Cognitive and affective deficits after chronic stress: role of inhibitory circuits

Wan-Yan-Chan, Derek L. (2023) Cognitive and affective deficits after chronic stress: role of inhibitory circuits. Masters thesis, Memorial University of Newfoundland.

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Abstract

Major depressive disorder (MDD) is a debilitating neuropsychiatric disease that affects millions of people worldwide. With an increasing prevalence, it is imperative to find a cure for such disorder. Stress is a major risk factor of MDD and thus understanding the pathophysiological mechanism underlying the onset of stress-dependent depression could translate into possible future therapies. In the present study, we investigated if different stress exposure duration, short-term (ST-UCMS) and long-term stress (LT-UCMS), would result in distinct phenotypic profile in a mouse model of depression. We found that LT-UCMS resulted in increased more anhedonia-like symptoms than ST-UCMS and surprisingly, LT-UCMS exposure enhanced cognitive abilities. Both stress duration increased the expression of small-conductance calcium-dependent potassium channel subtype 3 (SK3C) mRNA within somatostatin (SST)- and parvalbumin (PV)-positive neurons. Furthermore, LT-UCMS regimen resulted in significantly higher SK3C-SST and SK3C-PV co-expression levels in the medial prefrontal cortex and nucleus accumbens, respectively. A sex- and region-specific increase in SST mRNA was reported after LT-UCMS exposure only. Notably, after LT-UCMS exposure, stressed females show a significant increase in SK3C-PV co-expression level in the NAcc, which was not observed in males. Similarly, females expressed higher level of SST mRNA in the mPFC after LT-UCMS exposure compared to males, and regarding PV mRNA, only males showed a significant decrease in NAcc, whereas for the CA1 region, only females had a decrease. Our results demonstrate that the length of stress exposure is a determinant factor in the onset of MDD and its effects could be mediated through differential transcriptomic profiles.

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