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Dendrites and memory: role of dendritic spikes in information coding by hippocampal CA3 pyramidal neurons

Periodic Reporting for period 2 - DeCode (Dendrites and memory: role of dendritic spikes in information coding by hippocampal CA3 pyramidal neurons)

Reporting period: 2019-12-01 to 2021-05-31

Understanding how experiences establish memories is a fundamental goal of neuroscience. The hippocampus has a crucial role in episodic memory and spatial representations both in animals and humans. During such memory tasks, the hippocampus creates network codes in the form of ensembles of neurons that are activated by the same environmental feature or context. The mechanisms promoting the recruitment and consolidation of individual neurons into these information-coding ensembles are poorly understood.
The recurrent synaptic network of pyramidal cells (PCs) in the hippocampal CA3 area, receiving external inputs from the entorhinal cortex and the dentate gyrus, is thought to be essential for associative memory. Current models of the associative functions of CA3 are mainly based on plasticity of these synaptic connections, but recent work by us and others suggests that active, voltage-dependent properties of CA3PC dendrites may also promote ensemble functions. Dendritic voltage-dependent ion channels allow nonlinear amplification of spatiotemporally correlated synaptic inputs (such as those produced by ensemble activity) and can generate local dendritic spikes, which may elicit specific action potential patterns (e.g. bursts) and induce synaptic plasticity. Furthermore, dendritic processing may be modulated by activity-dependent regulation of dendritic ion channels. However, still little is known about the active properties of CA3PC dendrites and their functions during spatial coding or memory tasks.
We aim to test the hypothesis that active integration of inputs by dendrites of individual CA3PCs plays an important role in their recruitment into specific context-coding ensembles. Evidence for active dendritic integration will be studied combining in vitro (patch-clamp electrophysiology and two-photon (2P) microscopy in slices) and in vivo (2P imaging and activity-dependent labelling in behaving rodents) approaches.
The main overall objectives are the following:
Objective I. To elucidate the mechanisms, compartmentalization and plasticity of dendritic spikes underlying complex spike burst firing in CA3PCs in acute rodent brain slices;
Objective II. To elucidate the functional relevance of active dendritic integration in CA3PCs during spatial memory in vivo.
In accordance with the proposed goals, we investigated the mechanisms and relevance of dendritic spikes and complex spike bursts (CSBs) in CA3PC functions. We discovered that the heterogeneous propensity of principal neurons of the hippocampal CA3 to fire complex spike bursts is regulated differently depending on the topographic position of cells within the area. We pinpointed two specific dendritic ion channel types whose region-specific activity partly explains the topographic modulation of CSB propensity. We uncovered that the synaptic input-output transformation rules triggering CSBs are non-uniform among CA3PCs: CSBs serve as an associative input pathway signal in RS cells but can be triggered by any input type clustered in any individual dendritic branch in CSB cells. In ongoing work using dendritic recordings we discovered subtypes of dendritic spikes that determine CSB properties and other forms of input-output transformation.
We have established an in vivo (two-photon microscope combined with virtual reality) system for imaging hippocampal neurons, and began experiments in head-fixed mice navigating in various virtual spatial contexts. We developed software tools to program data acquisition protocols and monitor behavioral performance, and worked out spatial context discrimination training paradigms.
Using novel computational and experimental approaches we investigated how long-term synaptic plasticity depends on the spatial pattern of inputs as well as local and global dendritic integrative mechanisms in hippocampal neurons.
The project has already uncovered unexpected fine-tuned regulation of active dendritic properties and complex dendritic input-output functions in CA3 pyramidal neurons. The novel findings will require further study in the second term. We expect that by the end of the project the results will lay out a framework of general as well as cell-type specific dendritic computations contributing to the function of this canonical recurrent network. Building on the methodical progress and results provided by the first half of the project, a major goal of the second term is to determine the components of spatial learning and memory ensemble functions that global and local active dendritic response forms can be associated with.
CA3 pyramidal cell