Role Of The α1A-Adrenergic Receptor In Synaptic Plasticity, Cognition & Neurogenesis

<p>Norepinephrine (NE) is a neurotransmitter involved in learning and memory. NE activates adrenergic receptors (ARs) and stimulating the &#945;1A-AR subtype has been known to increase adult neurogenesis (ANG). We hypothesized that &#945;1A-AR-induced ANG would enhance learning and memory. Constitutively active mutant (CAM) &#945;1A-AR, &#945;1A-AR knock-out (KO), normal wild type (WT) mice, and mice treated with the &#945;1A-AR selective agonist cirazoline (CRZ) were tested on the Barnes maze. CAM &#945;1A-AR and CRZ-treated mice performed better and &#945;1A-AR KO mice performed poorer than WT. Long-term potentiation (LTP) experiments on aged CAM &#945;1A-AR mice revealed enhanced LTP in CAM &#945;1A-AR mice versus WT. Therefore, we hypothesized that &#945;1A-AR-induced ANG underlies enhanced learning, memory and synaptic function. We used CRZ to activate &#945;1A-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. </p> <p>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 &#945;1A-AR in exercise-induced neurogenesis using WT and &#945;1A-AR KO mice and running wheels. We measured anxiety-like behavior and neurogenesis and found enhanced anxiety and less neurogenesis in running &#945;1A-AR KO mice. Results from this study are ambiguous; therefore we cannot dismiss &#945;1A-AR involvement in exercise-induced neurogenesis. In conclusion, activating &#945;1A-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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biomedical Sciences

Year

2014

Author dc:creator

• Goldenstein, Brianna Lynn

Contributors dc:contributor

• Van Doze

• adrenoreceptor, hippocampus, memory, neurogenesis, noradrenaline, plasticity

Repository record dc:identifier

https://commons.und.edu/theses/1537

OAI identifier oai:identifier

oai:commons.und.edu:theses-2538