Brain changes in autism are far more comprehensive than previously known

Brain changes in autism are far more comprehensive than previously known

Brain changes in autism are far more comprehensive than previously known

Abstract: Brain changes associated with ASD span more areas than previously believed, a new study reports. The researchers identified brain-wide changes in all 11 cortical regions analyzed. The biggest drop in genes was found in the visual cortex and parietal cortex, an area of ​​the brain associated with processing information about touch, pain and temperature. The findings shed light on the sensory hypersensitivity associated with ASD. In addition, the researchers say that the RNA changes associated with ASD are more likely to be a cause than a consequence of autism.

Source: UCLA

Brain changes in autism are pervasive throughout the cerebral cortex, not just in specific areas thought to affect social behavior and language, according to a new UCLA-led study that significantly advances scientists’ understanding of how autism spectrum disorder ( ASD) progresses at the molecular level. .

A study published today in Nature, represents a comprehensive effort to characterize ASD at the molecular level. While neurological disorders such as Alzheimer’s disease or Parkinson’s disease have well-defined pathologies, autism and other psychiatric disorders lack a defined pathology, which makes it difficult to develop more effective treatments.

The new study finds brain-wide changes in nearly all 11 cortical regions analyzed, whether they are more critical association regions—those involved in functions such as reasoning, language, social cognition, and mental flexibility—or primary sensory regions.

“This work represents the culmination of more than a decade of work by many members of the lab, which was necessary to perform such a comprehensive analysis of the autistic brain,” said study author Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Sciences. Genetics, Neurology and Psychiatry at UCLA.

“We are now finally starting to get a picture of the state of the brain, at the molecular level, of the brain in individuals diagnosed with autism. This gives us molecular pathology, which, similar to other brain disorders such as Parkinson’s, Alzheimer’s and stroke, provides a key starting point for understanding the mechanisms of the disorder, which will inform and accelerate the development of disease-modifying therapies.”

Just over a decade ago, Geschwind led the first effort to identify the molecular pathology of autism by focusing on two brain regions, the temporal lobe and the frontal lobe. These regions were chosen because higher-order association regions are involved in higher cognition—especially social cognition, which is impaired in ASD.

Brain changes in autism are far more comprehensive than previously known
The new study finds brain-wide changes in nearly all 11 cortical regions analyzed, whether they are more critical association regions—those involved in functions such as reasoning, language, social cognition, and mental flexibility—or primary sensory regions. The image is in the public domain

For the new study, the researchers examined gene expression in 11 cortical regions by sequencing RNA from each of the four major cortical lobes. They compared brain tissue samples obtained after death from 112 individuals with ASD with healthy brain tissue.

While every cortical region profiled showed changes, the biggest declines in gene levels were in the visual cortex and the parietal cortex, which processes information such as touch, pain and temperature.

The researchers said this may reflect the sensory hypersensitivity that often occurs in people with ASD.

The researchers found strong evidence that genetic risk for autism is enriched in a specific neuronal module that has lower expression in the brain, indicating that RNA changes in the brain are likely the cause of ASD rather than a consequence of the disorder.

One of the next steps is to determine whether researchers can use computational approaches to develop therapies based on reversing the gene expression changes researchers have found in ASD, Geschwind said, adding that researchers can use organoids to model the changes to better understand their mechanisms.

Other authors include Michael J. Gandal, Jillian R. Haney, Brie Wamsley, Chloe X. Yap, Sepideh Parhami, Prashant S. Emani, Nathan Chang, George T. Chen, Gil D. Hoftman, Diego de Alba, Gokul Ramaswami, Christopher L. Hartl, Arjun Bhattacharya, Chongyuan Luo, Ting Jin, Daifeng Wang, Riki Kawaguchi, Diana Quintero, Jing Ou, Ye Emily Wu, Neelroop N. Parikshak, Vivek Swarup, T. Grant Belgard, Mark Gerstein, and Bogdan Pasaniuc. The authors declare no conflicting interests.

Financing: This work was funded by grants to Geschwind (NIMHR01MH110927, U01MH115746, P50-MH106438 and R01MH109912, R01MH094714), Gandal (SFARI Bridge to Independence Award, NIMH R01-MH121521, NIMH R01-MH12ICHD1-P930), and Haney (N75 N2HD1-P93). and Achievement Rewards for College Scientists Foundation, Los Angeles Founder Chapter, UCLA Neuroscience Interdepartmental Program).

About this autism research news

Author: Jason Millman
Source: UCLA
Contact: Jason Millman – UCLA
Picture: The image is in the public domain

Original research: Open access.
Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD” Daniel Geschwind et al. Nature


Abstract

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Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD

Neuropsychiatric disorders classically lack defining brain pathologies, but recent work has shown dysregulation at the molecular level, characterized by transcriptomic and epigenetic changes.

In autism spectrum disorder (ASD), this molecular pathology includes upregulation of microglial, astrocytic, and neural-immune genes, downregulation of synaptic genes, and attenuation of gene expression gradients in the cortex. However, it remains unknown whether these changes are restricted to cortical association regions or are more widespread.

To address this issue, we performed RNA-sequencing analysis of 725 brain samples spanning 11 cortical areas from 112 postmortem specimens of individuals with ASD and neurotypical controls.

We find widespread transcriptomic changes in the cortex in ASD, showing an anterior-posterior gradient, with the largest differences in the primary visual cortex, coincident with the attenuation of typical transcriptomic differences between cortical regions.

Single-core RNA sequencing and methylation profiling show that this robust molecular signature reflects changes in cell-type-specific gene expression, specifically affecting excitatory neurons and glia.

Both rare and common genetic variations associated with ASD converge within a down-regulated co-expression module involving synaptic signaling, and the common variation itself is enriched within a module of up-regulated protein chaperone genes.

These results highlight widespread molecular changes in the cerebral cortex in ASD, extending beyond the association cortex and broadly involving primary sensory regions.

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