Date of Award

January 2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

Van Doze

Abstract

Norepinephrine is a catecholamine neurotransmitter that signals through the adrenergic receptors (ARs), α1, α2, and β, each with three subtypes. There is little research on the function of α1AR subtypes, α1A- and α1BARs, in the brain. By using α1AR agonists, antagonists, and transgenic activation there appears to be a role for the subtypes in learning, memory, mood, adult neurogenesis, and cancer.

α1AAR activation enhances learning and memory in the adult mouse. In the current study, we used α1A- or α1BAR knockout mice (α1AAR or α1BAR-KO mice) and behavioral testing to examine learning, memory, depression, and anxiety. We found that KO of each α1AR subtype impairs novel object recognition, but not spatial memory. KO of either subtype did not reliably affect anxiety behavior. α1BAR-KO mice had a significantly lower depression level than wild type mice.

Activation of the α1AAR subtype increases proliferation of neural progenitor cells in the adult mouse dentate gyrus and in vitro work suggested a role in the differentiation stage. We used the α1AAR agonist, cirazoline, BrdU incorporation, and immunohistochemistry to determine whether activation of the α1AAR would direct cell fate toward an astrocytic phenotype. Cirazoline did not change the number or percent of new cells in the adult mouse dentate gyrus differentiating into neurons or astrocytes. The number of immature neurons, however, was significantly decreased.

The α1BAR was proposed as a proto-oncogene based on in vitro and tumorigenesis studies. An age-related neurodegenerative disorder occurs when a constitutively active mutant form of the receptor is overexpressed in mice (CAM-α1BAR mice). We tracked CAM-α1A- and CAM-α1BAR mouse lifespan, and performed gross pathology and histology to determine cancer occurrence. CAM-α1AAR mice had an increased lifespan and decreased cancer incidence. CAM-α1BAR mice had decreased lifespan but no change in cancer incidence.

The combined results show that the α1AAR subtype influenced novel object recognition, cancer incidence, and lifespan. Activation of the α1AAR did not change differentiation or survival of new cells during adult neurogenesis and KO did not have an effect on mood. The α1BAR affected lifespan but not cancer incidence and KO mice showed an anti-depressant phenotype. Further research should pursue the mechanism of the α1AR subtypes’ role in mood and cancer incidence. The use of α1AAR activation and of α1BAR blocking should be examined in a mouse model of depression to determine the benefit as treatments. The potential mechanism involving receptor heterodimerization should be pursued based on the conflicting results in α1AR KO mice as well. Future studies such as these are important to further define the roles of the α1AR subtypes in brain function.

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