Role of norepinephrine in olfactory learning: in young age, in adulthood, and in Alzheimer’s disease
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".