology recording devices, we have established a novel platform to facilitate quantitative examination of how the brain gives rise to social behaviors. We describe nine behavioral states during social competition that were accurately decoded from mPFC ensemble activity using a hidden Markov model combined with generalized linear models (HMM-GLM). Population dynamics in the mPFC were predictive of social rank and competitive success. This population-level rank representation translated into differences in the individual cell responses to task-relevant events across ranks. Finally, we demonstrate that mPFC cells that project to the lateral hypothalamus contribute to the prediction of social rank and promote dominance behavior during the reward competition. Thus, we reveal a cortico-hypothalamic circuit by which mPFC exerts topdown modulation of social dominance. Main TextThe medial prefrontal cortex (mPFC) is best known for its role in working memory, decision-making, reward learning and goal-oriented behavior [15][16][17][18][19] . Theories about mPFC function emphasize that it integrates sensory and limbic information to exibly guide behavior based on task rules 20,21 . mPFC circuitry has also been broadly implicated in social cognition [22][23][24] , social behaviors 25,26 , social

How do we know our social rank? Most social species, from insects to humans, self-organize into social dominance hierarchies (1–4). The establishment of social ranks serves to decrease aggression, conserve energy, and maximize survival for the entire group (5–8). Despite dominance behaviors being critical for successful interactions and ultimately, survival, we have only begun to learn how the brain represents social rank (9–12) and guides behavior based on this representation. The medial prefrontal cortex (mPFC) has been implicated in the expression of social dominance in rodents (10,11), and in social rank learning in humans (13,14). Yet precisely how the mPFC encodes rank and which circuits mediate this computation is not known. We developed a trial-based social competition assay in which mice compete for rewards, as well as a computer vision tool to track multiple, unmarked animals. With the development of a deep learning computer vision tool (AlphaTracker) and wireless electrophysiology recording devices, we have established a novel platform to facilitate quantitative examination of how the brain gives rise to social behaviors. We describe nine behavioral states during social competition that were accurately decoded from mPFC ensemble activity using a hidden Markov model combined with generalized linear models (HMM-GLM). Population dynamics in the mPFC were predictive of social rank and competitive success. This population-level rank representation translated into differences in the individual cell responses to task-relevant events across ranks. Finally, we demonstrate that mPFC cells that project to the lateral hypothalamus contribute to the prediction of social rank and promote dominance behavior during the reward competition. Thus, we reveal a cortico-hypothalamic circuit by which mPFC exerts top-down modulation of social dominance.

Basal forebrain cholinergic neurons are thought to modulate how organisms process and respond to environmental stimuli through impacts on arousal, attention, memory, and motivated behavior. We questioned whether basal forebrain cholinergic neurons are directly involved in conditioned behavior, independent of ancillary roles in stimulus processing. We found that cholinergic neurons are active during behavioral responding for a reward - even in the absence of reward or discrete stimuli. Photostimulation of cholinergic neurons in the basal forebrain or their terminals in the basolateral amygdala (BLA) selectively drove conditioned responding (licking), but not unconditioned licking nor innate motor outputs. In vivo electrophysiological recordings revealed reward-contingency-dependent-gating of cholinergic suppression of BLA neural activity during cholinergic photostimulation, but not dorsomedial prefrontal cortex (dmPFC). Finally, cholinergic terminals suppressed BLA projection neuron activity via monosynaptic muscarinic receptor signaling and facilitation of firing in GABAergic interneurons. Taken together, we show that cholinergic effects are modulated by reward contingency in a target-specific manner to promote conditioned responding. Given that the effects cholinergic photostimulation were modulated by rewards, our results constrain clinical goals of augmenting cholinergic function to improve neuropsychiatric symptoms.

Basal forebrain cholinergic neurons modulate how organisms process and respond to environmental stimuli through impacts on arousal, attention, and memory. It is unknown, however, whether basal forebrain cholinergic neurons are directly involved in conditioned behavior, independent of secondary roles in the processing of external stimuli. Using fluorescent imaging, we found that cholinergic neurons are active during behavioral responding for a reward – even in prior to reward delivery and in the absence of discrete stimuli. Photostimulation of basal forebrain cholinergic neurons, or their terminals in the basolateral amygdala (BLA), selectively promoted conditioned responding (licking), but not unconditioned behavior nor innate motor outputs. In vivo electrophysiological recordings during cholinergic photostimulation revealed reward-contingency-dependent suppression of BLA neural activity, but not prefrontal cortex (PFC). Finally, ex vivo experiments demonstrated that photostimulation of cholinergic terminals suppressed BLA projection neuron activity via monosynaptic muscarinic-receptor-signaling, while also facilitating firing in GABAergic interneurons. Taken together, we show that the neural and behavioral effects of basal forebrain cholinergic activation are modulated by reward contingency in a target-specific manner.

Basal forebrain cholinergic neurons modulate how organisms process and respond to environmental stimuli through impacts on arousal, attention, and memory. It is unknown, however, whether basal forebrain cholinergic neurons are directly involved in conditioned behavior, independent of secondary roles in the processing of external stimuli. Using fluorescent imaging, we found that cholinergic neurons are active during behavioral responding for a reward – even in prior to reward delivery and in the absence of discrete stimuli. Photostimulation of basal forebrain cholinergic neurons, or their terminals in the basolateral amygdala (BLA), selectively promoted conditioned responding (licking), but not unconditioned behavior nor innate motor outputs. In vivo electrophysiological recordings during cholinergic photostimulation revealed reward-contingency-dependent suppression of BLA neural activity, but not prefrontal cortex (PFC). Finally, ex vivo experiments demonstrated that photostimulation of cholinergic terminals suppressed BLA projection neuron activity via monosynaptic muscarinic-receptor-signaling, while also facilitating firing in GABAergic interneurons. Taken together, we show that the neural and behavioral effects of basal forebrain cholinergic activation are modulated by reward contingency in a target-specific manner.