Search Results (319)

Artificial sweeteners, or non-caloric sweeteners (NCSs), are widely consumed as sugar substitutes to reduce energy intake and manage obesity. Once considered inert, accumulating evidence now shows that NCSs interact with host physiology, altering gut microbiota composition and neural circuits that regulate feeding. This review synthesizes current knowledge on how NCSs disrupt the gut–brain axis (GBA), with particular focus on microbiota-mediated effects and neural reward processing. In homeostatic regulation, NCS-induced dysbiosis reduces beneficial taxa such as Akkermansia muciniphila and Faecalibacterium prausnitzii, diminishes short-chain fatty acid production, impairs gut barrier integrity, and promotes systemic inflammation. These changes blunt satiety signaling and favor appetite-promoting pathways. Beyond homeostasis, NCSs also rewire hedonic circuits: unlike caloric sugars, which couple sweet taste with caloric reinforcement to robustly activate dopaminergic and hypothalamic pathways, NCSs provide sensory sweetness without energy, weakening reward prediction error signaling and altering neuropeptidergic modulation by orexin, neurotensin, and oxytocin. Microbial disruption further exacerbates dopaminergic instability by reducing precursors and metabolites critical for reward regulation. Together, these top-down (neural) and bottom-up (microbial) mechanisms converge to foster maladaptive food seeking, metabolic dysregulation, and increased vulnerability to overeating. Identifying whether microbiome-targeted interventions can counteract these effects is a key research priority for mitigating the impact of NCSs on human health. Full article

Aim: The research examined the relationship between SLC6A3 3′-UTR and intron 8 VNTR polymorphisms and their influence on supra-second time estimation performance and EEG alpha band activity. Material and methods: A total of 178 male participants (aged 18 to 32 years) underwent genotyping for the SLC6A3 3′-UTR and intron 8 VNTR polymorphisms. An electroencephalographic assessment was conducted targeting the dorsolateral prefrontal cortex (DLPFC), simultaneously with the time estimation task. The 3′-UTR and intron 8 VNTRs polymorphisms were linked to absolute error and ratio in a time estimation task (target duration: 1 s, 4 s, 7 s, and 9 s) neurophysiological variable. Results: Regarding the absolute error and ratio, the combinatory effect of SLC6A3 3′-UTR and intron 8 VNTRs showed a difference in the interpretation of time only for 1 s (p = 0.0002). In the EEG alpha power, the analysis revealed a difference only for the left DLPFC (p = 0.0002). Conclusions: Electrophysiological and behavioral investigation in the time perception associated with the SLC6A3 gene suggests an alternative evaluation of neurobiological aspects inbuilt in timing. The 3′-UTR and intron 8 VNTR polymorphisms modulate dopaminergic neurotransmission during short-temporal scale judgment in the domain of supra seconds and indicate a role in its inputs to the left dorsolateral prefrontal cortex during the voluntary attention processes for visual stimulus. Our findings demonstrate that cognitive resources to capture and store time intervals can be measured based on the EEG power activity pattern. Full article

Background/Goal: Parkinson’s disease (PD) disrupts dopaminergic transmission, leading to motor deficits and altered activity in the primary motor cortex (M1). While M1 modulation is critical for motor control, its response to dopaminergic degeneration and treatment remains unclear. This study aimed to characterize M1 neuronal activity and motor behavior in hemiparkinsonian rats using in vivo calcium imaging across naïve, lesioned, and levodopa-treated states. Methods: Thirteen Sprague Dawley rats were injected with GCaMP6f in the M1 and implanted with a GRIN lens and guide cannula targeting the medial forebrain bundle. Calcium imaging and motor behavior were assessed longitudinally using a single pellet reaching test (SPRT) before and after unilateral 6-hydroxydopamine (6-OHDA) lesioning and subsequent levodopa/carbidopa treatment. Dopaminergic lesion severity was quantified via tyrosine hydroxylase immunohistochemistry. Calcium event frequency and influx were analyzed with CNMF-E and statistical modeling. Results: Levodopa treatment improved fine motor performance as shown by a significant reduction in grasp errors (mean difference: −8.91, 95% CI: −16.66 to −1.16, p = 0.031) and increased reaching duration (mean difference: 4.13, 95% CI: 0.94 to 7.32, p = 0.019) compared to the lesioned state. M1 calcium activity showed modulation dependent on lesion severity: low-lesion rats exhibited reduced event frequency (mean difference: 0.04 Hz, 95% CI: 0.001 to 0.08, p = 0.045) and increased influx post-lesion (mean difference: −0.20 z·s, 95% CI: −0.38 to −0.02, p = 0.038), while high-lesion rats showed increased influx only after levodopa treatment (mean difference: −0.34 z·s, 95% CI: −0.52 to −0.16, p = 0.003). Correlation analyses revealed that calcium influx, but not frequency, was negatively correlated with lesion severity during levodopa treatment (Spearman r = −0.857, p = 0.024). Conclusion: M1 neuronal activity appears to be differentially modulated by dopaminergic degeneration and levodopa treatment in a lesion-dependent manner. These preliminary findings suggest dynamic cortical responses in PD and support the utility of calcium imaging for monitoring circuit-level changes in disease and therapy. Further research with larger cohorts and complementary methodologies will be necessary to validate and extend these observations. Full article

