Date of Award

8-31-2020

Document Type

Doctoral Dissertation - Open Access

Degree Name

Doctor of Philosophy

Department

Biochemistry and Molecular Biology

First Advisor

Esther L. Sabban, Ph.D.

Second Advisor

Susan OIson, Ph.D.

Third Advisor

John Pinto, Ph.D.

Abstract

Post-traumatic stress disorder (PTSD) is a debilitating psychological disorder that develops in a subset of individuals after exposure to a traumatic stress. Neuropeptide Y (NPY) an endogenous 36 amino acid neuropeptide expressed in many areas of the brain and periphery especially those involved in stress may confer resilience to the harmful effect of stress. We demonstrated changes in the Single Prolonged Stress (SPS) PTSD model and potential for their modulation by delivery of intranasal NPY to the brain. There was a progressive worsening of anxiety symptoms at two weeks compared to one week after SPS. Previously we showed that 150µg of NPY was effective to reverse anxiety, depressive-like and hyperarousal symptoms one week after SPS, however this dose was not sufficient to reverse anxiety symptoms two weeks after SPS when symptoms have become more severe. We determined that doubling NPY dose to 300µg was sufficient to reverse symptoms of anxiety, depression and hyperarousal two weeks after more severe symptoms have manifested. Activation of the NPY Y1R subtype was sufficient to prevent the development of SPS elicited anxiety, social impairment and depressive-like behavior. Moreover, intranasal delivery of [D-His26] NPY was superior to NPY for preventing depressive-like behavior and has promise as an early intervention therapy following traumatic stress. Significant molecular impairments in gene expression for corticotrophin releasing hormone (CRH) and neuropeptide Y (NPY) systems in the locus coeruleus (LC) and mediobasal hypothalamus were observed two weeks following SPS. There was a divergence in the expression levels of the norepinephrine transporter (NET) mRNA in the LC after SPS, some animals had significantly higher NET mRNA levels and some had levels were xii similar or lower than unstressed controls. Nevertheless, NET protein levels were reduced in the hippocampus; projection region, likely by increasing noradrenergic activation. The SPS triggered hyperarousal was associated with the changes in NET gene expression. Animals with increased startle response also had increased NET mRNA. Within the subgroup of animals that had a lower acoustic startle response, there was a significant negative correlation with NET mRNA expression. Furthermore, SPS showed a potential effect in the epigenetic regulation of the NET. Increased methylation of the NET gene promoter region was observed in the lower NET responsive group and was associated with a reduction in NET mRNA expression. Overall these results shed new insights into mechanisms for resilience or susceptibility to development of hyperarousal, a diagnostic feature of PTSD and that NPY or a specific Y1R agonist (D-His26)NPY can effectively treat core symptoms of PTSD in an animal model.

Download

Share

COinS