Neural circuitries and neurobiological mechanisms relevant to stress resilience

摘要

Experiencing stressful life events increase the risk of later developing anxiety and depressive disorders While everyone experiences their stressful events there is considerable heterogeneity in responses Fear conditioning in animals has been used extensively to model clinical anxiety disorders Each individual exhibits marked differences in their propensity to undergo fear conditioning the physiologically relevant mediators and neuronal network have not yet been fully characterized In the present study we grouped the stress-resistant and stress-susceptible C57BL/6 inbred mice by chronic social defeat stress (CSDS) and social interaction test (SIT) paradigms They display different levels of fear responses in an auditory fear conditioning paradigm while there were no significant differences between groups in innate anxiety- and depressive-like behaviors Susceptible mice had significantly more c-Fos protein expression in neurons of the basolateral amygdala (BLA) after experiencing the conditioning Through the use of conditional brain-derived neurotrophic factor (BDNF) knockout strategies we find that elevated BLA BDNF level following fear conditioning training is a key mediator contributing to determine the levels of conditioned fear responses Results also show that relative to susceptible mice resistant mice had a much faster recovery from conditioned stimuli-induced cardiovascular and corticosterone responses Systemic administration of norepinephrine reuptake inhibitor atomoxetine increased c-Fos protein expression in BLA neurons following fear conditioning training and promoted the expression of conditioned fear in resistant mice Conversely administration of β-adrenergic receptor antagonist propranolol reduced fear conditioning training-induced c-Fos protein expression in BLA neurons and reduced conditioned fear responses in susceptible mice Furthermore by using bidirectional optogenetic manipulations and retrograde tract-tracing technique we demonstrate that the degree of prefrontal cortex (PFC) projection control of BLA activity modulates the levels of conditioned fear responses via regulating BDNF released from BLA In conclusion the data establish that naturally occurring differences in conditioned stimuli-induced BDNF release from the BLA functionally mediate individual differences in the acquisition and expression of conditioned fear and that PFC inputs to the BLA uniquely regulate the susceptibility to fear conditioning

獎項日期	2016 8月 3
原文	English
監督員	Kuei-Sen Hsu (Supervisor)