In their natural habitat, male Betta splendens are territorial resource defenders, whereas females are non-territorial opportunistic foragers. This ecological difference suggests that males may be more capable of delaying gratification for food rewards. The present study examined impulsive choice in Betta splendens through two experiments comparing subjects’ choices between a Smaller-Sooner (SS) reward (1 pellet immediately) and a Larger-Later (LL) reward (3 pellets after 15 s). In Experiment I, the choice distributions of males were more likely to stabilize on the LL option over the SS option, whereas females’ choice distributions were equally likely to stabilize on either option. These findings indicate that most males demonstrated spontaneous behavioral self-control without specialized training, while females were collectively indifferent. Experiment II investigated whether dopamine modulates this behavior by administering oral L-Dopa (60 mg/kg) to males before trials. Using the same procedures, only 30% of L-Dopa-treated males’ choice distributions stabilized on the LL reward, while 70% of experimental males’ choice distributions stabilized on the SS option; the choice distributions of control males were equally likely to stabilize on either reward. These results suggest that elevated dopaminergic activity increases impulsive choice in male Betta splendens. Future studies should examine dopamine agonists and antagonists, as well as female responses, to further clarify dopamine’s role in reward valuation and behavioral self-control in Betta splendens. Full article

Schinus terebinthifolia Raddi. leaf lectin (SteLL) has been investigated for its neuromodulatory effects. Given the etiological diversity of depression, this study evaluated the effects of SteLL in a pharmacological model induced by reserpine. Mice were administered reserpine intraperitoneally for 10 days to induce anxiety- and depression-like symptoms. Before reserpine administration, animals also received SteLL (2 or 4 mg/kg, i.p.) or fluoxetine (10 mg/kg, i.p.) for 10 days. Behavioral assessments included the open field test, elevated plus maze, and tail suspension test. Body weight variation and brain levels of cytokines, noradrenaline, dopamine, and serotonin were also analyzed. In reserpine-treated mice, SteLL administration (2 and 4 mg/kg) produced anxiolytic-like effects in the open field (reduced number of rearings) and elevated plus maze (increased time spent in open arms) and significantly reduced immobility time in the tail suspension test. Additionally, SteLL prevented the body weight loss typically induced by reserpine. SteLL treatment modulated neuroinflammation by reducing IL-2 and increasing IL-10 levels in the brain. SteLL treatment restored dopaminergic and noradrenergic levels, with no effect on serotonin. In conclusion, SteLL was effective in reserpine-induced monoaminergic depletion, reversing behavioral and biochemical alterations characteristic of depression, likely through dopaminergic, noradrenergic, and anti-inflammatory mechanisms. Full article

