The Distinctive Role Of Parvalbumin And Somatostatin Interneuron In Anterior Cingulate Cortex Underlying Social Recognition Behavior In Mice

Social behavior is an indispensable survival skill for social species,which is important for population maintenance and offspring reproduction.In fact,there are different types of social behaviors,such as social recognition,social hierarchy,social fear,courtship behavior,and parenting behavior.Among them,social recognition includes the ability to recognize unfamiliar conspecifics and distinguish between unfamiliar and familiar individuals.As the basic function of many social behaviors,social recognition behavior has been well preserved in evolution due to its importance in social life.Exploring the neural circuit mechanism of social behavior is not only of great significance for constructing the whole brain functional network and understanding the working process of the nervous system,but also has important reference value for the pathogenesis of related diseases,such as autism.Anterior cingulate cortex(ACC)plays an important role in the regulation of cognition,emotion,learning,and pain.Previous studies of others and our previous work have confirmed that ACC plays an important role in social behavior.ACC mainly consists of glutamatergic pyramidal neurons and GABAergic inhibitory interneurons.Pyramidal neurons of the ACC form projective circuits with the neurons of other brain regions to perform related functions.While inhibitory neurons form local microcircuit with pyramidal neurons or inhibitory neurons themselves and fine tune the functional stability of ACC by regulating pyramidal neurons.In recent years,many researches on the circuit mechanism of different social behaviors have been carried out.But they mainly focus on social hierarchy regulation,courtship and mating behavior,and social fear.However,there still is a lack of research on the circuit mechanism of basic social recognition behavior.In addition,studies of the role of ACC in social behavior have paid less attention than other cortex or regions such as the thalamus and amygdala.We have previously observed that there is a significant causal relationship between social recognition disorder and ACC pyramidal neuron dysfunction in mice with autism,suggesting that ACC pyramidal neurons play an important role in social recognition behavior.So,as the key factor of fine-regulating ACC function,what role of GABAergic interneurons play in social recognition?This becomes a meaningful scientific question,which is also the focus of our study.We explored it from the following three aspects:Part Ⅰ:The different roles of PV positive and SST positive neurons in ACC in social recognition.Objective:To investigate the activity changes of Parvalbumin(PV)-positive and Somatostatin(SST)-positive ACC interneurons during social recognition.Methods:The activity characteristics of PV-positive and SST-positive interneurons in ACC during social recognition were observed by using in vivo fiber photometry recording calcium signal,optogenetics method,and virus intervention,combined with social recognition behavior.Results:The fiber photometry recording showed that the activity of PV-positive and SST-positive interneurons was reduced during active social recognition behavior.But the decrease in PV-positive interneurons is more significant comparing with SST-positive interneurons.The activity of SST-positive neurons reduced significantly in social preference behavior.These two kinds of interneurons could inhibit social recognition behavior by optogenetic excitation.The PV-positive interneurons inhibited social recognition ability more significantly,while SST-positive neurons preferred to affect social preference behavior.Photogenetic inhibition of the two interneurons showed no significant effect on the regulation of social recognition behavior.Apoptosis of PV-positive neurons by apoptotic virus increased social exploration behavior,while apoptosis of SST-positive neurons increased interaction time with unfamiliar objects.Conclusion:Both PV-positive and SST-positive interneurons in ACC are involved in the regulation of social recognition behavior.PV-positive neurons tend to regulate active social exploration behavior,while SST-positive neurons play a significant role in social preference behavior.Part Ⅱ:The potential synaptic and excitability mechanisms of PV-positive and SST-positive neurons in ACC to regulate differences in social recognition behavior.Objective:To explore the difference of inhibitory synapse transmission between PV-positive and pyramidal neurons or SST-positive and pyramidal neurons in ACC and the characteristics of excitability.Methods:The function of inhibitory synapses formed between PV-positive interneurons and pyramidal neurons or SST-positive interneurons and pyramidal neurons in ACC was recorded by photogenetics combined with patch clamp technique.The passive and active membrane properties of PV-positive and SST-positive interneurons in ACC were recorded by patch clamp technique in vitro.Results:The optogenetic exciting PV-positive interneurons or SST-positive neurons in layer II and III can induce a post-synaptic current in pyramidal neurons,which can be blocked by GABA_Areceptor blockers,indicating that the current recorded are IPSCs.The inhibitory effect of PV-pyramidal synapse is significantly stronger than that of SST-pyramidal synapse.The two kinds of interneurons have their unique firing pattern and different passive membrane properties.Conclusion:The difference in social recognition behavior of PV and SST positive interneurons in ACC may be related to the difference in inhibitory innervation of PV and SST neurons to pyramidal neurons.And the difference in discharge pattern and passive membrane properties of the two types of interneurons may be caused by the expression of different receptors and ion channels.Whether these factors lead to the differential regulation of social recognition behavior between PV positive neurons and SST positive neurons needs to be further investigated.Part Ⅲ:The differences of circuit mechanism of PV-positive and SST-positive neurons in ACC region regulating social recognition behavior.Objective:To explore the difference of circuit mechanism of PV-positive and SST-positive interneurons in ACC.Methods:The upstream brain regions of PV-positive and SST-positive interneurons in the ACC region were traced by a retrograde trans-synaptic virus.The projection properties of PV and SST neurons from the upstream brain region to the ACC region were verified by patch clamp combined with optogenetics.The regulation of PV and SST neuron projective circuits in vivo was observed by using photogenetics and calcium signal fiber recording technology.Results:PV-positive neurons and SST-positive neurons in the ACC region shared most upstream brain regions.However,there are also some differential projections,among which LPMR(lateral posterior thalamic nucleus,mediorostral part,LPMR)region forms obvious projections with PV positive neurons,while v HPC(ventral hippocampus,v HPC)prefers to project to SST.Both LPMR to PV(ACC)and v HPC to SST(ACC)synapses were glutamatergic which was proved by patch clamp and optogenetics.Optogenetic activation of their upstream brain regions could increase the activities of the PV-positive or SST-positive neurons in ACC.Moreover,excitation of LPMR-PV(ACC)pathway can inhibit the social recognition ability of mice but does not affect the social preference behavior of mice.Excitation of v HPC-SST(ACC)synapse reduced the social preference ability of mice,but had no significant effect on the social exploration behavior of mice.Conclusion:LPMR-PV(ACC)is involved in the regulation of active social exploration behavior in mice;the projection of v HPC-SST(ACC)is involved in the regulation of social preference behavior in mice.Conclusion:PV positive and SST positive neurons in the ACC region can regulate the social recognition ability of mice.Among them,PV-positive neurons have a more significant regulation effect on active social exploration behavior,which may be related to the projection of the LPMR to ACC-PV neurons.The regulation of social preference ability in mice with SST-positive was more obvious,which might be related to the projection of v HPC region to ACC-SST neuron formation.