How early-life stress leaves a 'scar' inside brain cells

Amazing stuff! Good news!

"... "We have uncovered a new biological process linking experience of early-life adversity to this long-term vulnerability to mental illness," ...

"This finding reveals a physical scar left by trauma experienced during development inside brain cells, providing scientists with a concrete biological target to develop new treatments and interventions." ...

The researchers found that an enzyme called SETD7 was more abundant in the dopamine neurons of young mice that had experienced stress compared with mice reared in a typical environment.

SETD7 helps place a chemical tag—H3K4me1—on the genetic slinky [coiled DNA]], marking the structure for uncoiling, which in turn makes the cell more reactive to everything going on in the environment, Peña explained.

The researchers then artificially boosted SETD7 in young, stress-free mice. Even without early-life stress, these mice grew up with a stretched-open DNA structure in their dopamine-producing brain cells, making it easier to turn on the genes that respond to stress. Such mice had a lower tolerance for stress in adulthood.

The researchers found that, as adults, mice whose SETD7 levels had been boosted when they were young had more reactive dopamine neurons and more anxious behavior compared with mice with normal levels of SETD7 throughout their lives.

Conversely, when the researchers blocked the SETD7 enzyme from adding too much of the H3K4me1 tag after early-life stress, the slinky remained closed, shielding mice from becoming hypersensitive to stress later in life. Despite experiencing both early-life and adult stress, mice with their SETD7 levels dampened were able to remain as social and exploratory as unstressed mice, and their dopamine neurons were active at normal levels. ..."

From the highlights and abstract:

"Highlights

• Early-life stress increases H3K4me1 and the monomethyltransferase SETD7 in VTA

• Setd7-OE heightens gene expression, dopaminergic, and behavioral responses to stress

• Setd7 knockdown in VTA ameliorates the impact of early-life stress

• Such epigenetic priming is a novel mechanism for encoding lasting stress sensitivity

Summary

Early-life stress increases gene expression, neurophysiological, and behavioral responses to subsequent stress.

Here, we determined the role of chromatin in such long-lasting sensitivity. We used a combination of bottom-up mass spectrometry, viral-mediated epigenome editing, RNA sequencing, patch-clamp electrophysiology of dopamine neurons, and behavioral quantification in a mouse model of early-life stress, focusing on the ventral tegmental area (VTA), a key dopaminergic brain region.

We found that early-life stress enriches histone-3 lysine-4 monomethylation—associated with open chromatin and primed or active enhancers—and the H3K4 monomethylase SETD7.

Mimicking early-life stress through postnatal overexpression of Setd7 and enrichment of H3K4me1 in the VTA sensitizes transcriptional, physiological, and behavioral responses to adult stress, while Setd7 knockdown ameliorates the impact of early-life stress.

These findings link early-life stress experience to long-term stress hypersensitivity within the brain’s dopaminergic circuitry, providing a mechanism by which early-life stress increases risk for mood and anxiety disorders later in life."

How early-life stress leaves a 'scar' inside brain cells

Early-life stress alters H3K4me1 in VTA to prime stress sensitivity (open access)

Graphical abstract:

Figure 3 Juvenile Setd7 overexpression augments transcriptional responses to adult stress

Autism may have two distinct subtypes based on brain connectivity patterns

Amazing stuff! I procrastinated on blogging about this one!

"... Some neuroscientists have been exploring the possibility that this well-documented diversity partly reflects differences in the brain's organization and underlying neurobiology. However, so far only a few studies have been able to link differences in autistic behavior to specific neurobiological processes. ...

Their findings ... led to the identification of two distinct autism subtypes characterized by distinct connectivity patterns. ...

"Autism is extremely heterogeneous clinically, and for many years imaging studies have also reported heterogeneous and sometimes apparently conflicting findings: some studies found reduced functional connectivity, others found increased connectivity, and others found more complex patterns. ..."

From the abstract:

"It is often assumed that phenotypic heterogeneity in autism reflects underlying pathobiological variation. However, direct evidence supporting this link is lacking. Leveraging cross-species functional neuroimaging, we show that brain dysconnectivity patterns in autism can be parsed into biologically dissociable subtypes.

Specifically, we found that functional magnetic resonance imaging (fMRI) connectivity alterations in 20 distinct genetic mouse models of autism cluster into hypoconnectivity-dominant and hyperconnectivity-dominant subtypes.

