Role of norepinephrine in olfactory learning: in young age, in adulthood, and in Alzheimer’s disease

Ghosh, Abhinaba (2021) Role of norepinephrine in olfactory learning: in young age, in adulthood, and in Alzheimer’s disease. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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The objective of this dissertation is to elucidate the noradrenergic modulation of olfactory learning and memory, specifically, how it varies throughout developmental phases and in the context of disease. To that end, I have addressed three distinct but interrelated aspects. First, I characterized how locus coeruleus (LC)-mediated norepinephrine (NE) modulates L-type calcium channels (LTCCs) in neonatal odor preference learning. Long term potentiation (LTP) is dependent on calcium influx. In chapter 2, I show that β adrenoceptor (AR) enhances LTCC-mediated calcium influx within the critical period and is responsible for olfactory preference learning. Second, I studied how phasic and tonic firing patterns of LC differentially modulate olfactory discrimination learning and valence learning. Through optogenetic stimulation of rat LC neurons in 10-Hz phasic or 10-Hz tonic patterns, I show in chapter 3 that enhanced acquisition of similar odor discrimination occurs via phasic-stimulation through a LC-ventral tegmental area-piriform cortex-dopamine circuitry. 25-Hz tonic photostimulation induces conditioned odor aversion, but 10-Hz phasic stimulation produces an odor preference suggestive of a positive valence. 10-Hz phasic stimulation recruits more basolateral amygdala (BLA) cells that project to nucleus accumbens, while 25-Hz tonic stimulation preferentially activates BLA cells projecting to the central amygdala (CeA). Finally, I studied LC-degeneration in an Alzheimer’s disease (AD) pretangle tau model in rats. Braak’s staging of AD suggests that the first brain pathology is the appearance of hyperphosphorylated soluble tau in LC. It is not well understood if LC hyperphosphorylated tau initiates the pathology and causes the cognitive deficits in early stages. In a rat model I express pseudo-hyperphosphorylated human tau in LC through viral vector-dependent delivery of the appropriate transgene and test the hypothesis that LC pretangle human tau can cause preclinical AD (chapter 4). At 7 but not 4 months post-infusion, difficult odor discrimination learning is impaired in rats which received the infusion in young adulthood. This deficit is associated with low density of LC axons in the piriform cortex, and the pathology is aggravated in older rats. Altogether, this new animal model establishes the plausibility of Braak’s hypothesis that AD can originate with pretangle tau expression in LC.

Item Type: Thesis (Doctoral (PhD))
Item ID: 15747
Additional Information: Includes bibliographical references (pages 162-194)
Keywords: Locus coeruleus-Norepinephrine, olfactory learning, optogenetics, Alzheimer's disease, L type calcium channel
Department(s): Medicine, Faculty of
Date: February 2021
Date Type: Submission
Digital Object Identifier (DOI):
Medical Subject Heading: Olfactory Bulb; Smell; Long-Term Potentiation; Discrimination Learning; Alzheimer Disease; Norepinephrine

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