Biology subjects

Narain, P.

Publications and source records attributed to Narain, P..

6 recordsLinked to original sources

bioRxiv2026

Rhythmic expression of a cAMP phosphodiesterase switches neuronal excitability states in the mammalian suprachiasmatic nucleus

How the transcriptome of a neuron determines its electrophysiological properties and how this change in different contexts are major questions in neurobiology. The intracellular molecular clocks in the circadian pacemaker neurons in the mammalian suprachiasmatic nucleus (SCN) drive 24hr rhythms in clock gene expression via a transcriptional-translational feedback loop1,2. These molecular clocks also control 24hr rhythms in the firing of SCN neurons3-5 - a subset of which enter a silent depolarized state around midday6. We used single-cell RNA sequencing and identified that the Avp / Nms and Vip / Nms are the SCN neurons that undergo daytime silencing. We also found high level and rhythmic expression of the Pde10a phosphodiesterase in these Nms SCN neurons. Acutely inhibiting Pde10a activity or elevating intracellular cAMP - to bypass high Pde10a levels - specifically shifts these Nms+ SCN neurons into a depolarized silent state hours ahead of schedule. A similar mechanism may occur in other neurons that switch to silent depolarized states.

neuroscience↗

bioRxiv2026

Circuit-selective cognitive vulnerability to environmental stress: multi-domain assessment of space radiation in both sexes reveals countermeasure trade-offs

Environmental stressors rarely affect just one brain circuit. Most studies assess single cognitive endpoints, obscuring whether vulnerabilities are global or circuit-selective and how effects distribute across interconnected systems. To address this, we used galactic cosmic radiation (GCR), a Mars mission-relevant stressor that disrupts the hippocampal-nucleus accumbens-prefrontal circuit. C57BL/6J mice received 33-ion GCR simulation (33-GCR, 0.75 Gy) or sham radiation with the Nrf2-activating compound CDDO-EA or vehicle, followed by multi-domain behavioral testing in both sexes. Under very high memory load, male Veh/33-GCR mice showed enhanced pattern separation compared to Veh/Sham males, an effect normalized by CDDO-EA. Female mice showed no radiation-induced changes in pattern separation but weighed 9-18% more than Veh/Sham females and had reduced locomotor activity. Reward-based learning differed by sex: males showed no changes, while female Veh/33-GCR mice displayed enhanced reward anticipation that was further increased by CDDO-EA alone, with both treatments contributing to elevated goal-tracking. For behavioral flexibility, CDDO-EA impaired reversal learning in males regardless of radiation, while 33-GCR impaired reversal learning in females regardless of CDDO-EA. Principal component analysis revealed that treatments disrupted specific circuit relationships while leaving others intact, consistent with selective rather than global cognitive effects. Fiber photometry showed enhanced dentate gyrus encoding activity in irradiated males under high memory load. Combined CDDO-EA/33-GCR selectively reduced dentate gyrus progenitors in females. Males and females showed distinct, circuit-selective vulnerability patterns, demonstrating that multi-domain, both-sex assessment is necessary to capture how stressors and interventions affect integrated brain function. CDDO-EA proved to be a double-edged sword: protecting one cognitive domain while impairing another, a trade-off invisible to single-endpoint assessment. This framework has immediate relevance for astronaut risk assessment and extends to any context where neuroprotective interventions are evaluated against environmental stressors.

animal behavior and cognition↗

bioRxiv2025

Distinct depressive-like behavioural phenotypes in mice exhibit unique patterns of transcriptional perturbations across habenular cell subtypes

Major depressive disorder arises from diverse neurobiological mechanisms, yet how specific habenular cell types contribute to distinct depressive-like behaviours remains unclear. Using chronic social defeat stress, behavioural phenotyping, and single-cell RNA sequencing, we mapped stress-induced transcriptional changes across habenular cell types and lateral habenula (LHb) subregions. Our findings reveal that each behavioural phenotype is marked by its own transcriptional profile. These subregion-specific patterns across the LHb suggest that different cellular circuits contribute uniquely to depressive-like states.