These subtypes are linked to distinct biological pathways, with hypoconnectivity being associated with synaptic dysfunction and hyperconnectivity reflecting transcriptional and immune-related alterations.

Here we identified analogous hypoconnectivity and hyperconnectivity subtypes in a multicenter human fMRI dataset of n = 940 individuals with idiopathic autism and n = 1,036 neurotypical individuals. The human autism subtypes are highly replicable, are associated with distinct functional network architectures and behavioral profiles and recapitulate the synaptic and immune-related pathways identified in the rodent dataset.

Our work provides a new empirical framework for targeted subtyping of the autism spectrum."

Autism may have two distinct subtypes based on brain connectivity patterns

Nature Neuroscience: Autism subtypes identified using cross-species functional connectivity analyses "It is often assumed that phenotypic heterogeneity in autism reflects underlying pathobiological variation. However, direct evidence supporting this link is lacking. Leveraging cross-species functional neuroimaging, we show that brain dysconnectivity patterns in autism can be parsed into biologically dissociable subtypes."

Autism subtypes identified using cross-species functional connectivity analyses (open access)

Fig. 1: fMRI connectivity in 20 autism mouse models clusters into dominant hypoconnectivity and hyperconnectivity subtypes.

Has the definition of autism become too broad to be useful?

Good question! I tend to agree! The definition has become wishy washy! 

I have been critical of the diagnosis of autism here on my blog for several years.

What is a spectrum? Anything under the sun? Just kidding!

How about the great danger of overdiagnosis? It is very real!

Had I been born 20 years later or so maybe I would have been diagnosed with autism.

Google Search provides following short timeline of milestones:

"Autism became formally categorized as a spectrum in 1994 with the DSM-IV, and was unified into a single Autism Spectrum Disorder (ASD) category in 2013 by the DSM-5. ...

1980 (DSM-III): Separated autism from schizophrenia for the first time as a distinct developmental disorder. ...

1994 (DSM-IV): Introduced the concept of a broader spectrum by adding subcategories like Asperger's disorder and PDD-NOS under an umbrella framework. ..."

"The definition of autism may have become so broad that it risks confusion and even misdiagnosis, according to a new editorial by UCL professor Dame Uta Frith, whose pioneering research in the 1960s and '70s laid the foundations for how we understand autism.

Autism is currently diagnosed as autism spectrum disorder (ASD), a single condition that includes a huge range of people, from those needing round-the-clock care to those who live independently.

In Frith's editorial, published in Psychological Medicine, she argues that this "spectrum" may now be too broad to be useful. ..."

"... “Autism wasn’t always defined this way – a sort of catch-all diagnosis for a huge variety of conditions,” she said.

“When it was first identified in the 1940s, it referred to a small group of children with severe difficulties in social interaction, communication and behaviour. ...

The number of people diagnosed with autism has increased dramatically. In the 1960s, in the UK, about 4 in 10,000 children were diagnosed. Today, it’s around 1 in 57 schoolchildren in the UK - a more than 40-fold increase. ..."

From the abstract of the editorial:

"Abstract

Background

Since the 1940s, the concept of autism has undergone marked changes, and autism spectrum disorder (ASD) is a wildly heterogenous condition. At the same time, the prevalence of ASD has increased massively.

Methods

This essay considers possible reasons for the changes and their consequences.

Results

Among drivers for the increase in prevalence are cultural changes, such as the desire for inclusion, harm avoidance, reliance on self-report, and the acceptance of masking. These have all led to a lowering of the diagnostic threshold. Furthermore, the popularity of the concept of autism boosted numbers via self-diagnosis and a search for identity.

Conclusions

Marked differences now exist between those first diagnosed in childhood and others first diagnosed in adolescence or adulthood. The time has come to examine reasons for these conceptual changes and the consequences for clinical practice and research."

Has the definition of autism become too broad to be useful?

Has autism become too broad to be useful? (original news article) "The definition of autism may have become so wide that it risks confusion and even misdiagnosis, according to a new editorial by UCL Professor Dame Uta Frith, whose pioneering research in the 1960s and 70s lay the foundations for how we understand autism."

Autism spectrum disorder: has it lost its meaning and is it leading to misdiagnosis? (editorial, open access)

Utah Frith (Source)

Hundreds of different genes have been linked to autism – but a new study suggests it may be their path to the brain that matters

Good news!

