Master of Science
The stress response is essential for survival, but it can be detrimental when persistently activated during chronic stress. Therefore, the magnitude of the stress response must be finely-tuned in order to be adaptive. Indeed, an animal’s stress response system normally undergoes habituation that decreases responses to a repeated, familiar stressor. Importantly, the same animal still responds normally, or even becomes sensitized, to an unfamiliar (novel) stressor. This indicates that chronic stress simultaneously induces two opposing types of plasticity, one that underlies habituated responses and another that drives sensitized responses. The activation of the hypothalamic-pituitary-adrenal (HPA) axis — a hallmark of the stress response — relies on the release of corticotropin releasing hormone (CRH) from neuroendocrine neurons in the paraventricular nucleus of the hypothalamus (PVN). Our recent study found that, in a mouse model of habituation to a repeated stressor, the intrinsic excitability of CRH neurons decreases (representing a potential mechanism for habituation to a familiar stressor). In this thesis, we investigated a potential mechanism that enables a sensitized response to an unfamiliar stressor in the same habituation model. Considering that afferent glutamatergic synapses are the major excitatory inputs onto CRH neurons, we hypothesized that potentiation of these excitatory synapses represents a neural correlate for sensitized responses to an unfamiliar stressor. By using patch clamp electrophysiology, we studied glutamatergic synaptic transmission onto CRH neurons in ex vivo brain slices. In support of our hypothesis, we found that habituation to repeated stress potentiated glutamate synapses onto CRH neurons. More specifically, this potentiation manifested as a sensitization to cAMP signaling that facilitated the release of glutamate. Furthermore, we revealed that cAMP-induced facilitation of glutamate release was dependent on presynaptic hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels. This result identifies a possible mechanism that supports stress sensitization of the HPA axis and suggests a novel role for HCN channels in the PVN.
Sunstrum, Julia KJ, "Synaptic Correlates For Stress Sensitization" (2018). Electronic Thesis and Dissertation Repository. 5684.
Available for download on Saturday, August 01, 2020