Globally, Parkinson’s disease (PD) is the neurodegenerative condition with the most rapidly increasing prevalence, and a growing body of evidence associates its pathology with impairments in the gut–brain axis. Traditionally viewed as a disease marked by the loss of dopaminergic neurons, emerging evidence emphasizes that chronic neuroinflammation is a driver of neurodegeneration, with gut-originating inflammation playing a crucial role. Increased intestinal permeability, often called “leaky gut,” allows harmful substances, toxins, and misfolded α-synuclein into the systemic circulation, potentially exacerbating neuroinflammation and spreading α-synuclein pathology to the brain through the vagus nerve or compromised blood–brain barrier (BBB). This review synthesizes current insights into the relationship between gut health and PD, emphasizing the importance of gut permeability in disrupting intestinal barrier function. This paper highlights innovative therapeutic approaches, particularly personalized therapies involving gut microbiome engineering, as promising strategies for restoring gut integrity and improving neurological outcomes. Modulating specific gut bacteria to enhance the synthesis of certain metabolites, notably short-chain fatty acids (SCFAs), represents a promising strategy for reducing inflammatory responses and decelerating neurodegeneration in Parkinson’s disease. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the pathological aggregation of α-synuclein (α-syn), the loss of dopaminergic neurons, and the appearance of both motor and non-motor symptoms. Emerging evidence suggests a bidirectional influence of the microbiota–gut–brain axis in PD pathogenesis, where gut dysbiosis contributes to increased intestinal barrier permeability, immune activation, chronic inflammation, oxidative stress, α-syn misfolding, and neurotransmitter imbalance. These findings are increasing interest in probiotics as microbiota-targeted interventions that restore intestinal and systemic homeostasis. Lactiplantibacillus plantarum, a probiotic species with remarkable environmental adaptability and genomic plasticity, has emerged as a promising candidate for PD management. Preclinical studies demonstrate that specific Lpb. plantarum strains, such as PS128 or CCFM405, can beneficially modulate gut microbial communities, reinforce barrier integrity, regulate bile acid metabolism, attenuate neuroinflammatory responses, and improve motor deficits in PD-like mice. In addition, Lpb. plantarum DP189 or SG5 interventions can significantly reduce α-syn aggregation in the brain via suppression of oxidative stress, modulation of neuroinflammatory responses, and activation of neurotrophic factors. Recent evidence even suggests that Lpb. plantarum-derived extracellular vesicles may possess anti-PD activity by influencing host gene expression, neuronal function, and immune modulation. Although robust clinical data are still limited, preliminary clinical trials indicate that supplementation with PS128 or certain Lpb. plantarum-contained consortiums can alleviate constipation, improve gastrointestinal function, reduce systemic inflammation, and even ameliorate motor symptoms when used alongside standard dopaminergic therapies. In this review, we provide an integrated overview of preclinical, clinical, and mechanistic insights, and evaluate the translational potential of Lpb. plantarum as a safe and diet-based strategy to target the microbiota-gut–brain axis in PD. Full article

Fixational saccadic eye movements (microsaccades) have been associated with cognitive processes, especially in tasks requiring spatial attention and memory. Alterations in oculomotor and cognitive control are commonly observed in Parkinson’s disease (PD), though it is unclear to what extent microsaccade activity is affected. We acquired eye movement data from sixteen participants with early-stage PD and thirteen older healthy controls to examine the effects of dopamine modulation on microsaccade activity during the delay period of a spatial working memory task. Some microsaccade characteristics, like amplitude and duration, were moderately larger in the PD participants when they were “on” their dopaminergic medication than healthy controls, or when they were “off” medication, while PD participants exhibited microsaccades with a linear amplitude–velocity relationship comparable to controls. Both groups showed similar microsaccade rate patterns across task events, with most participants showing a horizontal bias in microsaccade direction during the delay period regardless of the remembered target location. Overall, our data suggest minimal involvement of microsaccades during visuospatial working memory maintenance under conditions without explicit attentional cues in both subject groups. However, moderate effects of PD-related dopamine deficiency were observed for microsaccade size during working memory maintenance. Full article

Insomnia is a common and complex disorder, rooted in the dysregulation of circadian rhythms, impaired neurotransmitter function, and disturbances in sleep–wake homeostasis. While conventional hypnotics such as benzodiazepines and Z-drugs are effective in the short term, their use is limited by a high potential for dependence, cognitive side effects, and withdrawal symptoms. In contrast, melatonergic receptor agonists—melatonin, ramelteon, tasimelteon, and agomelatine—represent a pharmacologically targeted alternative that modulates MT1 and MT2 receptors, which are pivotal to the regulation of circadian timing and sleep initiation. Clinical evidence supports the efficacy of these agents in reducing sleep onset latency, extending total sleep duration, and re-aligning disrupted circadian rhythms, particularly among older individuals and patients with non-24 h sleep–wake disorders. Notably, agomelatine offers additional antidepressant properties through selective antagonism of the 5-HT_2C receptor in micromolar concentrations. In contrast, its agonistic activity at melatonergic receptors is observed in the low sub-nanomolar range, which illustrates the complexity of this drug’s interactions with the human body. All compounds reviewed demonstrate a generally favorable safety and tolerability profile. Accumulating evidence highlights that selected medicinal plants, such as chamomilla, lemon balm, black cumin, valeriana, passionflower and lavender, may exert relevant hypnotic or anxiolytic effects, thus complementing melatonergic strategies in the management of insomnia. This structured narrative review presents a comprehensive analysis of the molecular pharmacology, receptor affinity, signaling pathways, and clinical outcomes associated with melatonergic agents. It also examines their functional interplay with serotonergic, GABAergic, dopaminergic, and orexinergic systems involved in arousal and sleep regulation. Through comparative synthesis of pharmacokinetics and neurochemical mechanisms, this work aims to inform the development of evidence-based strategies for the treatment of insomnia and circadian rhythm sleep–wake disorders. Full article