"... The researchers found that these genes “converge” on a shared set of biological pathways in the brain, triggering similar downstream effects as brain cells mature. ...

Using a CRISPR gene-editing tool, they switched off 23 genes associated with neurodevelopmental disorders in human brain cells. They then tracked how each genetic disruption altered gene activity across different stages of brain development.

Critically, they found that many of the at-risk genes produced similar effects downstream as brain cells matured. But they first converged in the same neural pathways, including pathways involved in synaptic communication, regulation of gene expression, and mitochondrial function ..."

From the abstract:

"Diverse risk genes have been identified for neurodevelopmental disorders (NDDs), but how these genes converge on similar biological pathways in neurons, and thus give rise to similar phenotypes, is unclear.

Here we apply a pooled CRISPR approach to successfully target 23 NDD loss-of-function genes with roles in chromatin biology and examine convergent effects on gene expression across human induced pluripotent stem cell-derived neural progenitor cells, glutamatergic neurons and GABAergic neurons.

Points of convergence vary between these cell types, with the greatest number of convergent genes and strongest convergent networks in mature glutamatergic neurons, where they broadly represent synaptic, epigenetic and, unexpectedly, mitochondrial pathways.

The most convergent networks were observed between NDD genes with shared biological annotations, clinical associations and co-expression patterns in human post-mortem brain.

Drugs that were predicted to reverse convergent transcriptomic signatures and/or arousal and sensory processing behaviors ameliorated behavioral phenotypes in zebrafish NDD gene mutants.

These results suggest that convergent effects of NDD risk genes could provide clinically useful insights."

Many genes have been linked to autism – but a new study suggests it may be their path to the brain that matters | Yale News "While scientists have identified hundreds of different genes that are associated with autism, a new Yale-led study suggests that the specific genes may be less important than the pathway they take to the brain."

Transcriptomic and phenotypic convergence of neurodevelopmental disorder risk genes in vitro and in vivo

Fig. 1: KO [knock out] effects of 21 NDD risk genes are most strongly correlated in mature neurons.

Fig. 2: Gene-level convergence is greatest in mature glutamatergic neurons.

Fig. 3: Network-level convergence resolves cell-type-specific and developmental-specific node genes.

Fig. 4: Functional similarity and brain co-expression between NDD genes predict gene-level and network-level convergence, with unique influences by cell type.

Researchers Discover Molecular Difference in Autistic Brains

Good news!

What does Autism Spectrum Disorder mean? Sounds impressive, but doctors don't have much of a clue yet!

"... Now, a new study ... has found that brains of autistic people have fewer of a specific kind of receptor for glutamate, the most common excitatory neurotransmitter in the brain. The reduced availability of these receptors may be associated with various characteristics linked to autism. ...

One of the leading hypotheses on the underlying causes of autism is an imbalance of excitatory and inhibitory signaling in the brain. ..."

From the abstract:

"Objective:

Autism spectrum disorder is a prevalent and heterogeneous condition with features ranging from social and communication differences to sensory sensitivities. Differences in excitatory neurotransmission have been identified in autism, but the molecular underpinnings are poorly understood. To investigate the mechanism underlying these observed differences, the authors assessed glutamatergic receptor density in autistic adults using positron emission tomography (PET) and related it to a functional EEG measure of excitatory activity.

Methods:

Metabotropic glutamate receptor 5 (mGlu5) availability was compared in autistic (N=16) and neurotypical (N=16) adults between 18 and 36 years of age, using the PET tracer 3-[18F]fluoro-5-(2-pyridinylethynyl) benzonitrile ([18F]FPEB). The PET outcome measure was volume of distribution (VT) computed with equilibrium analysis using a venous input function and partial volume correction. Group differences were quantified using mixed-model analyses. Heterogeneity was further parsed within the autistic group by quantifying the relationship between receptor availability and the slope of the EEG power spectrum, an index of excitatory-inhibitory balance. Correlations between EEG and VT were calculated using Spearman’s rho.

Results:

Across all brain regions, mGlu5 availability was significantly lower (by ~15%) in autistic relative to neurotypical control participants.

Group differences were generally greatest in the cerebral cortex. Within the autistic group, mGlu5 availability in all regions was significantly correlated with the slope of the EEG (e.g., cerebral cortex, r=0.67), such that shallower slope was associated with lower mGlu5 availability.

