Occasional stress is a normal aspect of mammalian life. However repeated or prolonged stress exposure dysregulates stress responses and contributes to the onset or exacerbation of affective disorders such as anxiety, depression and post-traumatic stress disorder (PTSD). Understanding the underlying mechanism of the effect of stress on affective behaviors is essential for effective prevention and treatment of these disorders.
All affective disorders share a deficit in the regulation of emotion. The amygdala plays crucial role in this regulation and is adversely affected by stress. This suggests that stress precipitates abnormal affective state by altering amygdala function. While the effect of acute stress on the amygdala has been well described, less is know about the impact of repeated stress nor its age-dependency. We hypothesized that repeated stress leads to a hyperactive amygdala and impairs the amygdala function in regulating affective behaviors, and such impacts are greater during prepubescence than during adulthood. In this study, we subjected prepubescent (postnatal day, PND ∼30) and adult rats (PND ∼65) to repeated restraint stress. We then measured the effect of stress on amygdala physiology and amygdala-dependent behavior in prepubescent (PND ∼40) and adult (PND ∼75) rats. The results were compared between age-matched non-restraint and repeated restraint groups and across age. Repeated restraint stress increased basolateral amygdala (BLA) spontaneous population activity in prepubescent rats whereas it enhanced individual neuron activity in adult rats. In parallel with these physiological changes, repeated restraint stress enhanced initial expression of conditioned fear in both age groups, but impaired within session fear extinction only in prepubescent rats. Further studies demonstrated that repeated restraint stress reduced the BLA projection neuron inhibition by exogenous GABA in prepubescent rats. However, repeated restraint stress enhanced the BLA projection neuron excitation by exogenous glutamate in adult rats. In addition, repeated restraint reduced basal GABA transmission and enhanced mPFC-induced excitation of spontaneously active BLA projection neurons in both age groups. Together, these findings indicate that repeated restraint results in a generalized hyperactive and hyper-responsive amygdala. The distinct changes in amygdala physiology at different developmental stages might underlie age-dependent effect of stress on affective behaviors. Overall, this study leads to a better understanding of the pathophysiology of stress-related affective disorders and provide insight into age-specific treatment of these disorders.
|Advisor:||Rosenkranz, Jeremy A.|
|Commitee:||Marinelli, Michela, Stutzmann, Grace E., Urban, Janice H., West, Anthony|
|School:||Rosalind Franklin University of Medicine and Science|
|Department:||Cellular & Molecular Pharmacology|
|School Location:||United States -- Illinois|
|Source:||DAI-B 74/10(E), Dissertation Abstracts International|
|Keywords:||Adolescent, Amygdala, Electrophysiology, Fear conditioning, Gaba, Stress|
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