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Unraveling the consequences of early cerebellothalamic dysfunction and its role in autism spectrum disorder symptoms

Periodic Reporting for period 1 - UNCERTHAIN (Unraveling the consequences of early cerebellothalamic dysfunction and its role in autism spectrum disorder symptoms)

Reporting period: 2019-06-01 to 2021-05-31

The Action “Unraveling the consequences of early cerebellothalamic dysfunction and its role in autism spectrum disorder symptoms” aimed to decipher anatomical and functional alterations resulting from abnormal cerebello-thalamic connectivity and its relationship with symptoms present in Autism spectrum disorder (ASD).
This topic is important for society because is estimated that worldwide one in 160 children has an ASD. Interestingly, early cerebellar lesions are the best known non-genetic risk factor associated to ASD.
The alteration of the development and function of the cerebral cortex due to an abnormal functioning of the cerebellum could explain the cerebellar origin of the high-order deficits present in major neurodevelopmental psychiatric disorders. And the thalamus is a key intermediate structure between the cerebellum and the cortex. However, any study has tackled this issue from a neurodevelopmental perspective.
The main objectives of this Marie Skłodowska-Curie Action (MSCA) have been to (a) study the formation of the cerebello-thalamic circuit; (b) develop strategies to alter this circuit and (c) investigate the anatomical and functional consequences of these alterations.
Thus, we have developed different experimental approaches to target and manipulate the embryonic cerebellum in vivo. These techniques allowed us to study in detail how the cerebellothalamic circuits develop during embryogenesis. Our results have stablished for the first time the spatial and temporal window by which the cerebellum could influence the development of thalamus and its circuits. Furthermore, abnormal cerebellar inputs to thalamus let to some structural and transcriptomic alterations in this region that might explain functional and behavioral dysfunctions associated with the cerebellar origin of ASD.
A parallel goal of this MSCA IF was foster the development of the individual researcher.
During the implementation of the grant, the overall scientific goals were achieved in the project.
First, we have described how the cerebellar axons contact with the thalamus during early brain development. To this aim we used a novel approach that combined in utero viral injections to trace the axons, clearing methods and 3D light sheet microscopy (WP1). Our results allowed us to study in three-dimensions how the cerebellar axons innervate the thalamus during development. These results point out that already at early stages of development cerebellar axons have the potential to influence immature motor and non-motor thalamic circuits.
Next aim was to clarify whether the cerebellum could influence the development of the thalamus. Thus, in the following step, we developed a strategy to manipulate the cerebello-thalamic connectivity (WP2) and study the impact on the development of the thalamus (WP3-WP4).
We reported that abnormal cerebellar inputs to the thalamus could alter the thalamocortical circuits. Furthermore, we observed that it triggers the alteration in the expression of genes involved in critical processes for brain development and wiring.
In summary, work performed under the present project adds to our understanding the temporal and spatial window by which the cerebellum could start to influence the development and maturation of thalamocortical circuits. Furthermore, we started to elucidate the molecular mechanism involved in those alterations, which it is a critical step forward towards the understanding of the cerebellar implication in high-order neurodevelopmental disorders.
The findings from the project have been disseminated among the scientific community in international conferences and among the general public in outreach activities.
Many ASD patients will display severe disabilities and will require life-long care and support. Brain disorders are a serious health problem that causes immeasurable human suffering and enormous economic costs to the patients’ families and governments. One of the major obstacles to develop better treatments is the incomprehension of the complex cellular and molecular mechanisms underlying these diseases. Thus, fundamental research, focus on how the cerebellar circuits develop and how the brain adapts after a cerebellar lesion, is indispensable to advance in the development of new therapeutic approaches. However, an explanation on how developmental alterations of the cerebellum derive in some high-order neurodevelopmental disorders (e.g. autism) is missing. This is due to the lack of knowledge about the alteration of the cellular and molecular mechanisms that occur after a cerebellar lesion.
Our results suppose an important advance to understand the mechanisms that shape the development and maturity of thalamocortical networks after a cerebellar alteration. They also provide the necessary background to follow up on the study of the cerebellar implication in neurodevelopmental disorders.
Our study not only established the scientific basis to study the neural mechanism that occurs after a cerebellar lesion and its possible relationship with high-order deficits but also the outcome of this project has promoted scientific excellence in Spain and Europe and endorsed further research with possible medical and social impact at long-term.
3D-Lighsheet microscopy picture of an mouse brain with a cerebellar lesion (magenta uninjured side).
Dr.Moreno-Bravo at the Brain Awareness Week of the Neuroscience Insitute of Neuroscience.