Conclusions:

This brain-wide investigation of mGlu5 availability with PET revealed pervasive lower mGlu5 availability across multiple brain areas in autism.

Additionally, multimethod analyses revealed associations with a noninvasive electrophysiological index of excitatory neurotransmission. These results indicate that lower brain-wide mGlu5 availability may represent a molecular mechanism underlying altered excitatory neurotransmission that has the potential to stratify the heterogeneous autism phenotype."

Researchers Discover Molecular Difference in Autistic Brains | Yale School of Medicine

Imaging Metabotropic Glutamate Receptor 5 and Excitatory Neural Activity in Autism (no public access)

Half of people arrested in London may have undiagnosed ADHD, study finds. Really!

Food for thought! Sounds like a serious case of overdiagnosis! How was ADHD defined? Call me skeptical!

Good news for defense attorneys!

Good news for criminals to plead not guilty for reasons of neurodevelopmental disorder!

Caveat: I did not read the entire article.

Half of people arrested in London may have undiagnosed ADHD, study finds | University of Cambridge "Offering screening for neurodivergence to people detained by the police could help ensure access to appropriate support and fairer treatment in the criminal justice system, say Cambridge researchers. A study from the team suggests that one in two individuals arrested and detained in London may have undiagnosed attention-deficit/hyperactivity disorder (ADHD) and one in 20 may have undiagnosed autism."

New hope for Huntington’s families as gene therapy shows remarkable results in small scale study

Good news! However, it requires a long, complex brain surgery!

"A company called uniQure has announced promising results from a trial of a new gene therapy for Huntington’s disease. ...

Huntington’s disease is a fatal brain disorder that runs in families, caused by a faulty gene that produces a protein called huntingtin. The disease typically begins to cause symptoms in people between 30 and 50 years old. ...

In this study, neurosurgeons delivered the treatment called AMT-130 directly into the brain using precise surgery guided by MRI scans. They targeted the striatum – the brain region most damaged by Huntington’s disease.

The treatment requires a single injection delivered during a complex 12- to 20-hour brain operation, which means it will probably be expensive.

AMT-130 uses a modified virus to carry genetic material that can reduce the amount of harmful huntingtin protein in brain cells. ...

The results showed that patients who received the high dose of AMT-130 (12 people) experienced significant benefits. The treatment appeared to slow disease progression by 75% over 36 months, compared with a carefully matched group of patients who didn’t receive the therapy and were from another study that investigates how the disease develops over time. ..."

"

• Pivotal study met primary endpoint; high-dose AMT-130 demonstrated statistically significant 75% disease slowing at 36 months as measured by cUHDRS compared to a propensity score-matched external control
• High-dose AMT-130 also demonstrated statistically significant slowing of disease progression as measured by TFC, a key secondary endpoint, and favorable trends across additional clinical measures
• Mean cerebrospinal fluid NfL levels were below baseline at 36 months
• AMT-130 continued to be generally well-tolerated with a manageable safety profile 
• uniQure plans to submit a BLA in the first quarter of 2026, with anticipated U.S. launch later that year, pending approval

..."

New hope for Huntington’s families as gene therapy shows remarkable results

uniQure Announces Positive Topline Results from Pivotal Phase I/II Study of AMT-130 in Patients with Huntington’s Disease (original news release)

Researchers find how epilepsy genes disrupt different brain regions using stem cell models

Good news!

"Key takeaways

• ... researchers used patient-derived stem cells to model how gene variants that cause developmental and epileptic encephalopathy type 13, a rare genetic childhood epilepsy, affect different regions of the brain.
• ​​​​​​The team discovered that the same variants drive seizure-like hyperactivity in the cortex but disrupt memory-related neural rhythms in the hippocampus by depleting inhibitory neurons — offering insight into why seizure medications alone may not address the full scope of symptoms.
• By reproducing abnormal brain activity observed in patients, the study establishes the first hippocampal assembloid model, creating a new platform for studying epilepsy, autism, Alzheimer’s disease and other brain disorders.

...

Using patient-derived induced pluripotent stem cells, the researchers generated advanced models known as 3D assembloids of two key brain areas:

the cortex, which is essential for movement and higher-order thinking, and

the hippocampus, which supports learning and memory. The results revealed strikingly different effects depending on the brain region.

In cortical models, the SCN8A variants made neurons hyperactive, mimicking seizure activity.

