Hultman, I. | bioRxiv Science

bioRxiv2023

Transcriptomic Evaluation of Stress Vulnerability Network using Single Cell RNA-Seq in mouse Prefrontal Cortex

Increased vulnerability to stress is a major risk factor for the manifestation of several mood disorders, including major depressive disorder (MDD). Despite the status of MDD as a significant donor to global disability, the complex integration of genetic and environmental factors that contribute to the behavioral display of such disorders has made a thorough understanding of related etiology elusive. Recent developments suggest that a brain-wide network approach is needed, taking into account the complex interplay of cell types spanning multiple brain regions. Single cell RNA-sequencing technologies can provide transcriptomic profiling at the single-cell level across heterogenous samples. Furthermore, we have previously used local field potential oscillations and machine learning to identify an electrical brain network that is indicative of a predisposed vulnerability state. Thus, this study combined single cell RNA-sequencing (scRNA-Seq) with electrical brain network measures of the stress-vulnerable state, providing a unique opportunity to access the relationship between stress network activity and transcriptomic changes within individual cell types. We found especially high numbers of differentially expressed genes between animals with high and low stress vulnerability brain network activity in astrocytes and glutamatergic neurons but we estimated that vulnerability network activity depends most on GABAergic neurons. High vulnerability network activity included upregulation of microglia and mitochondrial and metabolic pathways, while lower vulnerability involved synaptic regulation. Genes that were differentially regulated with vulnerability network activity significantly overlapped with genes identified as having significant SNPs by human GWAS for depression. Taken together, these data provide the gene expression architecture of a previously uncharacterized stress vulnerability brain state, enabling new understanding and intervention of predisposition to stress susceptibility. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=91 SRC="FIGDIR/small/540705v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1ebe036org.highwire.dtl.DTLVardef@cd2131org.highwire.dtl.DTLVardef@13e3519org.highwire.dtl.DTLVardef@1100e62_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

A critical role for touch neurons in a skin-brain pathway for stress resilience

Social touch can act as a stress buffer, reducing behavioral and physiological responses to stressful scenarios. However, skin-brain touch pathways that promote stress resilience remain unknown. Here, we show that mice with an early life genetic ablation of Mrgprb4-lineage touch neurons display stress vulnerability behaviors in adulthood. Chemogenetic activation of these touch neurons reduced corticosterone levels under mild acute stress conditions. In addition, whole-brain c-Fos activity mapping while chemogenetically turning on these neurons uncovered differential neural activity patterns in brain areas relevant to somatosensation, reward, and affect. To gain mechanistic insight into this skin-brain touch pathway for stress susceptibility, we used multi-circuit neurophysiological recordings across seven brain regions at baseline and after stress in mice that had Mrgprb4-lineage touch neurons ablated in early life. Interestingly, the Mrgprb4-lineage neuron-ablated mice have alterations in local field potential phase directionality and power in the theta frequencies in mesolimbic reward regions, which may underlie our observed stress susceptibility phenotype. Together, these studies revealed that sensory neurons in the skin engage networks across the brain to promote stress resilience.

neuroscience↗