Gene expression links functional networks across cortex and striatum

Abstract

The human brain is comprised of a complex web of functional networks that link anatomically distinct regions. However, the biological mechanisms supporting network organization remain elusive, particularly across cortical and subcortical territories with vastly divergent cellular and molecular properties. Here, using human and primate brain transcriptional atlases, we demonstrate that spatial patterns of gene expression show strong correspondence with limbic and somato/motor cortico-striatal functional networks. Network-associated expression is consistent across independent human datasets and evolutionarily conserved in non-human primates. Genes preferentially expressed within the limbic network (encompassing nucleus accumbens, orbital/ventromedial prefrontal cortex, and temporal pole) relate to risk for psychiatric illness, chloride channel complexes, and markers of somatostatin neurons. Somato/motor associated genes are enriched for oligodendrocytes and markers of parvalbumin neurons. These analyses indicate that parallel cortico-striatal processing channels possess dissociable genetic signatures that recapitulate distributed functional networks, and nominate molecular mechanisms supporting cortico-striatal circuitry in health and disease.

Convergent molecular, cellular, and neural signatures of major depressive disorder

“…Our results suggest that normative patterns of brain gene expression capture biologically meaningful information about depression related differences in cortex. These data converge with reports that spatial gene expression may reflect regional sensitivity to psychiatric illnesses 36,67 , neurodevelopmental disorders 37 , and normative brain function and organization 39,68,69 . Here, we demonstrate that gene-wise association to depression imaging phenotypes correlated with gene downregulation in post-mortem patient tissue samples ( Figure 3).…”

“…Considerable evidence indicates a preferential vulnerability of SST interneurons in depression and affective illness 11,40 . Multi-scale studies in humans link SST related transcription to reward related cortico-striatal circuitry as well as regional variation in cortical function 36,39 .…”

“…For instance, brain areas that preferentially express genes related to a psychiatric disorder may be particularly vulnerable to illness progression 36,37 . Reductions in somatostatin (SST) gene expression are a pronounced pathophysiological feature of depression 11,38 , underscored by the preferential expression of SST markers in cortico-striatal reward circuitry and mPFC in donor tissue from healthy populations 36,39 . SST expression is reduced within dorsolateral prefrontal cortex and subgenual mPFC in patients with depression 40,41 , and experimental manipulation of SST neurotransmission in rodents modulates anxiolytic and antidepressant behaviors 42 as well as socioaffective processing 43 .…”

Distinct genetic signatures of cortical and subcortical regions associated with human memory

“…While similar work has been done in recent years, most effort concentrate either on functional networks in either the cerebral cortex or subcortex due to the disparate patterns of gene expression across these regions 8,[12][13][14][15][16] . However, recent work also suggests that functional networks in the human brain have convergent gene expression patterns across cortical and subcortical areas 17 .…”

“…During neurodevelopment, functionally-related neurons may migrate across cortical or subcortical areas, and thus form a convergent gene expression profile across these regions 47,48 . During adulthood, neurons in different brain areas may be structurally 49,50 or functionally connected 51 , and thus share a common molecular mechanisms for areas within the same functional network [12][13][14]17,52,53 . These shared gene signatures may reflect cortico-cortical 13 and functional connectivity 14,54 .…”