Comprehensive anatomical, genetic and functional identification of cerebellar nuclei neurons and their roles in sensorimotor tasks

Project Information

CN Identity

Grant agreement ID: 852869

DOI

10.3030/852869

Project closed

EC signature date 7 October 2019

Start date 1 November 2019

End date 31 October 2025

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 400 000,00

EU contribution

€ 1 400 000,00

Coordinated by

ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Netherlands

Periodic Reporting for period 3 - CN Identity (Comprehensive anatomical, genetic and functional identification of cerebellar nuclei neurons and their roles in sensorimotor tasks)

Reporting period: 2022-11-01 to 2024-04-30

Summary of the context and overall objectives of the project

Cerebellum is critically involved in various motor and nonmotor functions during daily life, but the detailed input/output pathways by which cerebellum utilizes to compute these vital functions remain elusive. My overarching goal for this project is to identify the organization of CN input/output pathways and pinpoint their cell type and pathway specific involvements in sensorimotor tasks. The overall hypothesis is that CN activity can be facilitated as well as suppressed in the sensorimotor task, imposing a complex control over the corresponding downstream circuitries with millisecond precision. To meet the demands of such computation, the anatomical, genetic and functional properties of CN neurons are tailored to the particular task involved. To test this overarching hypothesis, I proposed to comprehensively examine the electrophysiological, anatomical and genetic logics of individual CN neurons and functionally dissect their specific roles in different sensorimotor tasks. The answers to these questions will provide us with much needed explanation as to how does cerebellum contribute to diverse motor and cognitive functions while maintaining the task specific computation. These findings are likely to have general implications beyond the neuroscience field, such as for robotic control and medicine.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We have successfully designed and tested the behavioural paradigm that requires the mice to conduct directed licking in response to specific sensory inputs. We trained mice to differentiate several sensory inputs, and response with either licking to the left or right accordingly. The training paradigms have been optimized in the lab and now it is a routine practise in the lab. During the course of these experiments, we have uncovered unexpectedly several other frontal cerebral regions that are critically involved in the working memory and decision. These surprising but encouraging findings spurred us to examine in more detail the communication between cerebral and cerebellar regions. One of these unexpected findings we pursued is that we examined the cerebro-cerebellar communication for motor planning. We found that frontal cortex and cerebellum forms reciprocal loops that are essential for animals’ decision making process. We have successfully map the anatomical and functional specificity of different cerebellar modules. This work has recently been submitted to a top tier journal for peer review.

We proposed to conduct optogenetic and electrophysiological methods to establish the functional role of cerebellum. Here we have conduced all the essential measures. In control mice, we introduced the AAV encoding ChR2 or Halo in the cerebellar nuclei neurons. We have validated the effectiveness of optogenetic stimulation on activating or inhibiting cerebellar nuclei neurons. Furthermore, by performing direct electrophysiological recordings in the cerebellar nuclei neurons during optogenetic stimulation, we have established the optimal conditions in controlling the cerebellar outputs. We have next examined the impacts of PFC on the cerebellar regions. Optogenetic or pharmacological inhibition of PFC neurons affected mice ability of performing eye blink conditioning, which has been previously suggested to rely on the PFC and cerebellar activity, but has never been proven. This study has been currently finalized and we expect to submit the manuscript very soon.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The first phase of the project focused on establishing the behavioural paradigms and gathering the pilot physiological and anatomical results that could be subsequently analysed.

As the involvement of cerebellum in controlling the planning of directional licking was initially described by us, our follow up studies on the roles of different cerebellar modules in controlling motor planning are all beyond of the state of the art.

According to the progress we anticipate that we will be able to address the key objectives listed in my proposal.