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Biology subjects

Rafael, L.

Publications and source records attributed to Rafael, L..

2 recordsLinked to original sources

Savings in visuomotor learning is associated with connectivity changes within a cerebello-thalamo-cortical network encoding movement errors

Savings refers to faster relearning upon re-exposure to a previously experienced movement perturbation. One theory suggests that the brain recognizes past errors and is therefore more able to learn from them. If true, there should be a modification of the neural response to errors during re-exposure to a perturbation. To test this idea, we imaged the brains of participants who underwent two sessions (1 day apart) of adaptation to a visuomotor perturbation and investigated brain responses to movement errors. The magnitude of movement error was entered into different types of GLMs to study error-related activation and coactivation (or functional connectivity). We identified a cerebello-thalamo-cortical network involved in the processing of movement errors during adaptation. We found that connectivity between regions of this network (i.e., between the cerebellum and the thalamus, and between the primary somatosensory cortex and the anterior cingulate cortex) became stronger during re-adaptation. Importantly, participants with the largest increases in connectivity strength were those who demonstrated the largest amounts of savings. These results establish a relationship between the ability of the brain to represent errors and the phenomenon of savings.

neuroscience↗

Rare genetic variation in Fibronectin 1 (FN1) protects against APOEe4 in Alzheimer's disease

The risk of developing Alzheimers disease (AD) significantly increases in individuals carrying the APOE{varepsilon}4 allele. Elderly cognitively healthy individuals with APOE{varepsilon}4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects of APOE{varepsilon}4; however, these mechanisms are unknown. We hypothesized that APOE{varepsilon}4 carriers without dementia might carry genetic variations that could protect them from developing APOE{varepsilon}4-mediated AD pathology. To test this, we leveraged whole genome sequencing (WGS) data in National Institute on Aging Alzheimers Disease Family Based Study (NIA-AD FBS), Washington Heights/Inwood Columbia Aging Project (WHICAP), and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) cohorts and identified potentially protective variants segregating exclusively among unaffected APOE{varepsilon}4 carriers. In homozygous unaffected carriers above 70 years old, we identified 510 rare coding variants. Pathway analysis of the genes harboring these variants showed significant enrichment in extracellular matrix (ECM)-related processes, suggesting protective effects of functional modifications in ECM proteins. We prioritized two genes that were highly represented in the ECM-related gene ontology terms, (FN1) and collagen type VI alpha 2 chain (COL6A2) and are known to be expressed at the blood-brain barrier (BBB), for postmortem validation and in vivo functional studies. The FN1 and COL6A2 protein levels were increased at the BBB in APOE{varepsilon}4 carriers with AD. Brain expression of cognitively unaffected homozygous APOE{varepsilon}4 carriers had significantly lower FN1 deposition and less reactive gliosis compared to homozygous APOE{varepsilon}4 carriers with AD, suggesting that FN1 might be a downstream driver of APOE{varepsilon}4-mediated AD-related pathology and cognitive decline. To validate our findings, we used zebrafish models with loss-of-function (LOF) mutations in fn1b - the ortholog for human FN1. We found that fibronectin LOF reduced gliosis, enhanced gliovascular remodeling and potentiated the microglial response, suggesting that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with FN1 LOF. Our study suggests vascular deposition of FN1 is related to the pathogenicity of APOE{varepsilon}4, LOF variants in FN1 may reduce APOE{varepsilon}4-related AD risk, providing novel clues to potential therapeutic interventions targeting the ECM to mitigate AD risk.

genetics↗