In hippocampal models, however, the variants disrupted the brain rhythms associated with learning and memory. This disruption stemmed from a selective loss of specific hippocampal inhibitory neurons — the brain’s traffic cops that regulate neural activity. 

These findings may help explain why patients with epilepsy often struggle with symptoms beyond seizures. ..."

From the highlights and abstract:

"Highlights

• Cortical assembloids with SCN8A mutations exhibit marked network hyperexcitability

• Hippocampal assembloids show theta-gamma coupling deficits, mirroring patient recordings

• Computational modeling predicts selective O-LM interneuron loss in the hippocampus

• scRNAseq and IHC reveal region-specific neuronal identity changes in DEE-13 assembloids

Summary

Neurodevelopmental disorders often impair multiple cognitive domains. For instance, a genetic epilepsy syndrome might cause seizures due to cortical hyperexcitability and present with memory impairments arising from hippocampal dysfunction.

This study examines how a single disorder differentially affects distinct brain regions using induced pluripotent stem cell (iPSC)-derived cortical- and hippocampal-ganglionic eminence assembloids to model developmental and epileptic encephalopathy 13, a condition arising from gain-of-function mutations in the SCN8A gene encoding the sodium channel Nav1.6.

While cortical assembloids showed network hyperexcitability akin to epileptogenic tissue, 

hippocampal assembloids did not, and instead displayed network dysregulation patterns similar to in vivo hippocampal recordings from epilepsy patients. Predictive computational modeling, immunohistochemistry, and single-nucleus RNA sequencing revealed changes in excitatory and inhibitory neuron organization that were specific to hippocampal assembloids.

These findings highlight the unique impacts of a single pathogenic variant across brain regions and establish hippocampal assembloids as a platform for studying neurodevelopmental disorders."

UCLA researchers find how epilepsy genes disrupt different brain regions using stem cell models | UCLA

Cortical versus hippocampal network dysfunction in a human brain assembloid model of epilepsy and intellectual disability (open access)

Graphical abstract

More insights into genetic factors underlying stuttering

Good news! Hopefully, better treatments will follow.

"... New research ... finds 57 unique DNA regions associated with stuttering in the largest and most comprehensive look at genetic stuttering to date.

Researchers looked at 1.1 million 23andMe genetic profiles, of those who self-reported stuttering and those who didn't, and located 57 DNA regions. Variants in these genes have been previously associated with neurodevelopmental disorders and trouble with rhythm. They also found causal links between stuttering, and depression and autism. ..."

From the abstract:

"Developmental stuttering is a highly heritable, common speech condition characterized by prolongations, blocks and repetitions of speech. Although stuttering is highly heritable and enriched within families, the genetic architecture is largely understudied. We reasoned that there are both shared and distinct genetic variants impacting stuttering risk within sex and ancestry groups. To test this idea, we performed eight primary genome-wide association analyses of self-reported stuttering that were stratified by sex and ancestry, as well as secondary meta-analyses of more than one million individuals (99,776 cases and 1,023,243 controls), identifying 57 unique loci. We validated the genetic risk of self-reported stuttering in two independent datasets. We further show genetic similarity of stuttering with autism, depression and impaired musical rhythm across sexes, with follow-up analyses highlighting potentially causal relationships among these traits. Our findings provide well-powered insights into genetic factors underlying stuttering."

ScienceAdviser

Large-scale genome-wide analyses of stuttering (open access)

Extended Data Fig. 1: Study design.

Researchers identify deletions in long noncoding RNA that lead to severe neurodevelopmental disorder

Good news! Apparently, these deletions have very severe consequences.

"... scientists reveal the role of CHASERR deletions in disrupting neurodevelopment through increased CHD2 protein expression. ...

All three patients had de novo deletions in the CHASERR gene, distinct from the promoter or coding region of CHD2. The deletions caused overexpression of the CHD2 gene on the same chromosome, leading to increased protein levels. ...

Clinical evaluations showed that the children exhibited severe encephalopathy, unique facial dysmorphisms, cortical atrophy, and cerebral hypomyelination, none of which are typical in patients with CHD2 haploinsufficiency. Brain imaging in the children revealed significant cortical atrophy, a thin corpus callosum by age 4, and generalized hypomyelination of subcortical white matter. ..."

