Nicholas Fitz

Defense Date

6-25-2008

Graduation Date

Spring 2009

Availability

Immediate Access

Submission Type

dissertation

Degree Name

PhD

Department

Pharmacology-Toxicology

School

School of Pharmacy

Committee Chair

David Johnson

Committee Member

Paula Witt-Enderby

Committee Member

Robert Gibbs

Committee Member

Michael Rhodes

Keywords

cognition, septal-hippocampal tract, 192 IgG-Saporin, steroid sulfatase inhibitor, DHEAS, aversive stimulus

Abstract

It is hypothesized that the loss of cholinergic function in the medial septum (MS), observed early in many forms of dementia, contributes to memory losses characterized in these diseases. The studies of this dissertation examined whether the selective loss of cholinergic neurons in the MS impairs acquisition of a delayed matching-to-position (DMP) spatial memory task. The results suggest a significant contribution of MS cholinergic neurons in acquisition of the DMP task. Specifically, 192 IgG-saporin SAP lesioned rats acquired the task at a slower rate and required more days to reach criterion. The results also suggest that male rats typically adopt a consistent turning strategy early in the training process, which is independent of extra-maze cues. For animals to reach criterion, an alternative learning strategy was adopted; one dependent on extra-maze cues. Cholinergic lesion of the MS resulted in a greater reliance on a consistent turning strategy, which accounted for the slower rate of acquisition of the DMP task.

Steroid sulfatase inhibitors increase whole brain DHEAS levels, enhance ACh release in the hippocampus, and enhance memory. The present study also investigated the cognitive effects of sulfatase inhibition in SAP lesioned animals. Steroid sulfatase inhibition further impaired acquisition of the DMP task in SAP lesioned rats while having no effect on cholinergically intact animals. Since DHEAS displayed memory enhancing properties in rodents, we also investigated the effects of DHEAS administration on MS SAP lesioned animals. DHEAS treatment had no significant effect on the acquisition of the DMP task in the SAP treated or control animals.

The final study of this dissertation examined the effect of arousal on DMP performance in SAP lesion of the medial septum. Arousal, induced by the IP injection of saline, decreased the number of days SAP lesioned rats needed to reach criterion and also improved the rate of acquisition. The results suggest that a mild aversive stimulus can attenuate cognitive deficits caused by MS cholinergic lesions.

Format

PDF

Language

English

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