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Principal Investigator: JERREL L YAKEL
Organization: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
Fiscal Year: 2024
Award: $2,741,932
Funding agency: National Institute of Environmental Health Sciences
There have been several major accomplishments within the past fiscal year. This year we published 4 major papers, one of which promises to be one of the most significant discoveries yet from my lab (published in Cell Reports, and an NIEHS Intramural paper of the month), we have discovered a novel circuit, the temporoamonic pathway (that leads from the entorhinal cortical layer 3 directly to the CA1 hippocampal region), which is a circuit that fires in synchrony in the delta wavelength during deep slow-wave sleep (SWS), and when the activation of this circuit is disrupted, has a deleterious effect on memory consolidation. It is known that in patients with Alzheimer’s disease, SWS is disrupted, and it is thought that this may have something to do with memory impairments. Thus understanding this circuit in more detail likely will have implications for the memory loss in Alzheimer’s disease.
Secondly, individuals infected by SARS-CoV-2 are at risk of developing neurological-related post-acute disorders. Disputed epidemiological data indicated nicotine may reduce the severity of infection. In work currently under review at Scientific Reports, we discovered that exposure to nicotine in drinking water does not alter the moribundity of hACE2 mice. However, pre-exposure to nicotine decreased the likelihood of SARS-CoV-2 RNA expression and pathology in the brain. These results suggest mechanisms involving targets of nicotine could be leveraged to prevent the neurovirulence of SARS-CoV-2. This paper was published in Scientific Reports last February.
Thirdly, cholinergic regulation of hippocampal theta oscillations has long been proposed to be a potential mechanism underlying hippocampus-dependent memory encoding processes. However, cholinergic transmission has been traditionally associated with type II theta under urethane anesthesia. The mechanisms and behavioral significance of cholinergic regulation of type I theta in freely exploring animals is much less clear. In this study, we examined the potential behavioral significance of cholinergic regulation of theta oscillations in the object location task in male mice that involves training and testing trials and provides an ideal behavioral task to study the underlying memory encoding and retrieval processes, respectively. Cholinergic regulation of hippocampal theta oscillations and the behavioral outcomes was examined by either intrahippocampal infusion of cholinergic receptor antagonists or knocking out cholinergic receptors in excitatory neurons or interneurons. We found that both muscarinic acetylcholine receptors (mAChRs) and α7 nicotinic AChRs (α7 nAChRs) regulated memory encoding by engaging excitatory neurons and interneurons, respectively. There is a transient upregulated theta oscillation at the beginning of individual object exploration events that only occurred in the training trials, but not in the testing trials. This transient upregulated theta is also the only theta component that significantly differed between training and testing trials and was sensitive to mAChR and α7 nAChR antagonists. Thus, our study (published in the prestigious Journal of Neuroscience) has revealed a transient cholinergic-sensitive theta component that is specifically associated with memory encoding, but not memory retrieval, in the object location task, providing direct experimental evidence supporting a role for cholinergic-regulated theta oscillations in hippocampus-dependent memory encoding processes.
Lastly, we found that genetic deletion of the α7 subytpe of nAChRs reduces hippocampal granule and pyramidal cell number in both sexes but impairs pattern separation in males only (Frontiers in Neuroscience). Neurogenesis within the dentate gyrus is thought to play an important role in cognitive processes such as reversal learning and pattern separation. The α7 nicotinic acetylcholine receptor (α7 nAChR) is expressed early in newly formed granule cells of the dentate gyrus, though its role in neurogenesis and related cognitive function is not fully understood. These findings argue that the α7 nAChR plays a critical role in hippocampal development, not just granule cell neurogenesis, and plays a sex-dependent role in cognitive function.
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