"

• Study focused on ‘Goldilocks Gene’ CHD2 that causes autism and epilepsy
• Deletion of long non-coding RNA CHASERR produces too much CHD2 protein in the cell, leaving patients non-ambulatory, nonverbal and with intellectual delays

..."

From the abstract:

"CHASERR encodes a human long noncoding RNA (lncRNA) adjacent to CHD2, a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Here, we report our findings in three unrelated children with a syndromic, early-onset neurodevelopmental disorder, each of whom had a de novo deletion in the CHASERR locus. The children had severe encephalopathy, shared facial dysmorphisms, cortical atrophy, and cerebral hypomyelination — a phenotype that is distinct from the phenotypes of patients with CHD2 haploinsufficiency. We found that the CHASERR deletion results in increased CHD2 protein abundance in patient-derived cell lines and increased expression of the CHD2 transcript in cis. These findings indicate that CHD2 has bidirectional dosage sensitivity in human disease, and we recommend that other lncRNA-encoding genes be evaluated, particularly those upstream of genes associated with mendelian disorders. ..."

Researchers identify deletions in long noncoding RNA that lead to severe neurodevelopmental disorder "Broad Institute-led research has revealed that deletions in the CHASERR gene cause a distinct neurodevelopmental disorder resulting in severe encephalopathy, cortical atrophy, and cerebral hypomyelination."

Little-studied RNA might be key to regulating genetic disorders like epilepsy, autism (original news release) "Future studies that manipulate this RNA could help treat neurodevelopmental diseases in humans"

Neurodevelopmental Disorder Caused by Deletion of CHASERR, a lncRNA Gene

Significant autism susceptibility added to growing list of things we’ve inherited from Neanderthals

Amazing stuff! At least this seems to defeat claims that disorders like autism are of modern origin.

"We know that present-day European and Asian-derived humans have inherited between 1.5% and 4% of Neanderthal DNA, but how does that seemingly small amount of ancient genetic material impact modern physical and mental health? ...
However, genome analysis has shown that they interbred, albeit on a limited scale. ..."

"... Fourteen years ago, the first whole-genome sequence of the Neanderthal genome was published after scientists extracted DNA from the bones of three female Neanderthals that were discovered in a cave in Croatia. ...

Since then, scientists have associated Neanderthal DNA to several human health conditions, including autoimmune diseases, prostate cancer, Type 2 diabetes, skull morphology, depression and protection against schizophrenia. ..."

From the abstract:

"Homo sapiens and Neanderthals underwent hybridization during the Middle/Upper Paleolithic age, culminating in retention of small amounts of Neanderthal-derived DNA in the modern human genome. In the current study, we address the potential roles Neanderthal single nucleotide polymorphisms (SNP) may be playing in autism susceptibility in samples of black non-Hispanic, white Hispanic, and white non-Hispanic people using data from the Simons Foundation Powering Autism Research (SPARK), Genotype-Tissue Expression (GTEx), and 1000 Genomes (1000G) databases. We have discovered that rare variants are significantly enriched in autistic probands compared to race-matched controls. In addition, we have identified 25 rare and common SNPs that are significantly enriched in autism on different ethnic backgrounds, some of which show significant clinical associations. We have also identified other SNPs that share more specific genotype-phenotype correlations but which are not necessarily enriched in autism and yet may nevertheless play roles in comorbid phenotype expression (e.g., intellectual disability, epilepsy, and language regression). These results strongly suggest Neanderthal-derived DNA is playing a significant role in autism susceptibility across major populations in the United States."

Autism added to growing list of things we’ve inherited from Neanderthals Since Neanderthals' whole genome was sequenced, there’s been growing interest in how their genetics influences our health. New research has found that genetic variations derived from our ancient relatives are associated with an increased susceptibility to autism.

Study implicates Neanderthal DNA in autism susceptibility (original news release)

Enrichment of a subset of Neanderthal polymorphisms in autistic probands and siblings

Fig. 1: Group Comparison of SNP Frequencies and Quantitative Trait Loci (QTL) Network.

Cerebral organoids Reveal The Genetic Origins of Autism Spectrum Disorder at high speed and high throughput and multiple mutations simultaneously

Amazing stuff! Potentially a breakthrough! This is stunning!

