ORCID
https://orcid.org/0000-0002-1434-7385
Date of Award
12-12-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Norepinephrine, a wakefulness-associated neuromodulator, profoundly reshapes neural systems, from synaptic circuits to behavior. Through decades of research, a substantial catalogue on the effects of noradrenergic signaling on behavior and networks has been generated. How norepinephrine remodels synaptic circuitry is widely thought to underlie the larger changes in neural networks and behavior, highlighting the need for a more thorough understanding of the circuit effects of norepinephrine neuromodulation. However, the mechanistic details of the norepinephrine on synapses are still unclear. In recent decades, a large body of work has shown that norepinephrine acts not just on neurons, but on glial cells including astrocytes, a type of glial cell that is intricately involved in shaping synaptic physiology. Notably, norepinephrine induces robust intracellular calcium mobilization within astrocytes, a hallmark of astrocyte activity. Inhibiting this norepinephrine-induced calcium activity leads to meaningful behavioral deficits, underscoring the importance of norepinephrine signaling to astrocytes. Indeed, the understanding of the role of astrocytes is evolving to consider these cells as an active element of circuit and synaptic computation. Yet, despite the abundant evidence that astrocytes respond to norepinephrine, and that astrocytes can meaningfully impact synaptic circuits and behavior, it is still unknown to what extent astrocytes contribute to the established sequelae of noradrenergic signaling. In this thesis, I focused specifically on one well-established effect of norepinephrine: the modification of synaptic circuitry. I used acute ex vivo hippocampal slices from adult mice to measure the norepinephrine-induced decrease in synaptic efficacy with electrophysiological recordings, as well as the norepinephrine-evoked calcium activity in astrocytes using calcium imaging techniques. I show here that the norepinephrine-induced remodeling of synapses in the hippocampus occurs entirely via a calcium-dependent, astrocyte-mediated mechanism gated by astrocytic α1A-adrenergic receptors. I further demonstrate that astrocytes modify synapses by releasing ATP, which is rapidly hydrolyzed to adenosine, inhibiting synaptic efficacy. The findings in this thesis suggest that norepinephrine acts on astrocytes, not neurons, to modify synaptic efficacy. The astrocyte-centered mechanism proposed here supports the need for a wider consideration of the integration of astrocytes into other known effects of norepinephrine and other neuromodulators that cannot be well explained by the action of neuromodulators on neurons alone. This work centers astrocytes as a key player in neuromodulatory systems, challenging the decades-old dogma that norepinephrine acts by signaling entirely through neurons directly.
Language
English (en)
Chair and Committee
Thomas Papouin
Committee Members
Aaron DiAntonio; Ciaran Murphy-Royal; Jordan McCall; Meaghan Creed; Valeria Cavalli
Recommended Citation
Lefton, Katheryn Bry, "Elucidating the role of astrocytes in norepinephrine neuromodulation" (2024). Arts & Sciences Electronic Theses and Dissertations. 3360.
https://openscholarship.wustl.edu/art_sci_etds/3360