Differential Regulation of Neuropeptide Y in the Amygdala and Prefrontal Cortex during Recovery from Chronic Variable Stress

Accumulating evidence from clinical studies and pre-clinical animal models supports a role for neuropeptide Y (NPY) in adaptive emotional response following stress. The long-term impact of stress, particularly chronic stress, on availability, and function of resilience factors such as NPY may be critical to understanding the etiology of stress-related psychopathology. In these studies, we examined expression of NPY during recovery from a chronic variable stress (CVS) model of repetitive trauma in rats. Due to the importance of amygdala and prefrontal cortex in regulating emotional responses, we predicted chronic changes in NPY expression could contribute to persistent behavioral deficits seen in this model. Consistent with the hypothesis, ELISA for NPY peptide identified a significant reduction in NPY at the delayed (7 days) recovery time-point. Interestingly, a significant increase in prefrontal NPY was observed at the same recovery time-point. The mRNA expression for NPY was not changed in the amygdala or PFC, although there was a modest but not statistically significant increase in NPY mRNA at the delayed recovery time-point in the prefrontal cortex. The observed changes in NPY expression are consistent with maladaptive coping and enhanced emotionality, due to the nature of NPY signaling within these respective regions, and the nature of reciprocal connections between amygdala and prefrontal cortex

Neural Control of Chronic Stress Adaptation

Stress initiates adaptive processes that allow the organism to physiologically cope with prolonged or intermittent exposure to real or perceived threats. A major component of this response is repeated activation of glucocorticoid secretion by the hypothalamo-pituitary-adrenocortical (HPA) axis, which promotes redistribution of energy in a wide range of organ systems, including the brain. Prolonged or cumulative increases in glucocorticoid secretion can reduce benefits afforded by enhanced stress reactivity and eventually become maladaptive. The long-term impact of stress is kept in check by the process of habituation, which reduces HPA axis responses upon repeated exposure to homotypic stressors and likely limits deleterious actions of prolonged glucocorticoid secretion. Habituation is regulated by limbic stress-regulatory sites, and is at least in part glucocorticoid feedback-dependent. Chronic stress also sensitizes reactivity to new stimuli. While sensitization may be important in maintaining response flexibility in response to new threats, it may also add to the cumulative impact of glucocorticoids on the brain and body. Finally, unpredictable or severe stress exposure may cause long-term and lasting dysregulation of the HPA axis, likely due to altered limbic control of stress effector pathways. Stress-related disorders, such as depression and PTSD, are accompanied by glucocorticoid imbalances and structural/ functional alterations in limbic circuits that resemble those seen following chronic stress, suggesting that inappropriate processing of stressful information may be part of the pathological process