All ETDs from UAB

Advisory Committee Chair

Lynn E Dobrunz

Advisory Committee Members

Linda Wadiche-Overstreet

Lori L McMahon

Craig Powell

Karen Gamble

Document Type

Dissertation

Date of Award

2021

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Anxiety disorders are the most common neuropsychiatric disorders diagnosed in adolescence and adulthood. While most animal models of trauma and stress-related disorders are performed in adults, and clinical trials for the treatment of these disorders typically include adult patients, there is a gap in knowledge for understanding how traumatic disorders develop in adolescence. Neuropeptide Y (NPY) is an endogenous peptide that provides anxiolytic benefits, and promotes feeding, arousal, and reduces inflammation. While being reduced in patients with depression and post-traumatic stress disorder (PTSD), animal models using NPY injections directly in to hippocampus have found it to be sufficient for blocking the effects of stress. For these reasons, intranasal NPY administration has been investigated in clinical trials for the treatment of PTSD in adult patients. There remains a gap in knowledge in understanding how Neuropeptide Y is affected by stress during adolescence and the mechanisms by which this peptide may influence circuit function. A major finding of my dissertation research is that traumatic stress actually increases hippocampal NPY levels in adolescent rodents, while NPY is reduced in adulthood. Additionally, I found that NPY overexpression impairs receptor sensitivity to exogenous NPY at critical synaptic inputs to area CA1, the temporoammonic pathway (TA). This finding is important because I provide the first piece of evidence that area CA1 can be modulated by two separate NPY receptor subtypes, the Y1 receptor which becomes impaired in the presence of chronically elevated NPY levels and the Y2 receptor which remains functional despite elevations in NPY levels. Overall, my research implicates NPY signaling in hippocampus, and the TA-CA1 synapses as key targets to study in the development of stress- or trauma-related disorders, particularly in adolescents and young adults. Importantly, this work highlights that adult data cannot simply be extrapolated to adolescents because there may be underlying biological differences.

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