"... With a revolutionizing novel system that combines brain organoid technology and intricate genetics, researchers can now comprehensively test the effect of multiple mutations in parallel and at a single-cell level within human brain organoids. This technology ... permits the identification of vulnerable cell types and gene regulatory networks that underlie autism spectrum disorders. ...
Compared to other animal species, the human brain has a mind of its own. To develop, the human brain relies on processes unique to humans, allowing us to build an intricately layered and connected cortex. These unique processes also make neurodevelopmental disorders more likely in humans. As an example, many genes conferring a high risk of developing autism spectrum disorder (ASD) are crucial for cortex development. Although clinical studies have shown causality between multiple genetic mutations and autism, researchers still do not understand how these mutations lead to brain developmental defects – and because of the uniqueness of human brain development, animal models are of limited use. ...
To help crack this black box open, researchers ... developed a technique to screen a complete set of key transcriptional regulator genes linked to autism. This development is especially impactful since the genes of interest can be examined simultaneously within a single mosaic organoid, marking the beginning of an era of intricate, efficient, and expedient genetic screening in human tissue. In the newly developed system, called “CHOOSE” (CRISPR-human organoids-scRNA-seq), each cell in the organoid carries at most one mutation in a specific ASD gene. The researchers could trace each mutation’s effect at a single-cell level and map each cell’s developmental trajectory. “With this high-throughput methodology, we can systematically inactivate a list of disease-causing genes. As the organoids carrying these mutations grow, we analyze the effect of each mutation on the development of each cell type,” ...

With the CHOOSE system ... advance research on disease-causing genes by a whole leap, providing researchers with access to a versatile and high-throughput method that can be applied to any disease and in any human model system. Importantly, CHOOSE considerably speeds up the analysis in comparison to traditional genetic loss-of-function approaches. “We can see the consequence of every mutation in one experiment, thus shortening the analysis time dramatically in comparison to traditional methods, using an approach that for decades was only possible in organisms like the fruit fly” ...

Using the CHOOSE system, the researchers show that mutations of 36 genes, known to put carriers at high risk of autism, lead to specific cell type changes in the developing human brain. They identified critical transcriptional changes regulated through common networks, called “gene regulatory networks” or GRNs. A GRN is a set of molecular regulators that interact with each other to control a specific cell function ... “We demonstrated that some cell types are more susceptible than others during brain development and identified the networks that are most vulnerable to autism mutations,” ..."

From the abstract:

"The development of the human brain involves unique processes (not observed in many other species) that can contribute to neurodevelopmental disorders. Cerebral organoids enable the study of neurodevelopmental disorders in a human context. We have developed the CRISPR–human organoids–single-cell RNA sequencing (CHOOSE) system, which uses verified pairs of guide RNAs, inducible CRISPR–Cas9-based genetic disruption and single-cell transcriptomics for pooled loss-of-function screening in mosaic organoids. Here we show that perturbation of 36 high-risk autism spectrum disorder genes related to transcriptional regulation uncovers their effects on cell fate determination. We find that dorsal intermediate progenitors, ventral progenitors and upper-layer excitatory neurons are among the most vulnerable cell types. We construct a developmental gene regulatory network of cerebral organoids from single-cell transcriptomes and chromatin modalities and identify autism spectrum disorder-associated and perturbation-enriched regulatory modules. Perturbing members of the BRG1/BRM-associated factor (BAF) chromatin remodelling complex leads to enrichment of ventral telencephalon progenitors. Specifically, mutating the BAF subunit ARID1B affects the fate transition of progenitors to oligodendrocyte and interneuron precursor cells, a phenotype that we confirmed in patient-specific induced pluripotent stem cell-derived organoids. Our study paves the way for high-throughput phenotypic characterization of disease susceptibility genes in organoid models with cell state, molecular pathway and gene regulatory network readouts."

Artificial Brain Reveals The Genetic Origins of Autism Spectrum Disorder : ScienceAlert (secondary news source)

CHOOSEn Fate: One Brain Organoid’S Tale On Autism (primary news source)

Single-cell brain organoid screening identifies developmental defects in autism

Fig. 1: The CHOOSE system for multiplexed screening of ASD risk genes in human cerebral organoids.

More evidence linking maternal vitamin D deficiency to the origins of schizophrenia

Good news!

"Previous studies have found that low levels of maternal vitamin D are one such risk factor, affecting how dopamine-producing (dopaminergic) neurons differentiate into their mature, specialized form. ...
The researchers discovered that vitamin D not only affected cell differentiation, but it also affected the neuron’s structure. ..."

