Newell, K. A. | Search bioRxiv

bioRxiv2026

Transcriptomic profiling of the human habenula reveals a shared molecular architecture across mood disorders

The habenula is a critical regulator of monoaminergic and reward circuitry and is increasingly implicated in the neurobiology of mood disorders. Preclinical studies demonstrate that habenula hyperactivity drives depressive-like behaviours and can be reversed by interventions such as ketamine and deep brain stimulation. However, the molecular architecture of the human habenula remains largely unexplored. Here, we applied a transdiagnostic framework to characterise shared and disorder-specific transcriptomic alterations across affective illness. Bulk RNA sequencing was performed on postmortem habenula-enriched tissue from controls (n = 6), major depressive disorder (MDD; n = 6), and bipolar disorder (BPD; n = 6) cases from the Netherlands Brain Bank. Differential gene expression and differential transcript usage (DTU) analyses identified diagnosis- and sex-associated transcriptional changes. Individual diagnostic comparisons revealed modest numbers of differentially expressed genes (MDD: 60; BPD: 66; FDR < 0.05), consistent with limited power and/or subtle disorder-specific effects. In contrast, transdiagnostic analysis combining affective cases (MDD + BPD; n = 12) identified 378 differentially expressed genes, indicating a robust shared molecular signature across mood disorders. Upregulated genes were enriched for potassium channel activity, calcium homeostasis, and Wnt signalling, consistent with altered neuronal excitability, while downregulated genes were enriched for metal ion binding. DTU analysis identified 49 isoform switches, highlighting isoform-specific regulation not captured at the gene level. Biological sex contributed substantially to transcriptomic variation, with 67 differentially expressed genes and 18 isoform switches differing between males and females, including sex-dependent regulation of GPR151, NLGN3, and KIF17, genes known to influence neuronal excitability. Together, these findings support a shared molecular architecture across mood disorders and underscore the importance of transdiagnostic and sex-informed approaches.

neuroscience↗

bioRxiv2025

THE EFFECT OF SERTRALINE AND VOLUNTARY EXERCISE DURING PREGNANCY ON LITTER CHARACTERISTICS AND POSTNATAL AFFECTIVE BEHAVIOUR IN RAT DAMS

IntroductionSertraline is the frontline pharmacotherapy for the treatment of depression and anxiety during pregnancy. However, there is little evidence regarding the effects of sertraline on maternal behaviour or the maternal brain. Furthermore, the efficacy of non-pharmacological approaches to treatment in pregnancy, such as exercise, are unclear. Therefore, the aim of this study was to examine the effects of sertraline and exercise during pregnancy on maternal postnatal depressive-like, anxiety-like and associated behaviours, as well as litter characteristics, in a rat model of depression. We also investigated the effects of these treatments on the maternal brain, focusing initially on DNA methylation and glutamatergic markers, which have been implicated in depression. MethodTwenty-four female Wistar-Kyoto (WKY; strain that models depression and anxiety) rats were divided into three groups: 1. WKY-Sertraline; 2. WKY-Exercise, 3. WKY-Vehicle; Six female Wistar rats were included as controls. Rats were treated with sertraline (10mg/kg) or vehicle (33% propylene glycol) twice/day, from gestational day (GD) 1 to postnatal day (PN) 14. The WKY-Exercise group were provided access to a running wheel during pregnancy for 3 hours/day from GD1-18. Dam and litter characteristics, as well as pup ultrasonic vocalisations (USVs), were measured. Dams underwent behavioural testing at 5-weeks postnatal to assess depressive-, anxiety- and cognitive-like behaviours. Gene expression of DNA methylation markers (Dnmt1, Dnmt3a) and glutamate receptors (Grin1, Grin2a, Grin2b) were measured in the prefrontal cortex (PFC), using RT-qPCR. ResultThe WKY-Sertraline group gained 39% less weight in their first pregnancy week compared to all other groups (p<0.05) and produced smaller litters compared to Wistar controls (-43%; p=0.003) and WKY-Exercise (-38%; p=0.012), and WKY-Sertraline pups had slightly smaller brain weights (p=0.031 compared to WKY-Vehicle). The WKY-Exercise pups produced increased number of USVs at PN7 compared to WKY-Vehicle, with no treatment differences at PN14. The WKY strain however, did showed reduced average mean amplitude of calls and reduced average duration of calls at PN7 compared to WIS (p<0.01) and reduced number of calls at PN14 (p<0.01). Maternal sertraline treatment did not significantly affect dam behavioural measures, all maternal cortical gene expression. The WKY-Exercise group however showed reduced anxiety-like behaviours, spending more time in the open arms (620%; p=0.027) and less time in the closed arms (-22%; p=0.047) of the elevated plus maze (EPM) compared to WKY-Vehicle, and more time in the centre of the open field test (OFT) compared to WKY-Vehicle (132%; p=0.057). Furthermore, WKY-Exercise dams showed a 64% increase in Dnmt3a mRNA levels in the PFC compared to WKY-Vehicle (p=0.019). ConclusionVoluntary exercise during pregnancy in the WKY rat model, reduced postnatal anxiety-like behaviour in the dam. This was accompanied by elevated DNMT3a gene expression in the PFC, suggesting this region may be sensitive to DNA methylation changes following maternal exercise. In contrast, maternal sertraline did not impact these behaviours or genes. Maintaining sertraline treatment beyond PN14, may have resulted in broader effects on dam behaviour, which should be explored further. Maternal sertraline did appear to have some adverse effects on the in utero environment, evidenced by smaller litters, with slightly smaller pup brain weights, which should be investigated further. Our findings suggest a long-term beneficial effect of exercise during pregnancy and supports future studies examining the effects of exercise in antenatal depression in the human population.

neuroscience↗