The sleep-mood connection: Temperament modulates neuroinflammation, clock genes, and dopaminergic receptors...

Temperament plays a critical role in individual susceptibility to mood disorders, particularly in contexts of sleep disruption, through still underexplored mechanisms. This study examined how paradoxical sleep deprivation (PSD) affects behavioral and neurobiological outcomes in high- and low-exploratory (HE and LE) Wistar rats, representing distinct temperament profiles. From a cohort of 80 periadolescent males, 20 HE and 20 LE rats were identified using an open-field test and randomly assigned to PSD or control conditions. Behavioral testing evaluated impulsivity, risk-taking, anxiety-like behavior, anhedonia, despair-like behavior, and memory performance. Biological endpoints included blood uric acid, plasma cytokines, and hippocampal oxidative stress (glutathione and lipid peroxidation), cytokines (interleukin [IL] 1β, IL-6, IL-4), gene expression of circadian regulators (Clock, Bmal1, Per and Cry genes), serotonergic and kynurenine pathway enzymes (Tryptophan Hydroxylase 2, Tph2; Tryptophan 2,3-Dioxygenase,Tdo2; Indoleamine 2,3-Dioxygenase,Ido1), and dopamine D1 (Drd1) and D2 receptor (Drd2) protein levels (measured by Western Blotting). PSD exacerbated risk-taking in HE rats and increased anhedonia and immobility in LE rats. Memory impairments were observed in both groups following PSD. At molecular level, HE rats exposed to PSD showed increased lipid peroxidation, inflammation, upregulation of circadian genes and Tph2, and elevated Drd1 expression. LE rats displayed reduced serotonergic gene expression, increased kynurenine pathway activation, and selective Drd2 upregulation. These findings indicate that temperament shapes behavioral and neurobiological vulnerability to rapid eye movement sleep loss, with distinct profiles associated with mania- and depression-like phenotypes. This supports the relevance of temperament-informed frameworks in understanding mood disorder pathophysiology and guiding personalized treatment strategies.