Background/Objectives: Neurotransmitters such as dopamine and serotonin are critical regulators of mood, cognition, and neuronal homeostasis. This study aimed to evaluate the neuropharmacological potential of Hawaiian plants by investigating their ability to modulate the expression of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), key enzymes in neurotransmitter biosynthesis. Methods: A total of 108 aqueous and methanolic extracts of Hawaiian plants were screened for cytotoxicity against PC-12 and Neuro-2A cells using the MTT assay. Fifty-six non-toxic extracts were selected and further analyzed for TH and TPH expression via quantitative real-time PCR (qPCR). Results: Several extracts significantly upregulated TH and TPH expression without inducing cytotoxicity. Extracts derived from Morinda citrifolia, Pipturus albidus, and Hedychium coronarium showed the most notable activity, suggesting their potential to enhance dopaminergic and serotonergic pathways. Conclusions: The findings highlight the promise of native Hawaiian flora as sources of neuroactive compounds that may support neuroprotection and regeneration. These results provide a foundation for in vivo studies and further exploration of novel neurotherapeutic agents. Full article

In this study, we explore the neuroprotective and modulatory potential of graphenic materials (GMs) in terms of the maturation of dopaminergic neurons and their capacity to counteract the cellular stress induced by toxins such as MPP⁺ (1-methyl-4-phenylpyridinium) and Tunicamycin. We found that GMs promote significant morphological changes in neuronal cells after prolonged exposure, enhancing both differentiation and cellular adhesion. Through structural analysis, we unveiled a complex organization of GMs and a marked upregulation of tyrosine hydroxylase (TH), a key marker of mature dopaminergic neurons. Under oxidative stress induced by MPP⁺, GMs significantly reduced the release of lactate dehydrogenase (LDH), indicating protection against mitochondrial damage. Moreover, GMs substantially decreased the levels of α-synuclein (α-Syn), a protein closely associated with neurodegenerative disorders such as Parkinson’s disease. Notably, partially reduced graphene oxide (PRGO) and fully reduced graphene oxide (FRGO) films were particularly effective at reducing α-Syn-associated toxicity compared to positive controls. Under conditions of endoplasmic reticulum (ER) stress triggered by Tunicamycin, GMs—especially PRGO microflakes—modulated the unfolded protein response (UPR) pathway. This effect was evidenced by the increased expression of BIP/GRP78 and the decreased phosphorylation of stress sensors such as PERK and eIF2α; this suggests that a protective role is played against ER stress. Additionally, GMs enhanced the synthesis of Torsin 1A, a chaperone protein involved in correcting protein folding defects, with PRGO microflakes showing up to a fivefold increase relative to the controls. Through the cFos analysis, we further revealed a pre-adaptive cellular response in GM-treated cells exposed to MPP⁺, with PRGO microflakes inducing a significant twofold increase in cFos expression compared to the positive control, indicating partial protection against oxidative stress. In conclusion, these results underscore GMs’ capacity to modulate the critical cellular pathways involved in oxidative, mitochondrial, and ER stress responses, positioning them as promising candidates for future neuroprotective and therapeutic strategies. Full article

Mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are among the leading causes of disability worldwide and are frequently associated with treatment resistance, functional impairment, and high comorbidity with metabolic dysfunction. Increasing evidence implicates insulin resistance (IR) as a key pathophysiological factor linking metabolic and psychiatric illness. IR is associated with chronic low-grade inflammation, hypothalamic–pituitary–adrenal (HPA) axis dysregulation, impaired neuroplasticity, mitochondrial dysfunction, and altered reward processing mechanisms that may contribute to core depressive features such as anhedonia, cognitive slowing, and emotional dysregulation. These processes are further exacerbated by the metabolic side effects of many psychotropic medications, creating a self-perpetuating cycle that worsens both psychiatric and physical health outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed for type 2 diabetes and obesity, have emerged as promising candidates to address this metabolic–psychiatric interface. Beyond improving glycemic control and promoting weight loss, GLP-1 RAs exert central actions relevant to mood disorders, including modulation of dopaminergic reward pathways, enhancement of hippocampal neurogenesis, attenuation of neuroinflammation, and regulation of appetite and energy balance. Preclinical studies demonstrate that GLP-1 RAs reduce microglial activation, promote hippocampal neurogenesis, and normalize stress-induced behavioral changes. Early clinical trials in patients with metabolic disorders suggest improvements in depressive symptoms, quality of life, and cognitive function, with some effects independent of weight loss or glycemic outcomes. Observational evidence also indicates reduced antidepressant use and psychological distress in diabetic and obese populations receiving GLP-1 RAs. While these findings are promising, large randomized controlled trials in primary psychiatric populations are lacking. Key challenges include clarifying dose–response relationships, disentangling central from peripheral effects, and addressing safety and adherence concerns in individuals with comorbid psychiatric conditions. Future research should focus on biomarker-informed stratification, comparative trials with standard treatments, and integration of GLP-1 RAs into multimodal care frameworks. Overall, GLP-1 RAs represent a biologically plausible and clinically relevant approach to bridging metabolic and psychiatric care, with the potential to improve outcomes in patients with mood disorders who carry a high metabolic burden. Full article

