Date of Award
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Neuroscience
First Advisor
Sayamwong E. Hammack
Second Advisor
Margaret A. Vizzard
Abstract
Depression is among the most prevalent mental health disorders and represents a significant healthcare burden in the modern world. Depression is a very heterogenous disorder which can present a variety of different behaviors, two of the most common being despair and anhedonia—which is a reduction in pleasure from normally pleasurable stimuli. Despite its prevalence, many treatments for depressive disorders lack efficacy and can even make symptoms worse in some cases. The inefficiency of treatments is at least in part due to an incomplete understanding of the neurocircuitry underlying depression
Pituitary adenylate cyclase activating polypeptide (PACAP) is a highly conserved neuropeptide expressed widely throughout the brain and periphery which has high affinity for the PAC1 receptor. Here, we identified a novel PACAP-expressing pathway originating in the bed nucleus of the stria terminalis (BNST) and terminating in the dorsal medial habenula (dMHb). PACAP, the BNST, and the MHb have all been independently identified to be implicated in depression-like behavior in rodent models. Here we aimed to show that PACAP signaling in the MHb is sufficient and necessary for depression-like behavior and that chemogenetic activation of the PACAPergic BNST-to-dMHb circuit can similarly induce such behavior, placing the circuit proposed herein within the known depressogenic circuitry.
To test the sufficiency of PACAP signaling in the MHb in depression-like behavior, we infused the MHb of male rats with PACAP prior to sucrose preference testing (SPT) and the forced swim test (common tests for anhedonia and despair-like behavior, respectively). We saw decreased sucrose intake and increased immobility time, indicating that PACAP infusion to the MHb was sufficient to induce depression-like behavior in male rats. Interestingly, replicating the SPT in female rats was not significant, warranting future investigation into potential sex differences in this circuit. A null effect on SPT following the infusion of the closely related vasoactive intestinal peptide (VIP) to the MHb of male rats indicates the previous effects were PAC1 receptor dependent. We also showed that activation of the PACAP-expressing cells originating in in the BNST and terminating in the dMHb of PACAP-cre mice also reduced sucrose preference, further bolstering the proposed circuit. Finally, we saw that 14 days of chronic variate stress was able to significantly reduce sucrose preference, and that infusion of PAC1 antagonists PACAP(6-38) and JF-214 is able to block the anhedonic effect of chronic stress—showing the necessity of PAC1 activation in the MHb for anhedonia-like behavior on the SPT.
From these studies, we can conclude that PACAP signaling from the BNST to the dMHb is a novel node on the neurocircuitry underlying depression. Further understanding of the neurological underpinnings of depression is vital for getting the field closer to developing more viable treatments for the often-debilitating disorder.
Language
en
Number of Pages
202 p.
Recommended Citation
Fontaine, Nicholas Roderick, "Identification And Characterization Of A Novel Pituitary Adenylate Cyclase Activating Polypeptide (pacap) Circuit In Depression-Like Behaviors" (2025). Graduate College Dissertations and Theses. 2026.
https://scholarworks.uvm.edu/graddis/2026
