The large knowledge base on neurobiological and behavioral aspects of associative learning in the eyeblink classical conditioning model in rabbits will be used to identify sites of action and possible mechanisms for cognition enhancing drugs. Eyeblink conditioning reveals natural age-related deficits with striking parallels in several species including humans. In patients with Alzheimer's disease (AD) eyeblink classical conditioning is profoundly impaired, making the procedure relevant for preclinical studies of cognition-enhancing drugs. In addition to parallels with human behavior and neurobiology, the essential neural circuitry for this form of learning has been localized in the cerebellum, with modulatory circuits identified in hippocampus and neocortex. The proposed research is innovative because it has a focus on novel pathways through which cognition-enhancing drugs may affect learning and memory. In addition to septohippocampal acetylcholine (ACh) routes of action, experiments will assess acetylcholinesterase inhibition (AChE-I) and nicotinic acetylcholine receptors (nAChRs) in cerebellum and cerebellar contributions to the facilitation of learning. The cerebellum is essential in classical eyeblink conditioning, but it also plays a demonstrated role in a diverse group of other cognitive functions. Normal age-related decline in cerebellar volume is well documented, yet the cerebellum is seldom studied as a target for drug action. As a brain structure preserved in AD better than the hippocampus, the cerebellum may be a useful target for drug action. Young and older rabbits will be assessed using delay (for which the cerebellum is essential) and trace (for which the hippocampus and the cerebellum are essential) eyeblink conditioning procedures.
Aim 1 focuses on site(s) of action of drugs known to ameliorate learning impairment in young and older rabbits using systemic drug injection, 600 and 750 ms delay conditioning, and AChE-I and nAChR binding in cerebellum and hippocampus.
Aim 2 focuses on site(s) of action of drugs known to ameliorate learning impairment in young and older rabbits using systemic drug injection, 600 and 750 ms trace conditioning, and AChE-I and nAChR binding in cerebellum and hippocampus. The targets of Aim 3 are the medial septum, cerebellar cortex, and interpositus nucleus where drugs will be infused and acquisition in the delay and trace procedures will be assessed. These studies will likely support hypotheses about ACh mechanisms in learning and memory and may identify the cerebellum as an additional site of drug action. ? ?
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