The Neural Circuits Of The Innate Defensive Behaviors Evoked By Visual Threat Signal And The Neural Mechanism Of The Adaptative And Non-adaptative Defensive Behaviors

Fear emotion is very important for perceiving potential dangerous information in the external environment,avoiding natural predators,and decision rapid defensive responses.Fear is one of the most basic and indispensable emotional representations for maintaining species reproduction and survival.Instinctive response is a specific and inherently conservative behavioral responses pattern in species evolution.Fear of natural predators is an inherent instinct formed during the survival,reproduction and evolution of species.By mean of visual system,the brain can quickly identify the dangerous information of natural predators in environmental cues,such as the appearance,size,moving direction and moving speed of natural predators.How to fast detect the dangerous signals of natural predators and select appropriate defensive response strategies according to environmental cues,whether there are modular neural nucleus in the brain,or whether there are specific neural circuits or specific neural matrix to mediate the fear processing of visual threat stimuli? A single experience without repetition is not biologically significance.What is valuable in biology is the learning of situational adaptability by organisms.Fear emotion is the combination of unconscious physiological defense response of fear and conscious fear,which is the product of adaptive learning in the evolution of species.The adaptive learning mechanism of instinctive fear helps us to understand the neural base of constructing conscious fear.Therefore,the study of the relationship between innate fear and learnd fear is an important research direction of neuroscience in the future.By using optogenetics,in vivo electrophysiology,pharmacogenetics,in vivo fiber photometry,neurotrophic virus-based neural loop tracing and other techniques,combined with behavioral paradigms such as upper visual field looming stimulus,learned fear and learned reward paradigms,the study has proved that: 1)VTA GABA neurons and DA neurons are involved in the upper visual field visual threat detection,2)On the condition that,"having a nest to escape",the CaMKIIa-positive neurons in the intermedial and deeper layer of the superior colliculus to VTA pathway mediate the defensive responses evoked by upper visual field looming stimulus,3)VTA GABA neurons are essential for "flight-to-the nest" defensive responses evoked by visual threat signal,4)VTA DA neurons are not essential for the "flight-to-the nest" behavior evoked by visual threat signal,5)Long projection VTA GABAergic neurons projected into the central amygdala mediate the defensive response evoked by visual threat signal,6)VTA VGLUT2 neurons respond strongly to unpredictable positive reward stimuli and negative fear stimuli(foot shock),7)VTA VGLUT2 plays a different role in the conditioning and retrieval phase in the positive reward conditioning and negative fear conditioning.VTA VGLUT2 is involved in the formation of conditioned fear memory but may not be so sensitive to reward memory.Although instinctive behavior is relatively conservative and innate,the complexity and variability of instinctive defensive behavior can be regulated by individual experience,environmental factors and the internal state of the brain.The activation of the survival circuit of instinctive defense also activates the cognitive system of emotion,motivation,learning and attention,which is the neural basis of instinctive fear acquisition.By combined using in vivo optical fiber calcium imaging,graphical theory analysis based on c-Fos protein expression,neurochemical retrograde labeling and optogenetics,we have proved that 1)long-term gentle handling reduces the intensity of visual instinct fear response and the activity level of neurons in the intermedial layer and deeper layer of superior colliculus,2)long-term gentle handling changes the response of brain network to visual innate fear,and 3)Intermedial layer and deeper layer of superior colliculus are the "node" connecting sensory input and instinctive fear neural network,it can accept extensive connections from cortex,thalamus,hypothalamus,brainstem and autonomic nervous system,4)In natural state,wild-type mice can be induced two type subpopulation of adaptability to repetitive upper visual field looming stimulus,one is “adaptive” defensive fight behavior sub-type and the other is “non-adaptive” defensive flight behavior,5)Optogenetic stimulation CaMKIIa-positive neurons to ventral tegmental area pathway can produce “non-adaptive” defensive flight behavior,6)By using stimulation CaMKIIa-positive neurons to ventral tegmental area pathway as unconditioned stimulus and tone as conditioned stimulus,the mice can established fear conditioned and induced long-term fear memory.The abnormality of neural circuits in dealing with innate fear and learned fear is an important mechanism of psychiatric disorders such as phobia,anxiety disorder and post-traumatic stress disorder.Therefore,the analysis of the neural circuits of innate fear and learned fear can help us understand the "fear affective disorder" diseases and find the intervention targets for rehabilitation and treatment of these diseases.Environmental and experience-dependent activities can change the state of brain network,which may help us to understand the enhancement of brain plasticity by the input of experience and environmental information through the variation mechanism of epigenetic molecular level,leading to individual and personality differences.If we can analyze the cognitive function caused by epigenetic changes of specific neurons in specific brain regions.Emotional changes may help us to analyze the molecular genetic epigenetic differences of affective disorders.Drug targeting epigenetic levels,such as methylation,acetylation,phosphorylation sites of small molecular drugs,may be expected to treat psychiatric and neurological diseases at the molecular and genetic levels.