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H2020Individual fellowship2019–2021

FunStructure · Interdependence of functional and structural plasticity in cerebellar climbing fibers in health and disease

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2019-07-01 → 2021-06-30
EU contribution
€171,473
Participants
1
Scheme
MSCA-IF-EF-RI

Lines connect the coordinator with its partners.

Results in brief

Interdependence of functional and structural plasticity in cerebellar climbing fibers in health and disease

How neurons encode memory remains one of the current challenges of neuroscience. The cerebellum represents a valuable model area to investigate this, for instance because of its simple and modular structural organization and for the direct control of simple motor outputs. It is known that a combination of phenomena occurring at different sites of the circuit can contribute to encode memory. These are several forms of “activity-dependent plasticity” (i.e. changes in properties of neurons that are caused by their activity, representing a trace of previous events and experiences). Understanding these mechanisms and how they are altered in pathological conditions allows identifying and designing better intervention strategies to restore brain functions in brain diseases. Specifically in this project we have investigated the role of one of the only two inputs of the cerebellum, known as “climbing fiber”. It is well known that it plays a crucial role in “instructing” the cerebellum on motor errors, and, by doing this, it fine-tunes the circuit. It has been, however, unknown whether this kind of fibers can significantly change their morphology based on their activity as other fibers can do in other brain areas, and whether this could contribute to encode memories. We have studied this possibility finding that they are actually able to change their structure based on their activity and we have provided first evidence suggesting that this may potentially affect the function of the circuit and that, therefore, this mechanism may contribute to encode memories. This is adding a new element in the complex group of mechanisms that allows the cerebellum to encode and store memories and the basis for a better understating of brain function and dysfunction.

Data: CORDIS, © European Union

Project objective

Modifications of the structure and intrinsic excitability of neurons (i.e. “structural plasticity” and “intrinsic plasticity”) have been proposed to contribute significantly in encoding memory in synergy with synaptic plasticity and have been shown to contribute to the pathogenesis of several diseases including multiple sclerosis (MS). However, it is still largely unclear how changes in intrinsic excitability affect structural plasticity and how this affects circuit function. A better understanding of this two-way interdependence is crucial to understand how brain circuits encode memory engrams and are affected by diseases. Here I propose to investigate the two sides of this function-structure relationship choosing cerebellar climbing fibers (CF) as a model. Using in vivo viral delivery in the inferior olive nucleus (where climbing fibers originate), electrophysiology, optogenetics and confocal microscopy I will modulate CF function or structure acutely in slice or chronically in vivo and analyze the corresponding effect on CF morphology or physiology, respectively. I will use previously developed viral constructs to silence the expression of the growth-associated protein 43 (GAP-43) or voltage-gated sodium channels to induce structural modifications or a reduction of excitability in CFs, respectively; I will also use optogenetics to specifically stimulate transduced CFs in slice and a recently established conditional knockout mouse for SK2-type calcium-gated potassium channels to increase CF excitability. In order to investigate how CF function and structure may be modified in pathological conditions I will focus on the effects of the upregulation of the RE1-Silencing Transcription Factor (REST) observed in MS and related to alterations of neuronal excitability and axonal structure. This project will show how CF activity can modify its structure and PF plasticity rules, contributing to memory formation and disease.

Original text from CORDIS.

Participants

  • FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA · GenovaCoordinatorItaly

Links

Data: CORDIS, © European Union