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Updated: May 26, 2025
Modulating Cognition Using Transcranial Direct Current Stimulation of the Cerebellum
Published on: February 15, 2015
Cerebellar output neurons can impair non-motor behaviors by altering development of extracerebellar connectivity
Andrew S Lee1,2, Tanzil M Arefin3,4, Alina Gubanova1
1Developmental Biology Program, Sloan Kettering Institute, New York, NY, USA.
Abstract:
The capacity of the brain to compensate for insults during development depends on the type of cell loss, whereas the consequences of genetic mutations in the same neurons are difficult to predict. We reveal powerful compensation from outside the mouse cerebellum when the excitatory cerebellar output neurons are ablated embryonically and demonstrate that the main requirement for these neurons is for motor coordination and not basic learning and social behaviors. In contrast, loss of the homeobox transcription factors Engrailed1/2 (EN1/2) in the cerebellar excitatory lineage leads to additional deficits in adult learning and spatial working memory, despite half of the excitatory output neurons being intact. Diffusion MRI indicates increased thalamo-cortico-striatal connectivity in En1/2 mutants, showing that the remaining excitatory neurons lacking En1/2 exert adverse effects on extracerebellar circuits regulating motor learning and select non-motor behaviors. Thus, an absence of cerebellar output neurons is less disruptive than having cerebellar genetic mutations.
Insights
Brain compensation varies. Ablating cerebellar output neurons causes less disruption than genetic mutations (Engrailed1/2) affecting learning and memory, revealing complex cerebellar circuit interactions.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Brain compensation mechanisms are crucial for development.
- Predicting the impact of genetic mutations on neuronal function is challenging.
- Cerebellar excitatory output neurons play a role in motor coordination and behavior.
Purpose of the Study:
- To investigate the brain's compensatory capacity following cerebellar output neuron ablation versus genetic mutation.
- To elucidate the distinct roles of cerebellar output neurons in motor coordination, learning, and social behaviors.
- To understand the impact of Engrailed1/2 (EN1/2) gene loss on cerebellar function and extracerebellar circuits.
Main Methods:
- Embryonic ablation of cerebellar excitatory output neurons in mice.
- Genetic manipulation to induce loss of Engrailed1/2 (EN1/2) transcription factors in cerebellar excitatory neurons.
- Behavioral testing for motor coordination, learning, and social behaviors.
- Diffusion MRI to analyze brain connectivity.
Main Results:
- Embryonic ablation of cerebellar output neurons allowed for significant compensation, primarily impacting motor coordination, not basic learning or social behaviors.
- Loss of EN1/2 in cerebellar excitatory neurons resulted in deficits in adult learning and spatial working memory, despite neuronal survival.
- Diffusion MRI revealed altered thalamo-cortico-striatal connectivity in EN1/2 mutants, indicating adverse effects on extracerebellar circuits.
Conclusions:
- Cerebellar genetic mutations, specifically EN1/2 loss, are more disruptive to brain function than the complete absence of cerebellar output neurons.
- The remaining cerebellar neurons lacking EN1/2 exert detrimental effects on extracerebellar circuits involved in motor learning and non-motor behaviors.
- This study highlights the critical role of specific genes in neuronal function and brain circuit integrity, beyond mere cell presence.
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