Date of Award

January 2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

Van Doze

Abstract

Norepinephrine (NE) is a neurotransmitter involved in learning and memory. NE activates adrenergic receptors (ARs) and stimulating the α1A-AR subtype has been known to increase adult neurogenesis (ANG). We hypothesized that α1A-AR-induced ANG would enhance learning and memory. Constitutively active mutant (CAM) α1A-AR, α1A-AR knock-out (KO), normal wild type (WT) mice, and mice treated with the α1A-AR selective agonist cirazoline (CRZ) were tested on the Barnes maze. CAM α1A-AR and CRZ-treated mice performed better and α1A-AR KO mice performed poorer than WT. Long-term potentiation (LTP) experiments on aged CAM α1A-AR mice revealed enhanced LTP in CAM α1A-AR mice versus WT. Therefore, we hypothesized that α1A-AR-induced ANG underlies enhanced learning, memory and synaptic function. We used CRZ to activate α1A-ARs and the anti-mitotic agent cytosine arabinoside (Ara-C) to impair ANG in CRZ-treated and WT mice, and tested mice on novel object recognition (NOR), Morris water maze (MWM), and open field (OF). No difference was found in NOR and OF. MWM revealed that CRZ-treated mice were protected from Ara-C-induced learning and memory impairments, and surgery-induced learning impairments.

We observed that Ara-C treatment was causing weight gain and hypothesized that Ara-C inhibits cellular proliferation in the hypothalamus, the metabolic center of the brain. Fat deposition analysis and hypothalamic stereological investigation revealed that Ara-C treated mice gained significantly more weight and had significantly fewer dividing cells and immature neurons than WT mice. We concluded stem cells and immature neurons in the hypothalamus are important in metabolism and normal weight gain. We launched a pilot study investigating the α1A-AR in exercise-induced neurogenesis using WT and α1A-AR KO mice and running wheels. We measured anxiety-like behavior and neurogenesis and found enhanced anxiety and less neurogenesis in running α1A-AR KO mice. Results from this study are ambiguous; therefore we cannot dismiss α1A-AR involvement in exercise-induced neurogenesis. In conclusion, activating α1A-ARs increases neurogenesis, enhances learning and memory, and has neuroprotective effects against brain injury. These insights may lead to therapeutic interventions for patients suffering from chemotherapy's negative effects on memory and other neurodegenerative diseases, as Ara-C (also known as cytarabine) is a common leukemia treatment in humans.

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