Inhibitory Neurons in Nucleus Tractus Solitarius Are Involved in Decrease of Heart Rate Variability and Development of Depression-Like Behaviors in Temporal Lobe Epilepsy

Abstract

Background Diminished heart rate variability (HRV) has been observed in epilepsy, especially in epilepsy with depressive disorders. However, the underlying mechanism remains elusive. Methods We studied HRV, spontaneous recurrent seizures (SRSs) and depression-like behaviors in different phases of pilocarpine-induced temporal lobe epilepsy (TLE) in mice. Single-cell RNA sequencing analysis was used to identify various nerve cell subsets in TLE mice with and without depression. Differentially expressed gene (DEG) analysis was performed in epilepsy, depression and HRV central control-related brain areas. Results We found decreased HRV parameters in TLE mice, and alterations were positively correlated with the severity of depression-like behaviors. The severity of depression-like behaviors was correlated with the frequency of SRS. Characteristic expression of mitochondria-related genes was significantly elevated in mice with depression in glial cells, and the enrichment analysis of those DEGs showed an enriched GABAergic synapse pathway in the HRV central control-related brain area. Furthermore, inhibitory neurons in the nucleus tractus solitarius (NTS), which is an HRV central control-related brain area, were specifically expressed in TLE mice combined with depression compared to those in mice without depression. A significantly enriched long-term depression pathway in DEGs from inhibitory neurons was found. Conclusions Our study reported correlations between HRV and epilepsy-depression comorbidity in different phases of TLE. More importantly, we found that HRV central control-related inhibitory neurons are involved in the development of depression in TLE, providing new insights into epilepsy comorbid with depression.