Date of Award

11-17-2022

Document Type

Doctoral Dissertation - Open Access

Degree Name

Doctor of Philosophy

Department

Biochemistry and Molecular Biology

First Advisor

Esther L. Sabban

Abstract

The incidence of many stress-elicited disorders is markedly influenced by sex. Women are twice as likely as men to develop posttraumatic stress disorder (PTSD), depression, anxiety disorders, and social impairments following exposure to traumatic stress. However, most of the studies in animal models examining putative therapeutics for stress-triggered impairments, including single prolonged stress (SPS), were performed predominantly with males. Previous studies in males demonstrated that intranasal neuropeptide Y (NPY) can provide therapeutic relief of many SPS-triggered symptoms. Nevertheless, the overwhelming majority of studies found that NPY levels in females in many brain regions are lower than in male rodents. NPY processing by proteolytic enzymes, such as dipeptidyl peptidase IV (DPP4), may contribute to decreased full-length NPY levels. Here, we examined SPS as an appropriate model to elicit many PTSD-associated symptoms in females, whether intranasal NPY is able to alter the development of SPS-triggered behavioral impairments and factors that may contribute to NPY dosage requirement for females. Sprague Dawley, SPS-exposed female rats were compared to unstressed controls on forced swim test (FST) for depressive/despair behavior and for levels of expression of several genes in the locus coeruleus (LC) 12 days after SPS exposure. Using a separate cohort of animals, stressed females and unstressed controls were examined on the elevated plus maze (EPM) for anxiety behavior and LC gene expression 7 days after SPS stressors. Starting at 7 days after SPS, the third cohort of stressed females was tested on several behavioral tests, including the open field test (OFT) and EPM for anxiety and for social interaction. Immediately after the SPS stressors in experiment 1, 2 and 3, female rats were given intranasal NPY at 150 µg, 300µg and 600µg, respectively, or the vehicle. To further investigate a dose-response effect of NPY, SPS-exposed females were immediately infused intranasally with one of several doses, starting with 600µg/rat - 4 times the dose effective in males – and tested for depressive/despair behavior on the FST more than 14 days afterwards. In a fifth cohort of animals, females were infused intranasally with either 600μg NPY, omarigliptin (a DPP4 inhibitor), or both right after the SPS stressors. After 14 days they were tested on several behavioral tests. Lastly, CSF was collected from male and female rats 30 min after intranasal delivery of NPY and its levels were measured to assess potential differences in intranasal uptake of the peptide. SPS elicited significant depressive/despair like behavior on the FST, anxiety behavior on the OFT and EPM, as well as impaired social interaction. Following FST, the rats displayed elevated tyrosine hydroxylase (TH), CRHR1 and Y1R mRNA levels in the LC, consistent with increased activation of the noradrenergic system. The expression level of these mRNAs was unchanged following EPM, except Y1R. On the FST, there was a dose-response effect of intranasal NPY, with 1200µg, but not 600µg, preventing development of the SPS-elicited depressive-like behavior. The omarigliptin and 600µg NPY combined treatment, but neither alone, was also sufficient at preventing depressive-like behavior on the FST. This combined treatment did not significantly prevent the development of anxiety behavior on the OFT and EPM or impaired social interaction. The results demonstrate that: (1) SPS elicits several behavioral manifestations and molecular indicators of PTSD in females; (2) early intervention with a high dose of intranasal NPY has therapeutic potential also for females; (3) NPY cleavage by DPP4 may play a role in the higher dose requirement for females.

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