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Can we be genetically predisposed to psychiatric disease and addiction?

A recent study, published in NeuroResource, has used single-nucleus transcriptome analysis to identify cell-type-specific molecular signatures in the brain that are associated with genetic risk for both psychiatric disease and addiction.

Single-nucleus transcriptome analysis of the brain

Advances in single-cell and single-nucleus RNA-sequencing technologies has facilitated the molecular characterisation of diverse cell types in post-mortem brain tissue. These technologies have also been used to assess cell-type-specific gene expression differences in several brain disorders, including Alzheimer’s disease, autism spectrum disorder and multiple sclerosis. Identification of cell-type-specific gene expression signatures has contributed to our understanding of the relationship between molecular identity and cell function.

While substantial advancements have been made in understanding cell heterogeneity within and across individual regions of the human brain, the majority of single-nucleus RNA sequencing (snRNA-seq) reports are in a small number of brain areas. These primarily include the hippocampus and several heavily studied subregions of the cortex. Molecular profiling of other significant cortical subregions, including the nucleus accumbens (NAc), is lacking in the human brain.

Why is molecular profiling of cortical subregions needed?

The NAc and other cortical subregions are interconnected with well-established circuit loops that mediate important behavioural and neurobiological functions. These functions include, signalling for reward and motivation as well as processing emotional valence, such as responding to threatening stimuli. Moreover, the cellular composition of individual neuronal subtypes in these regions substantially differs from previously well characterised cortical and hippocampal regions.

For example, the NAc contains dopaminoceptive populations and GABAergic medium spiny neurons (MSNs) that harbour unique physiological and cellular properties. Recent snRNA-seq studies in rodents has revealed complex transcriptional diversity in MSNs. Moreover, subpopulations of MSNs are differentially recruited in response to cocaine exposure. However, whether and to what extent this transcriptional diversity is conserved in these regions of the human cortical has not yet been explored.

Additionally, transcriptional diversity in the cortical subregions is believed to affect an individual’s risk of psychiatric disease. Previous genome-wide association studies (GWAS) have identified a variety of genetic risk variants or loci for common psychiatric disorders, including schizophrenia. Furthermore, GWAS has also been used to identify the genetic risk and correlations for alcohol and tobacco use. Researchers have developed approaches to try and aid the identification of biological context and relevance of these loci as well as to determine their heritability.

Identifying cell-type-specific signatures associated with genetic risk of psychiatric disease and addiction

Given the evidence for the importance of specific cell types in the cortical subregion in rodents and the results of previous GWAS studies, single-cell profiling of these regions in humans may help identify analogous cell populations. These can then be used to understand genetic risk factors for human brain disorders.

To this end, the researchers behind this study created a snRNA-seq resource of 70,615 high-quality nuclei to generate a molecular taxonomy of cell types across five human brain regions, that serve as key nodes of human brain reward circuitry. The five regions studied included: the nucleus accumbens, the amygdala, the sub-genual anterior cingulate cortex, the hippocampus and the dorsolateral prefrontal cortex.

The team first identified novel subpopulations of interneurons and MSNs in the nucleus accumbens. They then further characterised the robust GABAergic inhibitory cell populations in the amygdala. Following that, joint analysis of the 107 reported cell classes revealed cell-type substructures and unique patterns of transcriptomic dynamics.

The researchers were able to identify discrete subpopulations of D1- and D2-expressing MSNs in the nucleus accumbens, to which they were able to map cell-type-specific enrichment for genetic risk associated with both psychiatric disease and addiction.

Summary and future implications for psychiatric disease and addiction

In summary, this study used snRNA-seq to profile five human brain regions with roles in the reward circuitry. The researchers defined the transcriptomic profiles for 107 regionally defined cell-type classes. This enabled them to identify associations with genetic risk for psychiatric diseases and substance use phenotypes.

This study provides a significant step towards constructing a single-nucleus transcriptomic atlas of the human brain for use in future research. Moreover, this research demonstrates the utility of this type of data in understanding the diversity of cell populations, and their roles in development of disease.

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