Biology subjects

Varela, R. B.

Publications and source records attributed to Varela, R. B..

4 recordsLinked to original sources

bioRxiv2025

Unpredictable circadian rhythm disruption in Wistar rats: biological and behavioural changes reflecting bipolar disorder pathophysiology

Circadian disturbances are implicated in dysregulation of arousal and general neurobiological function, contributing to conditions such as bipolar disorder (BD). However, the behavioural and biological consequences of circadian disruption on arousal dysfunction remain poorly quantified. Here, we developed a novel unpredictable circadian disruption (UCD) protocol - consisting of unpredictable exposure to light and sound - to investigate its impact on locomotor activity and its association with metabolic, inflammatory, stress, and circadian markers in the nucleus accumbens (NAc). Forty-eight Wistar rats were exposed to UCD or control conditions, with or without corticosterone administration, for five weeks. Body weight was tracked throughout the study. Locomotor activity was assessed over the final two weeks (nine sessions) in an open-field arena. Real-time PCR was used to quantify NAc gene expression of inflammatory, metabolic, stress, and circadian markers, while liquid chromatography-mass spectrometry (LC-MS) measured neurotransmitter and central carbon metabolite concentrations. UCD animals exhibited initial hyperactivity at three weeks, followed by hypoactivity at four weeks. UCD was associated with increased NAc expression of inflammatory, stress, and circadian markers. Male UCD animals showed significant weight gain, an effect reversed in females. UCD also induced increases in NAc insulin resistance markers and reductions in central carbon metabolites, indicating disrupted striatal glucose metabolism. These findings highlight the central effects of circadian disruption on locomotor behaviour, stress, and immunometabolic signalling, offering mechanistic insights into arousal dysfunction in BD. HighlightsO_LIUnpredictable circadian disruption (UCD) triggers a biphasic shift in locomotor behaviour C_LIO_LIUCD alters levels of striatal inflammatory, circadian, stress, and metabolic markers C_LIO_LIUCD has sex-specific effects on behaviour, weight, and molecular biomarkers C_LIO_LICorticosterone administration mitigates key molecular disruptions induced by UCD C_LI

neuroscience↗

bioRxiv2025

Melatonin mitigates oxidative stress and metabolic dysfunction induced by interleukin-6 and dopamine in SH-SY5Y cells

Melatonin has emerged as a promising pharmacological candidate for bipolar disorder (BD), though its mechanisms of action remain incompletely understood. Its antioxidant, anti-inflammatory, and anti-dopaminergic properties suggest potential relevance to BD pathophysiology. This study investigated melatonins effects on dopamine signalling, metabolism, and oxidative stress under inflammatory and hyperdopaminergic conditions in differentiated SH-SY5Y neuronal cells. Cells were pretreated with 100nM melatonin or vehicle for 2 hours, then exposed to vehicle, IL-6 (20ng/mL), dopamine (5{micro}M or 500{micro}M), or dopamine (500{micro}M) with ascorbic acid (1mM) for 12 or 24 hours. Dopaminergic markers were assessed via real-time PCR and HPLC; metabolic outcomes were measured using Seahorse assay, central carbon metabolomics, in-cell Western assay, and glucose uptake assay; and oxidative stress was evaluated via reactive oxygen species (ROS), superoxide (SOX), and total antioxidant capacity (TAC) assays. IL-6 increased dopamine levels, p-Erk1/2/Erk1/2, p-AMPK/AMPK, nucleotide pools, and TAC, while reducing dopamine turnover, SV2C expression, and spare respiratory capacity. Melatonin alone increased nucleotides and NADH, while reducing dopamine turnover, ROS, and glucose-1-phosphate. In IL-6 conditions, melatonin pretreatment enhanced spare respiratory capacity, glucose uptake, and NADH, while reducing dopamine, TAC, p-AMPK/AMPK, p-GSK3{beta}/GSK3{beta}, and non-mitochondrial oxygen consumption. High-dose dopamine (500{micro}M) elevated SOX, p-Erk1/2/Erk1/2, insulin receptor-, GLUT1, glycolytic ATP (glycoATP), and non-mitochondrial oxygen consumption. Melatonin pretreatment attenuated p-Erk1/2/Erk1/2 and GLUT1 elevations. Combined dopamine and ascorbic acid further increased glycolytic intermediates, ROS, p-AMPK/AMPK, and TAC, while reducing p-Erk1/2/Erk1/2, p-mTOR, GLUT1, glucose uptake, and glycoATP. Overall, melatonin mitigated IL-6-induced dopaminergic, oxidative, and metabolic alterations, and partially protected against dopamine-induced metabolic shifts. These findings suggest melatonin may alleviate manic symptoms in BD via both direct dopaminergic modulation and indirect antioxidant and metabolic regulatory effects.

