Graduation Year

2026

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Physics

Major Professor

Ghanim Ullah, Ph.D.

Committee Member

Aman Ullah, Ph.D.

Committee Member

Sagar Pandit, Ph.D.

Committee Member

Martin Muschol, Ph.D.

Keywords

Acid-base, Astrocytes, Heterogeneity, Ion Homeostasis, Metabolic stress, Neurotransmitter

Abstract

Astrocytes play a central role in maintaining ionic homeostasis, neurotransmitter clearance, and brain en-ergy metabolism. Their excitability, reflected in activity-evoked intracellular sodium (Na+, [Na+]i) and calcium (Ca2+,[Ca+]i) dynamics, is increasingly recognized as a critical determinant of neuronal function and vulnerability, particularly under metabolic stress. Despite their importance, the mechanisms underlying astrocytic ionic signaling and its regional heterogeneity remain incompletely understood. In this thesis, I developed detailed computational and biophysical models to investigate astrocytic Na+ and Ca2+ dynamics, their bioenergetic consequences, and the roles of key ion transporters under physiological and metabolically stressed conditions, validating the models against experi- mental data. Modeling revealed that activity-evoked [Na+]i transients are larger in cortical than hippocampal astrocytes, producing enhanced [Ca2+]i dynamics and higher ATP consumption in the cortex, largely explained by region-specific NMDA receptor expression. Higher resting [Na+]i in cortical astrocytes further amplifies activity-evoked Na+ and Ca2+ transients, increasing energy demand and susceptibility to ionic and metabolic stress. Simulations of transient ischemia showed that inward operation of the sodium-bicarbonate cotransporter NBCe1 reduces acidosis but promotes Na+ ac- cumulation and ATP depletion, consistent with experimental observations of its dual role in pH regulation and energy consumption. Modeling the function of sodium-calcium exchanger (NCX1) during metabolics stress revealed oppos- ing effects. Astrocytic NCX1 knockout (KO) led to increased Na+ load and glutamate release, maintained elevated Ca2+ concentration, and caused increased Na+ and Ca2+ load in neurons.. Together, these studies provide an integrated computational framework linking astrocytic heterogeneity, baseline sodium, transporter function, and bioenergetics, offering mechanistic insight into neuronal vulnerability and guiding potential strategies for stroke and neuroprotection.

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