Section on Developmental Neurogenomics

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

This work is conducted under protocol 89-M-0006 (NCT00001246) and falls into three broad research themes: Theme 1: Deep phenotypic studies of participants with gene dosage disorders We study brain and behavioral changes in individuals with genetically defined neurodevelopmental disorders - focusing on sex chromosome aneuploidy syndromes (SCAs). We aim to build on past work by gathering more comprehensive measures of brain structure and function, as well as providing more fine-grained information regarding the cognitive and behavioral variations that can be seen in SCA. These data clarify the developmental risks and resiliencies associated with X- and Y-chromosome dosage variation in humans, and identify neurobiological systems that might underpin these associations. We hope these insights will allow more targeting provision of clinical assessment and care in SCA, while also illuminating biological mechanisms of risk for mental health difficulties. During the last year, we have published work in two main areas. (1) Detailing the effects of individual genetic disorders on mental health. We have collaborated with Danish colleagues to map the prevalence and psychiatric risk profiles associated with >20 different genetic disorders caused by carriage of abnormal gene dosage (i.e. deletions or duplications in parts of the genome) (Vaez et al, JAMA Psychiatry, 2024). This work improves the level of information available to affected individuals, family members and clinicians facilitating access to targeted clinical assessment and follow-up. (2) Comparing the effects of different genetic disorders on human brain development. We have used detailed neuroimaging data from our own clinical protocol to map the changes in human brain organization that accompany carriage of an additional chromosome X, Y and 21 (Levitis et al, Biological Psychiatry. 2024). We find that although each individual aneuploidy induces a unique fingerprint of brain change, there is a common backbone of brain change that is shared across addition of chromosomes X, Y and 21. Strikingly this shared backbone looks like the shared signature of brain change across multiple psychiatric disorders suggesting that it might represent a useful common pathway marker for increases in psychiatric risk due to diverse causes. Theme 2: Sex differences in human brain organization Males and females differ in risk for multiple psychiatric disorders, and this robust observation may partly reflect an intersection between sex-biased brain development in human and mechanisms of risk and resilience for mental health difficulties. Therefore, understanding sex differences in human brain development may help us to better understand the biology of mental health difficulties. Over the last year, we have focused on using the mouse to narrow hypotheses about mechanisms for sex differences in the human brain. Ethical and logistic considerations make is hard to experimentally study potential mechanisms for sex differences in human brain development. In contrast, mouse models provide exquisite access to experimental methods but we have lacked ways of prioritizing which brain regions to study in the mouse when seeking to most closely model events in the human. Our Section has collaborated with experts at UCLA and the University of Oxford to carry out parallel neuroimaging studies in humans and mice (Guma et al, eLife, 2024) which identify mouse brain regions that show a similar volumetric sensitivity to sex chromosome dosage as seen in humans. We are now analyzing these murine brain regions to understand the cellular and molecular basis for sex chromosome dosage effects in brain development which will in turn narrow down our hypotheses in humans. Theme 3: Computational tools for bridging different scales of human brain organization The human cerebral cortex is an astoundingly complex structure that underpins many of our distinctive facilities and vulnerabilities. Achieving a mechanistic understanding of cortical organization in health and disease requires integrating information across its many spatial scales. However, a hard obstacle to this goal is that there are major methodological mismatches between tools we use to measure the human cortex at macro- (e.g. visible features from brain scans) vs. microscales (e.g. molecular or cellular features). In particular, neuroimaging gives dense measures of structure and function at thousands of points across the cortical sheet, whereas postmortem measures of microscale organization are often derived from disjointed cortical samples with missing data in between. Ameliorating this problem would make it easier for neuroscientist to more flexibly move between neuroimaging and genomic descriptions of the cortex thereby more firmly connecting different scales of human brain organization. Over the last year, we have worked to addresses this obstacle by building on the Allen Human Brain Atlas microarray dataset to create, validate, use and share dense neuroimaging-like maps of cortical expression for >20k genes (Wagstyl et al, eLife, 2024). This resource has enabled us to identify cortical zones with distinctive gene expression signatures post mortem which we show to overlap with cortical zones with functional specialization by brain imaging and cellular specialization postmortem. By clustering gene maps we found that regional expression gene patterns in the human cortex can be grouped into a small set (16) of canonical maps. These maps each capture different cellular and developmental properties of the cortical sheet and a subset are enriched for genes associated with psychiatric disorders. For example, risk genes for autism fall into two expression map clusters one of which predicts regional changes in cortical thickness and gene expression between people with ASD and neurotypical controls. Taken together these tools will enable diverse researchers to better connect information from neuroimaging and genomics when studying the human brain in health and disease.