Prefrontal nicotinic receptors: endogenous regulation and therapeutic manipulation in aging and Alzheimer’s disease
Bibliographic record
Abstract
Cholinergic modulation of the prefrontal cortex is essential for attention and executive function. While this system changes markedly in aging and Alzheimer’s disease (AD), it is unclear whether alterations are only deleterious. The cholinergic system may be a locus of cognitive reserve protecting against cognitive decline. The complexity of cholinergic synapses provides substantial scope for compensation. Functional insight is essential to ascertain cholinergic changes and relevant treatment strategies. Therefore, I optophysiologically and pharmacologically interrogate the impact of age and AD-pathology on endogenous cholinergic signalling in the prefrontal cortex. First, I investigate changes in prefrontal cholinergic signalling during adulthood. I hypothesize that declines in prefrontal endogenous cholinergic signalling arise through aging. In prefrontal brain slices from transgenic mice, I assess the electrophysiological response to optogenetically-induced release of acetylcholine and demonstrate a decline in cholinergic responses in mid-life. With pharmacological interrogation, I pinpoint this decline to a decrease in nicotinic receptor availability. To strengthen signalling, I combine two treatment interventions: NS9283 to potentiate nicotinic receptors via positive allosteric modulation and xanomeline to increase nicotinic receptor availability via muscarinic second messenger activation. These interventions restore endogenous nicotinic responses. Next, I test the impact of AD pathology on prefrontal cholinergic signalling in mouse and rat transgenic models. Based on suggestions in the literature, I hypothesize that compensatory postsynaptic amplification of cholinergic signalling arises in AD. In both models, I detect upregulation in cholinergic responses at early to mid AD. Pharmacological interrogation suggests the increase is specific to nicotinic receptor signalling. To examine the impact of intervention on the adapted circuit, I test cholinergic and nicotinic-selective pro-cognitive treatments. Treatment directly targeting nicotinic receptors enhances optogenetic-elicited cholinergic responses while better maintaining their rapid kinetics, outcompeting the effect of standard-of-care cholinergic treatment acetylcholinesterase inhibitor. Overall, my dissertation generates new understanding of nicotinic receptor regulation in aging and AD, identifying new therapeutic strategies to boost this cognitively-essential circuit. Age-related functional change at prefrontal cholinergic synapses and strong neuropathology-related plasticity in this circuit give new opportunities for therapeutic treatment. Therapeutic avenues harnessing endogenous neuromodulatory mechanisms show promise to retain the rapid kinetics of cholinergic signalling important to enhance cognition.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".