Date of Completion

6-5-2013

Embargo Period

5-26-2020

Keywords

Prefrontal Cortex Dendritic Excitability Glutamate Excitotoxicity

Major Advisor

Srdjan D. Antic

Associate Advisor

Leslie R. Bernstein

Associate Advisor

Leslie M. Loew

Associate Advisor

Richard E. Mains

Associate Advisor

Douglas L. Oliver

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Campus Access

Abstract

The prefrontal cortex (PFC) contains neural networks essential for

cognitive, emotive, and executive function. Cortical layer 1 is densely innervated

by axonal afferents projecting from the association cortices, thalamus, and

midbrain. These layer 1 axons intercept the apical tuft dendrites of layer 5

pyramidal neurons (L5P) and release a variety of neurotransmitters and

neuromodulators. How apical tuft dendrites integrate layer 1 inputs is currently

unknown. It is also unknown how L5P neurons respond to excitotoxic interactions

with glutamate and dopamine. Intense cortical activity produces massive

releases of the excitatory neurotransmitter glutamate and monoamine

neuromodulator dopamine from thousands of synaptic contacts distributed on

L5P neurons. In this dissertation, two projects investigate how L5P neurons

respond to high frequency synaptic stimulation in cortical layer 1, as well as

excitotoxic interactions with glutamate and dopamine. All experiments were

performed in brain slices containing the prelimbic and infralimbic cortex.

Backpropagating action potentials (APs) were used as a probe of dendritic

excitability. The efficacy of backpropagation was evaluated by the amplitude of

the AP-associated dendritic calcium transient in the apical tuft. Our results

indicate that high-frequency synaptic stimulation in cortical layer 1 facilitates AP

backpropagation into distal apical tuft dendrites. The immediate physiological

responses to excitotoxicity were assessed by using a 30 minute model of

glutamate-induced injury in brain slices. Changes in resting membrane potential,

spontaneous electrical activity, prevalence of physiologically compromised L5P

neurons, as well as the number of necrotic cells in brain slices (propidium iodide

staining) were used to estimate the extent of an injury. Our results indicate that

dopamine exacerbates glutamate-induced physiological changes and neuronal

death in the PFC.

Available for download on Tuesday, May 26, 2020

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