Modulation of hypothalamic synapses by stress: variations on a theme of retrograde signalling

Date
2013-12-18
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Physiological or psychological stress challenges recruit an evolutionarily hardwired endocrine stress response resulting in surges of glucocorticoids (GCs) into the blood. This adaptive response is orchestrated by a cluster of parvocellular neuroendocrine cells (PNCs) located in the paraventricular nucleus of the hypothalamus (PVN). Homeostatic control of stress responses is determined by a) GC feedback and b) synaptic connections from brain stress-circuits to PNCs. This is obligatory for survival, and yet PNC responses are also extremely plastic over the course of life. What cellular and synaptic mechanisms could mediate such learning and memory is largely unknown. Here, I tested a hypothesis that PNCs exhibit a capacity for autoregulatory control over information carried by incoming GABA and glutamate synapses. Furthermore, I hypothesized that adaptive stress responses could be achieved through dynamic regulation of this/these mechanisms by a history of stress/GC exposure. Using electrophysiological recordings from rodent PNCs, I found that increases in PNC activity caused suppression of both GABA/glutamate neurotransmitter release. First, brief bouts of PNC activity liberated endocannabinoids (eCBs) that acted as retrograde signals to transiently suppress neurotransmitter release. In further exploring this mechanism, I found that stress/GCs acutely potentiated signalling, while accumulations of predictable or novel stress challenges over time led to bimodal shifts in CB1 receptor (CB1R) function at presynaptic terminals. Under these circumstances I found that CB1R function is regulated by presynaptic activity state, reflecting stressor valence-dependent shifts in stress-circuit activity. I next found that sustained periods of synaptic and PNC activation caused persistent suppression of GABA/glutamate release through somatodendritic release and retrograde actions of opioids. Here, acute stressor exposure, through PNC GC receptor activation, was a metaplastic switch that was necessary for opioid release. Lastly, I investigated a transgenic approach that can be used in future studies to test the role of discrete cellular mechanisms in PNC neurons in vivo. Together the data in this thesis provide comprehensive evidence for how adaptive and homeostatic control over PNC activity during stress challenges may be mediated by embedded eCB and opioid circuit breaker mechanisms.
Description
Keywords
Neuroscience
Citation
Wamsteeker, J. (2013). Modulation of hypothalamic synapses by stress: variations on a theme of retrograde signalling (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/26979