"... They cultured the neurons both in the presence and absence of the active vitamin D hormone. In three different model systems they showed dopamine neurite outgrowth was markedly increased. They then showed alterations in the distribution of presynaptic proteins responsible for dopamine release within these neurites.

“What we found was the altered differentiation process in the presence of vitamin D not only makes the cells grow differently, but recruits machinery to release dopamine differently,” ..."

From the abstract:

"Vitamin D has been identified as a key factor in dopaminergic neurogenesis and differentiation. Consequently, developmental vitamin D (DVD) deficiency has been linked to disorders of abnormal dopamine signalling with a neurodevelopmental basis such as schizophrenia. Here we provide further evidence of vitamin D's role as a mediator of dopaminergic development by showing that it increases neurite outgrowth, neurite branching, presynaptic protein re-distribution, dopamine production and functional release in various in vitro models of developing dopaminergic cells including SH-SY5Y cells, primary mesencephalic cultures and mesencephalic/striatal explant co-cultures. This study continues to establish vitamin D as an important differentiation agent for developing dopamine neurons, and now for the first time shows chronic exposure to the active vitamin D hormone increases the capacity of developing neurons to release dopamine. This study also has implications for understanding mechanisms behind the link between DVD deficiency and schizophrenia."

Origins of schizophrenia may be linked to mom’s vitamin D Researchers have used molecular imaging technology to confirm maternal vitamin D levels' crucial role in developing the brain cells that produce dopamine, the body’s ‘feel-good’ chemical. The finding provides a greater understanding of the mechanisms underlying neurodevelopmental disorders like schizophrenia.

Vitamin D deficiency alters dopaminergic neuron differentiation in schizophrenia

Vitamin D: A potent regulator of dopaminergic neuron differentiation and function (open access)

Study: ADHD in US women has almost doubled; nearly 20% increase in prescriptions for women in early 20s

I remember feminists saying for decades that men are inferior because of diseases or disorders like ADHD and the Y chromosome! 😊

There is more to gender equality than meets the eye or so they say!

I find ADHD kind of a nebulous disorder with lots of grey zone! It gives doctors too much discretion!

"While men have historically been more likely to be diagnosed with attention-deficit hyperactivity disorder, a recent study shows women have been closing the gap, nearly doubling their number of diagnoses in recent years, according to a study reported by Fox News.

From 2020 to 2022, the number of American women ages 23 to 49 years old diagnosed with ADHD has nearly doubled. ...

"There are three main kinds of ADHD: inattentive, hyperactive-impulsive, and combined inattentive and hyperactive-impulsive. The inattentive type is most common in girls. It doesn't always catch the attention of teachers and parents," a medically reviewed fact sheet says.

Adult ADHD can make it hard for women to handle day-to-day stress or keep their jobs reined in. It can also involve struggling to manage finances, complete household tasks, or care for children."

Study: ADHD in US women has almost doubled; nearly 20% increase in prescriptions for women in early 20s - TheBlaze

Number of ADHD Patients Rising, Especially Among Women

Senioren mit ADHS: Manche erhalten erst im hohen Alter die Diagnose

Das scheint ein sehr interessantes und relevantes Thema zu sein. Mehre Fragen sind hier wohl notwendig.

Hier stellt sich wieder eine fundamentale Frage, ob nicht zu schnell und zu oft relative normales Verhalten als Krankheit diagnostiziert wird. Wenn es nach den Ärzten und dem Geldbeutel ginge wäre doch jeder Mensch krank! (Vorsicht: Satire)

Auf der anderen Seite ist ADHS, Autism usw. möglicherweise viel weiter verbreitet als bisher angenommen und indizieren möglicherweise eine schweres, bisher unterschätztes Gesundheitsproblem. 

Dank der heutigen Medizin und der fortgeschrittenen Zivilisation ist natürlich auch die Überlebenschance dieser Menschen deutlich angestiegen. Oder ist die Zivilisation ursächlich beteiligt am vermehrten Auftreten dieser Krankheiten?

Senioren mit ADHS: Manche erhalten erst im hohen Alter die Diagnose ADHS betrifft nicht nur Kinder, manche erfahren erst als Senioren, dass sie betroffen sind. Für viele ist die Diagnose im hohen Alter ein Schock – für andere eine Erleichterung.