Acetylcholine in learning and memory

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

Our major objective this year was to move our research on cholinergic (ChAT+) neurons in memory forward, given that we (finally) have the needed numbers of animals in our new colonies of re-derived, genetically modified mice. These genetically modified mice express both activity-dependent and cholinergic-specific markers. Continued viral development, with the collaboration of Dr. Talmage (NINDS) and help of Dr. Fields in the NINDS Viral Core, are ongoing for additional approaches to selectively label memory-activated, cholinergic neurons independent of species. We have begun our studies of cholinergic memory encoding with an in-depth analysis of (a) the features of basal forebrain cholinergic neurons (BFCNs) associated with aversive vs. appetitive memories and by (b) assessing cholinergic circuits involved in innate vs cue-associated learning. These studies use genetic, immunological and retrograde markers to identify specific BFCNs, their projection targets, and their engagement in memory. Memory encoding is assessed by using intersectional genetics to determine whether or not the ChAT+ neurons were activated by the learned stimulus (whether positive or negative valence and whether cue-associated or innate) Encoding of cue-associated learning requires both activation with learning (training) and reactivation with memory retrieval. A thorough analysis of the intrinsic properties and key features of BFCNs classified by projection target and/or memory related activation has yielded complete electrophysiological profiles on well over 100 identified BFCNs. Relocation and re-construction of the dendritic arbors has been completed on about half of these, with a focus on those with known BLA or auditory cortical projections. Most striking are the distinct intrinsic properties of BFCNs engaged in innate vs cue associated behaviors, despite their having shared projection targets in the temporal lobe (amygdala). So far, our analyses indicate that the plastic changes in intrinsic properties that cue-associated BFCNs undergo with learning (enrollment in the engram) include the same set of properties that distinguish them from BFCNs that encode innate learning and that project to the same target. Hence encoding state, whether innate or cue-associated, may be reflected in basic aspects of the electrophysiological profile of cholinergic engram neurons. Another striking feature of BFCNs is their extreme axon length and axon terminal field complexity. The fidelity of axonal propagation and whether axonal excitability is locally modulated in these intricate terminal networks is not known. We have begun to ask these questions with combined physiological and high-resolution functional imaging assays. Certain aspects of the laboratorys memory program also involved continued collaboration with individuals at universities that were more open and operational than the NIH and as such, we were able to complete and submit multiple manuscripts. In particular we were able to foster and sustain ongoing collaborations with Dr. Talmage, NINDS IRP and Dr. Ari Kaufman (Department of Computer Sciences) and Drs. Parsey and De Lorenzo (Department of Psychiatry; all at Stony Brook University) and with Dr. Marina Picciotto at Yale University Department of Psychiatry. The collaboration with Dr. Talmage and (a) Dr. Kaufman yielded four publications, (b) Drs Parsey and De Lorenzo, established the human studies of the cholinergic system during normal and pathological aging (publications pending) and (c) with Dr. Picciotto and colleagues we have 1 paper in eLife, and another en route to eLife, with the first identifying specific populations of cholinergic neurons that participate in distinct types of memory and the second demonstrating for the first time that cholinergic neurons participate directly in memory engrams. A new collaboration with Dr. Jerrel Yakel of the NIEHS IRP on high resolution calcium imaging of cholinergic circuits is also now underway.