Brain changes in autism are much bigger than previously thought

Summary: ASD-associated brain changes encompass more areas than previously believed, a new study finds. The researchers identified brain-wide changes in the 11 cortical regions analyzed. The greatest gene losses were found in the visual cortex and parietal cortex, an area of ​​the brain associated with processing information about touch, pain and temperature. The results shed light on the sensory hypersensitivity associated with ASD. Additionally, the researchers say that the RNA alterations associated with ASDs are more likely a cause than a result of autism.

Source: UCLA

Brain changes in autism are comprehensive throughout the cerebral cortex rather than particular areas thought to affect social behavior and language, according to a new UCLA-led study that greatly refines scientists’ understanding of disorder progression of the autism spectrum (ASD) at the molecular level.

The study, published today in Nature, represents a comprehensive effort to characterize ASDs at the molecular level. While neurological disorders like Alzheimer’s disease or Parkinson’s disease have well-defined pathologies, autism and other psychiatric disorders lack definition of pathology, making it difficult to develop more effective treatments.

The new study reveals brain-wide changes in virtually all 11 cortical regions analyzed, from higher 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 autism brain,” said study author Dr. Daniel Geschwind, Gordon and Virginia MacDonald Emeritus Professor of Humanities. Genetics, Neurology and Psychiatry at UCLA.

“We are finally starting to get a picture of the brain state, at the molecular level, of the brain in people who have been diagnosed with autism. This provides us with molecular pathology that, like other brain disorders such as Parkinson’s disease, Alzheimer’s disease and stroke, provides a key starting point for understanding disease mechanisms, 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 regions of the brain, the temporal lobe and the frontal lobe. These regions were chosen because they are higher-order association regions involved in higher cognition – particularly social cognition, which is disrupted in ASD.

The new study reveals brain-wide changes in virtually all 11 cortical regions analyzed, from higher critical association regions – those involved in functions such as reasoning, language, social cognition and mental flexibility – or primary sensory regions. Image is in 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 people with ASD with healthy brain tissue.

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

The researchers said this may reflect the sensory hypersensitivity commonly reported in people with ASD.

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

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

Funding: This work was supported by grants to Geschwind (NIMHR01MH110927, U01MH115746, P50-MH106438 and R01MH109912, R01MH094714), Gandal (SFARI Bridge to Independence Award, NIMH R01-MH121521, NIMH R01-MH123922 and NICHD-P50-HD103521) and Haney (57) 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
Image: Image is in public domain

Original research: Free access.
Extensive transcriptomic dysregulation occurs in the cerebral cortex in ASD” by Daniel Geschwind et al. Nature


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Extensive transcriptomic dysregulation occurs in the cerebral cortex in ASD

Neuropsychiatric disorders typically lack defining brain pathologies, but recent work has highlighted dysregulation at the molecular level, characterized by transcriptomic and epigenetic alterations.

In autism spectrum disorders (ASD), this molecular pathology involves the upregulation of microglial, astrocyte, and neuronal-immune genes, the downregulation of synaptic genes, and the attenuation of gene expression gradients in the cortex. . However, it is unclear whether these changes are limited 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 samples from individuals with ASD and neurotypical controls.

We find widespread transcriptomic changes across the cortex in ASDs, exhibiting an anterior-posterior gradient, with the greatest differences in the primary visual cortex, coinciding with an attenuation of typical transcriptomic differences between cortical regions.

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

Genetic variations associated with rare and common ASDs converge in a down-regulated co-expression module involving synaptic signaling, and the common variation alone is enriched in an up-regulated protein chaperone gene module.

These findings highlight widespread molecular changes in the cerebral cortex in ASD, extending beyond the association cortex to broadly involve primary sensory regions.

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