molecular biology↗

bioRxiv2023

The role of IL-6 in dopamine dysregulation underlying anhedonia phenotype in rats

AimsTo investigate the role of peripheral metabolic change and chronic low-grade inflammation on striatal dopamine dynamics and anhedonia-like behaviour induced by hypothalamic-pituitary-adrenal (HPA) axis disruption. MethodsWistar rats were trained in a progressive-ratio/concurrent effort-related choice paradigm to assess effort-related decision making. After reaching a stable baseline, animals received daily injections of adrenocorticotrophic hormone (ACTH) or saline for 24 days. On the 23rd and 24th day, animals received a bupropion challenge (10mg/kg and 20mg/kg respectively) 30 minutes prior to the behavioural testing session. On the 25th day, animals received a single injection of bupropion (20mg/kg) 30 minutes prior to euthanasia. Peripheral and central inflammatory markers were assessed through ELISA and In-Cell Western assay; glucose transport activity was assessed in peripheral blood mononuclear cells though a commercial assay kit; brain levels of dopaminergic and inflammatory markers were assessed in the nucleus accumbens (NAc) and prefrontal cortex (PFC) through immunohistochemistry; and serum central carbon metabolism metabolites were assessed through a metabolomics approach. ResultsACTH induced an anhedonia-like phenotype, decreased tyrosine hydroxylase (TH) levels in the NAc, increased peripheral IL-6 levels, and decreased glucose transport activity and glucose metabolites when compared to control group. Bupropion treatment was not able to reverse the anhedonic phenotype. Glucose uptake was positively correlated to behaviour; TH levels were correlated to microglia volume; metabolites were correlated to TH levels; and IL6 was correlated to TH levels and metabolites. ConclusionChronic ACTH treatment can induce treatment-resistant anhedonia in rats, and the interaction between peripheral immunometabolic state and central dopamine synthesis is a potential mechanism underlying this phenotype.

neuroscience↗

bioRxiv2023

Anti-manic effect of deep brain stimulation of the ventral tegmental area in an animal model of mania induced by methamphetamine

BackgroundTreatment of refractory bipolar disorder (BD) is extremely challenging. Deep brain stimulation (DBS) holds promise as an effective treatment intervention. However, we still understand very little about the mechanisms of DBS and its application on BD. AimThe present study aimed to investigate the behavioural and neurochemical effects of ventral tegmental area (VTA) DBS in an animal model of mania induced by methamphetamine (m-amph). MethodsWistar rats were given 14 days of mamph injections, in the last day animals were submitted to 20 minutes of VTA DBS in two different patterns: intermittent low frequency stimulation (LFS) or continuous high frequency stimulation (HFS). Immediately after DBS, manic-like behaviour and nucleus accumbens (NAc) phasic dopamine (DA) release were evaluated in different groups of animals through open-field test and fast-scan cyclic voltammetry. Levels of NAc dopaminergic markers were evaluated by immunohistochemistry. ResultsM-amph induced hyperlocomotion in the animals and both DBS parameters reversed this alteration. Mamph increased DA reuptake time post-sham compared to baseline levels, and both LFS and HFS were able to block this alteration. LFS was also able to reduce phasic DA release when compared to baseline. LFS was able to increase dopamine transporter (DAT) expression in the NAc. ConclusionThese results demonstrate that both VTA LFS and HFS DBS exert anti-manic effects and modulation of DA dynamics in the NAc. More specifically the increase in DA reuptake driven by increased DAT expression may serve as a potential mechanism by which VTA DBS exerts its anti-manic effects.

neuroscience↗