Differential impact of hypothalamic and hippocampal corticotropin-releasing hormone neurons on stress, cognition, and seizure susceptibility
regulation of the hypothalamic-pituitary-adrenal axis permits the adaptive, integrated
response to stress. Corticotropin-releasing hormone neurons in the paraventricular
nucleus of the hypothalamus reside at the apex of this stress signaling axis, so any
genetic or environmental insult to the normal modulation of their activity can
profoundly disrupt healthy stress signaling. ... read moreAdditionally, there exist
corticotropin-releasing hormone neurons in other brain regions, notably the hippocampus.
Much less is known about the function of this population, but it is thought to be
critical for stress effects on cognition. The main focus of my thesis work has been
twofold: first, to investigate the cellular mechanisms that regulate the activity of
hypothalamic corticotropin-releasing hormone neurons involving robust inhibitory
constraint by GABA and the rapid erosion of inhibition; and second, to explore the
characteristics and functional relevance of hippocampal corticotropin-releasing hormone
neurons, with particular emphasis on their stress-reactivity and impact on the
excitability of the hippocampal network. The relatively recent advent of genetic tools
to isolate specific cell types in the brain for identification and manipulation provided
the foundation for my investigations of these two neuronal populations: specifically, a
transgenic mouse line that expresses Cre recombinase under the control of the promoter
for the corticotropin-releasing hormone gene. For my investigations in the hypothalamus,
I combined this line with a Cre-dependent mouse line that abolishes the
chloride-extruding capacity of KCC2, in order to generate a mouse model exhibiting
impaired inhibitory constraint of the neuroendocrine stress response, enabling me to
study stress-related physiology and behavior which depend on this inhibitory constraint.
For my investigations in the hippocampus, I combined the Cre recombinase line with a
number of Cre-dependent molecular tools, including tracer viruses to study anatomical
connectivity, the light-activated cation channel Channelrhodopsin to study functional
connectivity and circuit-level effects, and Designer Receptors Exclusively Activated by
Designer Drugs to study effects of manipulating this population's activity on
hippocampal-dependent behavior and seizure susceptibility. I confirmed that inhibitory
constraint of hypothalamic corticotropin-releasing hormone neurons is critical for
regulating stress-reactive emotional behaviors, and helped to reveal that this
inhibitory constraint is compromised following seizures. Unexpectedly, I also uncovered
a novel projection from the hypothalamic population to the tuberal nucleus of the
lateral hypothalamus, as well as a possible functional role for this population in body
weight homeostasis. In the course of my hippocampus-oriented project, I characterized
back-projecting corticotropin-releasing hormone neurons as a novel interneuron
population. In addition to extensively characterizing the intrinsic properties of this
population, I also uncovered their functional relevance in hippocampal-dependent
learning and memory, excitability of the hippocampal network, and seizure
susceptibility. My results from studying hypothalamic chloride plasticity helped to
identify a mechanism that gives rise to the vicious cycle of mutual reinforcement
between pathological stress and seizures. This mechanism highlights KCC2 as a drug
target with great potential for alleviating stress-related disorders and seizures, and
breaking the vicious cycle between them. My characterization of back-projecting CRH
interneurons adds another layer of complexity to the circuitry of the hippocampus.
Additionally, my findings on CRH interneurons' impact on both the physiological function
of learning and memory, and the pathophysiology of seizure susceptibility, highlight the
importance of this interneuron class in hippocampal function. Finally, my results on the
circuit-level impact of manipulating these interneurons provide the beginning of a
mechanistic framework for how this single cell type contributes to a complex behavior,
while raising exciting new questions about the differential effects of synaptic versus
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Neuroscience.
Advisor: Jamie Maguire.
Committee: Maribel Rios, Stephen Moss, Leon Reijmers, and Kerry Ressler.
Keyword: Neurosciences.read less