Neural Circuit Mechanisms Underlying Regulation Of Social Interaction Behavior By Basal Forebrain

Sociability is fundamental for our daily life and is compromised in major neuropsychiatric disorders.However,the neural circuit mechanisms underlying prosocial behavior are still elusive.With great change of living environment,the number of neuropsychiatric patients with social impairments is gradually increased,especially in the global epidemic of COVID-19 in 2020,which aggravates the common concern of mental health.Nearly 1 billion people around the world are threaten by mental problems,which makes it more urgent to figure out the mechanism of social behavior.We found that the inhibitory neurons in basal forebrain(BF)can control prosocial behavior by disinhibiting dopamine(DA)neurons in the ventral tegmental area(VTA)in the midbrain.The basal forebrain is a collection of brain structures located in the rostroventral forebrain and was traditionally defined by the presence of cholinergic projection neurons.Accordingly,previous studies have been mostly focused on cholinergic neurons and have revealed essential roles of this neuronal population in the regulation of arousal,attention,learning and memory.In addition to cholinergic neurons,the BF also comprises other major neuronal types including glutamatergic neurons and GABAergic neurons expressing either somatostatin(SST)or parvalbumin(PV).Recently,a diversity of brain functions has started to be unraveled for the non-cholinergic neuronal types in the BF as well.For instance,BF SST inhibitory neurons promote high-calorie food intake,yet glutamatergic neurons drive food avoidance through projections to the lateral hypothalamus.Also,cortically projecting BF PV inhibitory neurons regulate cortical gamma band rhythms.However,the functional role of the BF in social behavior and its neuronal substrate has not been investigated.In previous studies,neuronal structure abnormalities in the BF have been identified in patients with autism spectrum disorders(ASDs),which are characterized by severe impairments in social cognition and interaction.Consistently,brain imaging studies have also highlighted functional reduction of the BF in low-functioning autistic children.They suggested that BF may play a very important role in regulating social behavior.Recent neural tracing studies with advanced viral genetic tools reveal dense anatomical connections between the BF and the VTA.Given that VTA DA neurons are found to produce a rewarding effect and to mediate prosocial behavior by releasing DA in nucleus accumbens(NAc)during social interaction in mice,we hypothesized that the BF projections to the VTA may carry information important for prosocial behavior.Firstly,we found BF SST neurons were robustly activated during social interaction with fiber photometry.Optogenetic inhibition of these neurons in BF or their axon terminals in the VTA largely abolished social preference.Electrophysiological examinations further revealed that BF SST neurons predominantly targeted VTA GABA neurons rather than VTA DA neurons.Consistently,optical inhibition of BF SST neuron axon terminals in the VTA decreased DA release in the NAc during social interaction,confirming a disinhibitory action.These data reveal a previously unappreciated function of the BF in prosocial behavior through a disinhibitory circuitry connected to the brain’s reward system,and suggest a potential therapeutic target for social deficits commonly observed in major neuropsychiatric disorders.