neuroscience↗

bioRxiv2023

Nighttime-specific gene expression changes in suprachiasmatic nucleus and habenula are associated with resiliency to chronic social stress

The molecular mechanisms that link stress and circadian rhythms still remain unclear. The habenula (Hb) is a key brain region involved in regulating diverse types of emotion-related behaviours while the suprachiasmatic nucleus (SCN) is the bodys central clock. To investigate the effects of chronic social stress on transcription patterns, we performed gene expression analysis in the Hb and SCN of stress naive and stress exposed mice. Our analysis revealed a large number of differentially expressed genes and enrichment of synaptic and cell signalling pathways between resilient and stress-naive mice at ZT16 in both the Hb and SCN. This transcriptomic signature was nighttime-specific and observed only in stress-resilient mice. In contrast, there were relatively few differences between the stress-susceptible and stress-naive groups across timepoints. Our results reinforce the functional link between diurnal gene expression patterns and differential responses to stress, thereby highlighting the importance of temporal expression patterns in homeostatic stress responses.

neuroscience↗

bioRxiv2023

Chronic social stress blunts core body temperature and molecular rhythms of Cirbp and Rbm3 in mice lateral habenula

Chronic social stress in mice causes behavioral and physiological changes that result in perturbed rhythms of body temperature, activity and sleep-wake cycle. To further understand the link between mood disorders and temperature rhythmicity in mice that are resilient or susceptible to stress, we measured core body temperature (Tcore) before and after exposure to chronic social defeat stress (CSDS). We found that Tcore amplitudes of stress-resilient and susceptible mice are dampened during exposure to CSDS. However, following CSDS, resilient mice recovered temperature amplitude faster than susceptible mice. Furthermore, the interdaily stability (IS) of temperature rhythms was fragmented in stress-exposed mice during CSDS, which recovered to control levels following stress. There were minimal changes in locomotor activity after stress exposure which correlates with regular rhythmic expression of Prok2 - an output signal of the suprachiasmatic nucleus. We also determined that expression of thermosensitive genes Rbm3 and Cirbp in the lateral habenula (LHb) were blunted 1-day after CSDS. Rhythmic expression of these genes recovered 10 days later. Overall, we show that CSDS blunts Tcore and thermosensitive gene rhythms. Tcore rhythm recovery is faster in stress-resilient mice, but Rbm3 and Cirbp recovery is uniform across the phenotypes.

neuroscience↗

bioRxiv2020

Blunted Diurnal Firing in Lateral Habenula Projections to Dorsal Raphe Nucleus and Delayed Photoentrainment in Stress-Susceptible Mice.

Daily rhythms are disrupted in patients suffering from mood disorders. The lateral habenula (LHb) and dorsal raphe nucleus (DRN) contribute to circadian timekeeping and regulate mood. Thus, pathophysiology in these nuclei may be responsible for aberrations in daily rhythms during mood disorders. Using the chronic social defeat stress (CSDS) paradigm and in-vitro slice electrophysiology we measured the effects of stress on diurnal rhythms in firing of LHb cells projecting to the DRN (cellsLHb[->]DRN) and DRN cells alone. We also performed optogenetic experiments to investigate if increased firing in cellsLHb[->]DRN during exposure to subthreshold social defeat stress (SSDS), induces stress-susceptibility. Last we investigated whether exposure to CSDS affected the ability of mice to phototentrain to a new LD cycle. The cellsLHb[->]DRN and DRN cells alone of stress-susceptible mice express greater blunted diurnal firing compared to stress-naive (control) and stress-resilient mice. Day-time optogenetic activation of cellsLHb[->]DRN during SSDS induces stress-susceptibility which shows the direct correlation between increased activity in this circuit and putative mood disorders. Finally, we found that stress-susceptible mice are slower, while stress-resilient mice are faster, at photoentraining to a new LD cycle. Our findings suggest that CSDS induces blunted daily rhythms in firing in cellsLHb[->]DRN and slow rate of photoentrainment in susceptible-mice. In contrast, resilientmice may undergo homeostatic adaptations that maintain daily rhythms in firing in cellsLHb[->]DRN and also show rapid photoentrainment to a new LD-cycle.

neuroscience↗