Single-nucleus RNA sequencing reveals cellular and molecular signatures in the prefrontal cortex of a hypoactive sexual desire disorder rat model.

BACKGROUND

Hypoactive sexual desire disorder (HSDD), a prevalent condition affecting sexual health in women, is induced by imbalanced neurobiological regulation of excitatory and inhibitory pathways associated with sexual response. The prefrontal cortex (PFC) is a key region in the sexual desire response pathway. Nevertheless, the cellular dynamics and molecular mechanisms driving the pathophysiology of HSDD remain unclear, limiting targeted therapeutic development.

AIM: To explore the cellular and molecular mechanisms of HSDD using a female rat model.

METHODS

We established a translational HSDD model using female Sprague-Dawley rats with low sexual desire. Subsequently, single-nucleus RNA sequencing (snRNA-seq) and multimodal bioinformatics analyses were used to comprehensively characterize cellular diversity and transcriptional signatures in the PFC.

OUTCOMES: Primary: neuronal/glial composition; secondary: disease-relevant pathway dysregulation.

RESULTS

SnRNA-seq profiling revealed altered PFC cell composition in rats with low sexual desire (LSD), with increased proportions of inhibitory neuron subtypes (Inh1-3) and microglia, concomitant reductions in excitatory neuron populations (Ex1 and Ex3), and disrupted oligodendrocyte precursor cell (OPC) maturation. Transcriptomic analysis revealed 506 differentially expressed genes (DEGs), of which 91.3% were downregulated in the LSD group. Enrichment analyses linked the DEGs to mitochondrial dysfunction, lysosomal function, and neurodegenerative disease-associated pathways.

CLINICAL IMPLICATIONS: These preliminary findings potentially advance our understanding of HSDD neurobiology, and identify testable targets for therapeutic intervention.

STRENGTHS & LIMITATIONS: The high-throughput analysis offered detailed information, but the small sample size and potential confounding factors in phenotype classification were limitations.

CONCLUSIONS

We have established a stable translational model of HSDD through rigorous screening and validation, demonstrating specific molecular and cellular alterations in the PFC of model rats characterized by: (1) excitatory-inhibitory neuronal imbalance, (2) microglial activation indicative of neuroimmune dysregulation, and (3) OPC maturation deficits.