Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - HippAchoMod (Deciphering the cholinergic modulation of the hippocampal place code.)

Teaser

A central component of the brain’s navigation circuit, where complex representations of the environment emerge, is the hippocampal formation. Place cells of the hippocampus exhibit location-specific firing and they are part of an internal map of the environment that guides...

Summary

A central component of the brain’s navigation circuit, where complex representations of the environment emerge, is the hippocampal formation. Place cells of the hippocampus exhibit location-specific firing and they are part of an internal map of the environment that guides the behavior of the organism. The central question since the discovery of place cells has been what mechanisms endow the hippocampus’ principal neurons with location-specific firing or, in other words, how the map of the environment is formed in our brain? A key step in hippocampal map formation is the synchronization of the activity state of place cells and the impulse flow through their inputs. The so-called theta oscillation is crucial for this synchronization process. The brain region, that is the master clock of theta oscillation is the medial septum. The three major neuron types of this region send projection to virtually all areas involved in coding the environment. We hypothesize that the medial septum, besides pacing the theta rhythm, may shape the location-coupled firing of hippocampal neurons or, in a broader context, the hippocampal coding process.
Generation of an internal map, also called a cognitive map of the environment is absolutely pivotal for our survival. Uncovering the governing principles of how the brain models the environment. In human diseases with severe cognitive deficits like Alzheimer’s or schizophrenia basal forebrain, including the medial septum, the hippocamplus and connected cortical structures are irreversibly damaged. I hope our results would point to components in the navigation - episodic memory system that can explain impairments and uncover points of intervention of human disease conditions.
We have thus two main objectives: we would like to reveal fundamental yet elusive aspect of place field formation and we aim to show how the main temporal organizer of the brain’s navigation circuit modulates coding processes besides generating a timing signal.

Work performed

The main goal of the Project was to uncover how the medial septum modulates the hippocampal spatial code. We planned to explore the role of the cholinergic septo-hippocampal projection. However, according to our hypothesis, the concerted action of all of its components is indispensable for modulating the spatial code in the hippocampus. To address our question, we implemented a location-contingent closed-loop optogenetic stimulation strategy: the medial septum was light-activated when the animal entered a pre-defined location monitored. The duration of stimulation (1.2 seconds) was set to correspond to the time of crossing a place cell’s firing field by the animal. Our prediction was that at the stimulated location new place fields emerge. In order to activate all neuron types in the medial septum, we used a neuron-specific construct that contained the light-addressable non-selective cation channel Channelrhodopsin2 packaged into an adeno-associated virus vector. Few weeks (6 - 8) after virus injection an optic fiber was implanted into the medial septum for delivering light whereas a 64-channel silicone probe attached to a custom-made microdrive was lowered into the hippocampus for recording the response of hippocampal neurons to medial septum-activation. I injected 24 mice, of which 14 were implanted and 9 generated data by recording 146 sessions in them. The data analysis is still ongoing therefore the results detailed below are only preliminary. I presented our findings on one local (restricted to the NYU Neuroscience Institute) and three international conferences and on a seminar organized in my home institute.
First, we observed a reduction in the animals’ running speed while traversing the stimulated location. Strikingly, if light was delivered while the animal was sleeping or eating in its homecage, stimulation triggered arousal. In parallel, theta was disrupted by the stimulation. Finally, medial septal stimulation induced remapping of about 50% of the recorded and already analyzed neurons. The most common effect was the emergence of a new place field. The disappearance of existing place fields was also observed. Notably, in control sessions without delivering any light, about 30% of place cells exhibited spontaneous remapping. In order to exclude that the observed remapping in stimulation sessions was caused by the light leaked out of the optic fiber and not by medial septum illumination, a subset of animals was equipped by a sham optic fiber terminated in the cement crown above the skull. Light from this fiber was clearly visible for the animal. However, sham manipulation did not cause remapping different than that observed in control, non-manipulated sessions. Thus, our results indicate the medial septum can indeed, change the spatial code carried by the location-coupled activity of place cells.

Final results

In recent years, considerable amount of information has been accumulated about how the brain represents the environment. We know that in the hippocampus, the brain\'s memory center, a large proportion of neurons carry information either about the location of the animal, or their activity is related to certain features or objects of the environment. The question of how this complex code emerges or, in other words, what are the mechanisms that endows hippocampal pyramidal cells with location, object or event-specific activity is still unanswered. The transformation of a silent neuron to a coding neuron is strictly coupled to time windows determined by the theta oscillation generated by the medial septum (MS), the main modulator of hippocampal function. Our hypothesis moves beyond the traditional view of the MS as the pacemaker of theta by raising the possibility of its contribution to the formation of the hippocampal code. Our experimental approach was based on the location-contingent activation of the MS in a closed-loop configuration, to test if we were able to artificially create or erase the place code corresponding to the location of activation. At the end of the project, we expect to reveal if and how the MS controls the hippocampal coding process. Deciphering the mechanisms by which the hippocampus codes the environment and forms memories can facilitate the understanding of diseases connected to hippocampal dysfunction. Significance of our work is underlined by the increasing prevalence of neurpsychiatric syndromes, especially Alzheimer\'s disease, associated with hippocampal pathologies and the lesion of the basal forebrain neural network of which the MS is a key component.