Extrasynaptic Modulation of GABA Synapses in the Paraventricular Nucleus of the Hypothalamus
Abstract
Challenges within an organisms’ environment elicit an evolutionarily conserved, adaptive, physiological stress response. Investigations into stress circuits have revealed complex, overlapping systems maintaining homeostatic control over internal and external environments, ensuring survival. In this thesis, I studied stress response regulation in mice. A small population of corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) govern activation of the stress response. The output of these neurons is under dense inhibitory constraint. Using electrophysiological and optogenetic tools, I examined plasticity in the GABA system regulating CRH neuron activity. Here, I tested the general hypothesis that extrasynaptic modulation of GABA transmission in the PVN plays an important role in shaping the output of PNCs. I found many forms of communication rely on GABA spillover to maintain proper function. Upon entering the extrasynaptic space, GABA can bind presynaptic GABABRs to constitutively self-regulate GABA release, or bind to extrasynaptic GABAARs to tonically inhibit CRH neuron excitability. Next, I found that corticosterone alters the strength of extrasynaptic GABAARs directly. Next, I examined the role of endocannabinoids (eCB) in modulating GABA synaptic strength. I found activation of extrasynaptic mGluRs curtailed the duration of eCB actions at GABA terminals. Specifically recruiting eCB action at GABA synapses in the absence of glutamate allowed persistent eCB effects. In conclusion, research in this thesis provides novel findings for extrasynaptic modulation of CRH neurons that are likely to have broader implications in other brain regions.
Description
Keywords
Neuroscience
Citation
Colmers, P. (2017). Extrasynaptic Modulation of GABA Synapses in the Paraventricular Nucleus of the Hypothalamus (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28739