Hippocampal Contributions to Stress: What the Hippocampus Tells the HPA Axis and What Could Go Wrong?
AdvisorThompson, Scott M.
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AbstractThe links between stress and psychiatric illnesses are numerous and bidirectional. Stress is highly correlated to psychiatric illness, increasing the risk of illness and often precipitating its onset. The primary class of neuroendocrine stress hormones, glucocorticoids, is often dysregulated in patients with major depression. Understanding the neurobiological changes underlying these findings is crucial for the development of improved therapeutic strategies and better patient outcomes. Prior work suggests that the hippocampus is stress-sensitive, substantially altered in major depression, and plays an important regulatory role in HPA axis function. Our understanding of the processes regulating the stress response is incomplete, particularly in regards to the various brain regions responsible for its central regulation. In this document I strive to clarify our understanding of a specific component of stress regulation, namely the hippocampal contribution, which could prove important to understanding the various links between stress and psychiatric illness. To do this, I targeted the ventral hippocampus with injections containing virus that expressed the light-sensitive ion channel channelrhodopsin (ChR-EYFP) in glutamatergic neurons. I determined the extent of glutamatergic hippocampal terminal expression in brain regions thought to regulate the paraventricular nucleus of the hypothalamus (PVN), and then stimulated those terminals while recording from corticotropin-releasing factor-positive (CRF+) neurons in the PVN in a whole-cell voltage clamp recording configuration. Using parasaggital brain sections, I was able to induce optically-evoked inhibitory post-synaptic currents in CRF+ neurons of the PVN, demonstrating the first direct functional evidence of hippocampal inhibition of the PVN. I used a similar injection scheme to record GAD+ neurons in the BNST. Finally, I utilized in vivo optical stimulation of hippocampal terminals within the BNST during acute restraint stress and observed a significant decrease in circulating levels of corticosterone. My data indicates that the hippocampus sends dense projections to the BNST and optical excitation of these hippocampal terminals produce inhibitory currents in CRF+ neurons of the PVN. Our data suggests a disynaptic hippocampus-BNST-PVN circuit of regulation by which the hippocampus inhibits the CRF+ PVN cells. The in vivo results indicate that the hippocampal inhibition of these neurons is capable of functionally inhibiting the HPA axis.
DescriptionUniversity of Maryland, Baltimore. Physiology. Ph.D. 2022
Keywordbed nucleus of the stria terminalis (BNST)