Modulatory Neural Circuit Mechanisms Underlying Sex Differences In Visually-evoked Innate Fear Behavior

Fear emotion and associated behaviors are crucial for individual survival and successful reproduction within species.Emotional behaviors in response to fear exist in a wide range of species of multi-level evolutionary process,including zebrafish,fruit flies,rodents,non-human primates,and humans,and there is often sexual dimorphism of these behaviors.Appropriate fear responses can ensure that individuals escape from natural enemies and increase the survival chance,while the absence or abnormal amplification of fear can lead to suicide,anxiety and other mental disorders.Therefore,in-depth analysis of sex differences in fear behavior is crucial for understanding the mechanism underlying sex differences in fear disorders and thus developing more effective intervention and treatment strategies for fear-related psychiatric disorders.The ability of the central nervous system to process dangerous information that triggers fear responses tends to be"stored"in very evolutionarily conservative nuclei,such as subcortical regions.The superior colliculus(SC)is the"integration center"for the rapid processing of visual and other sensory and perceptual information,and participates in the regulation of multi-types of fear responses,such as visual innate fear and auditory innate fear.However,the specific cell types and circuits of the SC that are involved in fear processing,and the characteristics of sex differences arising from these,are not well understood.A variety of neurotransmitters and neuromodulators in the brain,such as glutamate,gamma-aminobutyric acid(GABA),dopamine,serotonin,endocannabinoid(e CB)etc.,play an important role in the regulation of fear and related mental disorders.The main component of the e CB system,the cannabinoid 1receptor(CB₁R),is highly conserved in evolution and participates in the regulation of a variety of emotions,including learned fear,anxiety,depression and a variety of innate behaviors,including maternal behavior,sleep,and feeding,etc.However,the regional and neural-circuit specificity of CB₁R,in the regulation of visual innate fear behavior,needs further analysis.This project applied a combination of high-precision animal behavior using a multi-view three-dimensional animal motion-capture system,refined neuronal circuit tracing,cell-type-specific gene deletion,in vivo recording of neuronal activity,real-time neurotransmitter detection based on fluorescence probes,optogenetics,in vitro electrophysiological recording and in situ hybridization technology.The research contents include:(1)characteristics of sex differences in visually-evoked innate fear behavior;(2)investigation of the key brain regions and associated upstream and downstream neural circuits involved in visually-evoked innate fear behavior,and(3)the regulatory mechanism of the endocannabinoid system in this circuit.We found(1)that male and female mice display have a similar ability to handle life-threatening cues by using different strategies,(2)sexual dimorphism of inputs to the lateral habenula in mice,and(3)the normal function of CB₁R in GABAergic terminals from superior colliculus to the lateral habenula is the biological basis for maintaining the same defensive ability of two sexes under normal condition.This study provides evidence that adds a great deal to our understanding of the pathogenesis of sex differences associated with fear disorders.