Probing cholinergic modulation of hippocampal circuits implicated in the processing of memories and emotions

• Applicant: Dr. Ricardo dos Santos, Ph.D.
• Subject Area: Experimental and Theoretical Network Neuroscience ; Cognitive, Systems and Behavioural Neurobiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 500072028

Acetylcholine (ACh) is a neuromodulator strongly implicated in the mnemonic and emotion-related functions of the hippocampus. Accordingly, dysregulation of ACh signaling underlies cognitive deficits associated with neurodegenerative and mental disorders.During wakefulness, ACh release enhances hippocampal theta rhythmicity, which orchestrates computations of space and emotions in the dorsal and ventral hippocampus (dHipp and vHipp), respectively. These oscillations can be subdivided into theta1, strongly expressed in dHipp during spatial navigation, and theta2, enhanced during emotionally-charged states mainly in vHipp. Importantly, while ACh signaling is thought to correlate with both, it is not necessary for theta1 generation.In contrast, low extracellular ACh during sleep favors the occurrence of hippocampal sharp-wave/ripples (SWRs), leading to the replay of pyramidal cell sequences, which are critical for memory consolidation.Knowledge on the above-mentioned topics has been mainly based on state-related correlations, pharmacology and optogenetics. However, the ACh changes associated with brain state transitions or evoked by causal manipulations are not representative of the spontaneous non-stationary interactions between ACh, behavior and neuronal network activity. To characterize these correlations, it is essential to track them at a fast time-scale.Here, I have optimized and combined high spatio-temporally resolved ACh measurements in mice hippocampus with multichannel electrophysiology and fine behavioral tracking. My preliminary findings point towards two research directions. Firstly, data under multiple behavioral paradigms support that emotionally-charged states drive ACh release in hippocampus, coupling it to theta2, rather than theta1. This ACh-dependent dissociation of theta rhythms might be critical for the processing of emotions independently from space and context. Secondly, based on sleep recordings, I hypothesize that ascending and descending circuits generate phasic ACh dynamics during sleep, shaping the occurrence of SWRs and modulating the replay of sequences. These effects highlight a novel role of ACh on memory consolidation.To test the aforementioned hypotheses, I plan to: a) investigate differential behavioral-state specific correlations between phasic ACh dynamics and theta oscillations in dHipp and vHipp; b) address the ascending and descending pathways that might shape cholinergic dynamics during sleep and further characterize ACh-SWRs interactions, assessing replay events based on single unit recordings. The causal effects of phasic ACh on either theta or SWRs will be tested using optogenetics.This cutting-edge combination of measurements and perturbations will provide unprecedented details into the cholinergic mechanisms underlying hippocampal processing of memory and emotions, laying the foundations to accelerate the discovery of new treatments for neurodegenerative and mental disorders.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Anton Sirota