Parkinson’s disease (PD) is one of the most rapidly growing neurological disorders globally. The molecular relationship between common respiratory infections (RIs) and idiopathic Parkinson’s disease (iPD) remains a controversial issue. Multiple studies have linked acute respiratory infections to PD, but the molecular mechanism behind this connection is not significantly defined. Therefore, the aim of our study was to investigate potential molecular interactions between RIs and PD. We retrieved eight publicly available RNA-seq datasets from the NCBI Gene Expression Omnibus (NCBI GEO) and performed extensive bioinformatics analysis, including differential gene expression (DGE) analysis, the identification of overlapped differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), pathway and functional enrichment analysis, the construction of protein–protein networks, and the identification of hub genes. Additionally, we applied a machine learning method, a Random Forest model (RF), to external RIs datasets to identify the most important genes. We found that ribosomal subunits, mitochondrial complex proteins, proteasome subunits, and proteins encoding ubiquitin are simultaneously downregulated and co-expressed in RIs and PD. Dysregulation of these proteins may disturb multiple pathways, such as those responsible for ribosome biogenesis, protein synthesis, autophagy, and apoptosis; the ubiquitin–proteasome system (UPS); and the mitochondrial respiratory chain. These processes have been implicated in PD’s pathology, namely in the aggregation of α-synuclein, mitochondrial dysfunction, and the death of dopaminergic neuron cells. Our findings suggest that there are significant similarities in transcriptional responses and dysfunctional molecular mechanisms between RIs, PD, and aging. RIs may modulate PD-relevant pathways in an age- or immune-dependent manner; longitudinal studies are needed to examine the RIs risk factor. Therefore, future studies should experimentally investigate the influence of age, vaccination status, infection type, and severity to clarify the role of RIs in PD’s pathogenesis. Full article

Striatum can be described as a brain region containing a general neuronal mechanism to associate actions or events with reward. In particular, neural activity in the human striatum is modulated by social actions and, critically, by the conjunction of social actions and own reward. To perform this function, dopamine and oxytocin signaling reaching the striatum represent a key factor. These neurotransmitters, in both humans and animals, are released in response to afferent vagal and sensory stimulation, as well as sexual and social interactions, conveying information related to reward and pleasure associated with an event. Dopamine and oxytocin have several effects in common, but of particular interest is evidence indicating that they can mutually modulate their action. The present review focuses on available data delineating interactions between dopaminergic and oxytocinergic signaling in the striatum. In this context, recent data on the possible role played by striatal astrocytes and microglia as key modulators of this crosstalk will be briefly discussed. Full article

Background/Objectives: Personality traits influence motivation, self-regulation, and adaptation in high-performance sports, and are partially modulated by dopaminergic genetic variability. This study aimed to examine the association between the DRD2 Ex8 rs6276 polymorphism and NEO Five-Factor Inventory (NEO-FFI) personality traits in elite athletes and non-athlete controls. Methods: A total of 323 participants were included: 141 athletes and 182 controls. Genomic DNA was isolated from venous blood, and DRD2 Ex8 rs6276 genotypes (A/A, A/G, G/G) were determined using real-time PCR with melting-curve analysis. Personality traits were assessed using the NEO-FFI, and group differences as well as genotype × group interactions were evaluated using multivariate analyses and non-parametric tests. Results: Athletes scored significantly higher on Conscientiousness than controls. A genotype × group interaction was observed for Extraversion, and the main effect of the genotype was found to be Agreeableness. Athletes with the A/A genotype exhibited the highest Extraversion scores, whereas those with the G/G genotype demonstrated higher Agreeableness than other genotypes. Conclusions: These findings indicate that dopaminergic variation contributes to individual differences in social and motivational traits, which may support athletic engagement and adaptation to high-demand environments. The results should be interpreted with caution due to the moderate sample size, deviation from the Hardy–Weinberg equilibrium in the athlete group, and reliance on a single personality assessment tool. Full article