Findings suggest that PER3 gene variants prevent adrenal adaptation to winter daylight, leading to serotonin disruption and depression-like behaviors.
A recent study in Nature Metabolism used humanized mice with modified PERIOD3 gene variants (P415A and H417R) to explore the genetic role in winter seasonal affective disorder (SAD). Male mice exposed to short, winter-like daylight showed SAD-like behaviors, validating them as potential models for SAD research.
The study revealed that these gene variants increase corticosterone biosynthesis and disrupt HPA axis regulation, leading to elevated glucocorticoid signaling. This signaling represses Tryptophan hydroxylase 2 (Tph2), resulting in depression-like behaviors.
Study background
Several human physiological processes and clinical conditions exhibit seasonal rhythms, often linked to increases in pathogen or vector populations (in the case of transmissible diseases) or changes in environmental cues (such as mood and physiological shifts due to jetlag).
A growing body of research describes seasonal trends in psychiatric disorders, with conditions like depression, schizophrenia, and suicidal tendencies peaking during specific times of the year and subsiding during others.
The most well-documented of these trends is “winter seasonal affective disorder” (SAD), a relatively rare condition marked by the predictable onset of depressive episodes in autumn and winter, with remission in spring and summer.
SAD affects an estimated 1-10% of the population, with symptoms that can persist for up to 40% of the year, causing significant distress for patients and their families. Previous research has suggested that circadian misalignments and associated changes in monoamine neurotransmitters may play a role in SAD, but the precise mechanisms and potential genetic factors remain unconfirmed.
About the study
In their previous work, the present study group identified genetic variants of the PERIOD3 (PER3) gene that demonstrate advanced sleep patterns and seasonal mood alterations reminiscent of SAD. Called ‘P415A’ and ‘H417R’, these variants could hold the key to understanding SAD and form the basis of future therapeutic interventions against the debilitating condition.
The study used humanized mice (C57BL/6J and B6.129) genetically modified to express P415A and H417R for experimental procedures. Case (P415A or H417R) and control (wild type [WT]) mice were raised under varying daily light and dark cycles to simulate winter photophases. Advanced biochemical assays (immunoblotting, reverse transcription polymerase chain reaction [RT-PCR], plasma corticosterone assessments) were used to monitor both cohorts’ responses to photoperiod alterations.
Social interaction tests, tail suspension tests (TSTs), and forced swim tests (FST) were used to assess mood and behavioral alterations during experimental exposures (varying photoperiods).
Once the study had established the association between SAD and the genetic variants under study, Fluoxetine hydrochloride was administered to evaluate the mechanisms governing these associations.
Fluoxetine hydrochloride functions as a serotonin uptake inhibitor and helps reveal the importance of neurotransmitter concentrations and signaling under these conditions.
Study findings
Comparisons between case and control mice exposure to 4 h light-20 h dark (4L20D; “winter”) and 12 h light-12 h dark (12L12D; “normal”) photoperiods revealed substantial differences between carriers of the WT PER3 gene and those with the P415A or H417R variants.
Under 4L20D conditions, case mice were observed to significantly underperform controls in both TST and FST tests, displaying extended latency and immobilization across both examinations. These observations are nearly identical to the behavioral responses of SAD patients.
Social experiments revealed similar trends. Cases exposed to winter photoperiods displayed SAD-like isolation tendencies absent in controls.
These findings verify the humanized murine models used herein as apt representations of SAD across both physiology and behavior. Furthermore, these changes were reversed when mice were returned to 12L12D photoperiods.
Biochemical assays, in contrast, reported unexpected increases in corticosteroid concentrations.
Unlike previous studies, which regularly observed decreases or no changes in corticosteroid quantities, mice with P415A or H417R unregulated their neurotransmitter concentrations compared to controls, which downregulated corticosteroid production.
Fluoxetine hydrochloride drug administration was observed to rescue case mice both from corticosteroid upregulation and holistic SAD symptoms. Surgical removal of the adrenal glands (adrenalectomy) produced similar results.
Conclusions
The present study presents one of the first pieces of evidence of a genetic underpinning (herein, variants of the PER3 gene) governing periodic cyclic psychiatric states.
Experiments on humanized murine model systems revealed that P415A and H417R variants unregulated (rather than downregulated) corticosterone production, thereby disrupting normal stress responses and triggering situation-dependent depression.
These findings advance our understanding of the pathophysiology of SAD, provide a model system for future investigation (humanized mice), and highlight corticosterone modulation as a potential therapeutic intervention against human SAD.
- Gao, Q., Tang, Z., Wang, H. et al. (2024) Human PERIOD3 variants lead to winter depression-like behaviours via glucocorticoid signalling. Nat Metab. doi:10.1038/s42255-024-01163-z.https://www.nature.com/articles/s42255-024-01163-z
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