Search Results (406)

Although exercise is known to exert anti-inflammatory effects in neurodegenerative diseases, its specific impact and underlying mechanisms in Parkinson’s disease (PD) remain poorly understood. This study explores the effects of exercise on microglia-mediated neuroinflammation and apoptosis in a PD model, focusing on the role of irisin signaling in mediating these effects. Using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, we found that a 10-week treadmill exercise regimen significantly enhanced motor function, reduced dopaminergic neuron loss, attenuated neuronal apoptosis, and alleviated neuroinflammation. Exercise also shifted microglia from a pro-inflammatory to an anti-inflammatory phenotype. Notably, levels of irisin, phosphorylated AMP-activated protein kinase (p-AMPK), and sirtuin 1 (Sirt1), which were decreased in the PD brain, were significantly increased following exercise. These beneficial effects were abolished by blocking the irisin receptor with cyclic arginine–glycine–aspartic acid–tyrosine–lysine (cycloRGDyk). Our results indicate that exercise promotes neuroprotection in PD by modulating microglial activation and the AMPK/Sirt1 pathway through irisin signaling, offering new insights into exercise-based therapeutic approaches for PD. Full article

The developmental processes of microglia follow a general pattern, from immature amoeboid (activated) cells to fully ramified (inactivated) surveilling microglia. However, little is known about the mechanisms controlling the transition of microglia from an activated to an inactivated state during brain development. Due to the complexity of microenvironmentally dynamic changes during neuronal differentiation, interactions between developing nerve cells and microglia might be involved in this process. Extracellular vesicles (EVs) are cell-released particles that serve as mediators of cellular crosstalk and regulation. Using neural progenitor cells (NPCs) and a long-term neuron culture system, we found that EVs derived from NPCs or developing neurons possessed differential capacity on the induction of microglial activation. The exposure of microglia to NPC- or immature neuron (DIV7)-derived EVs resulted in the higher expression of protein and mRNA of multiple inflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6), when compared with mature neuron-derived EVs. Exploration of the intracellular signaling pathways revealed that MAPK signaling, IκBα phosphorylation/degradation, and NF-κB p65 nuclear translocation were strongly induced in microglia treated with NPC- or immature neuron-derived EVs. Using a pharmacological approach, we further demonstrate that Toll-like receptor (TLR) 7-mediated activation of NF-κB and MAPK signaling cascades contribute to EV-elicited microglial activation. Additionally, the application of conditioned media derived from microglia treated with NPC- or immature neuron-derived EVs is found to promote the survival of late-developing dopaminergic neurons. Thus, our results highlight a novel mechanism used by NPCs and developing neurons to modulate the developmental phases and functions of microglia through EV secretion. Full article

The hypothalamus belongs to the central brain structure designed for the neuroendocrine regulation of many organismal functions, including the stress response, cardiovascular system, and blood pressure, and it is well known that the serotonergic hypothalamic system plays a significant role in these processes. Unfortunately, the genetic determination of serotonergic hypothalamic mechanisms has been little studied. The aim of this article is to describe the expression profile of the genes in the hypothalamic serotonergic synapses in hypertensive ISIAH rats in comparison with normotensive WAG rats in control conditions and under the influence of a single short-term restraint stress. It was found that 14 differentially expressed genes (DEGs) may provide the inter-strain differences in the serotonergic synaptic function in the hypothalamus between the hyper- and normotensive rats studied. In hypertensive rats, downregulation of Slc18a1 gene in the presynaptic serotoninergic ends and decreased expression of Cacna1s and Htr3a genes determining the postsynaptic membrane conductance may be considered as a main factors causing differences in the function of hypothalamic serotoninergic synapses in hypertensive ISIAH and normotensive WAG rats at the basal conditions. Under basal conditions, glial cell genes were not involved in the formation of inter-strain differences in serotonergic synaptic function. The analysis of transcriptional responses to restraint stress revealed key genes whose expression is involved in the regulation of serotonergic signaling, and a cascade of interrelated changes in biological processes and metabolic pathways. Stress-dependent changes in the expression of some DEGs are similar in the hypothalamus of hypertensive and normotensive rats, but the expression of a number of genes changes in a strain-specific manner. The results suggest that in hypothalamic glial cells of both strains, restraint stress induces changes in the expression of DEGs associated with the synthesis of Ip3 and its receptors. Many of the identified serotonergic DEGs participate in the regulation of not only serotonergic synapses but may also be involved in the regulation of cholinergic, GABAergic, glutamatergic, and dopaminergic synapses. The results of the study provide new information on the genetic mechanisms of inter-strain differences in the functioning of the hypothalamic serotonergic system in hypertensive ISIAH and normotensive WAG rats at rest and under the influence of a single short-term restraint (emotional) stress. Full article

Industrial development has increased environmental dioxin concentrations, sparking concern about human health impacts. Examining dioxin neurotoxicity has highlighted associations with cognitive impairment and behavioral abnormality. Dioxins are ligands of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor; it is speculated that dioxin-induced AHR activation is pivotal for toxic effects. Accurate AHR-expressing cell identification is therefore indispensable for understanding the molecular and cellular mechanisms of dioxin toxicity. Herein, current knowledge regarding AHR expression in the mammalian brain is summarized, and dioxin neurotoxicity mechanisms are discussed. Histological studies show AHR-expressing neurons in multiple brain regions, including the hippocampus and cerebral cortex. Dopaminergic and noradrenergic neurons exhibit AHR expression, suggesting possible roles in the monoaminergic system. AHR overactivation evokes dendritic arborization atrophy, whereas its deficiency increases complexity, implying that AHR-mediated signaling is crucial for neuronal growth and maturation. AHR is also involved in neurogenesis and neuronal precursor migration. Collectively, these findings support the notion that dioxin-induced AHR overactivation in individual neurons disrupts neural circuit structure, ultimately leading to impaired brain function. However, as AHR downstream signaling is intertwined with various molecules and pathways, the precise mechanisms remain unclear. Further studies on the expression, signaling, and roles of AHR are needed to clarify dioxin neurotoxicity. Full article

Alcohol is a prevalent psychoactive substance and a risk factor for developing injuries and non-communicable diseases, representing a significant health and economic burden. Alcohol involves numerous molecular pathways. Its metabolism is regulated by alcohol dehydrogenases and aldehyde dehydrogenases; it also stimulates cholinergic interneurons, increasing the sensitivity of 5-HT3 receptors, while chronic alcohol consumption alters the mesolimbic dopaminergic system involved in reward processing. The treatment of alcohol use disorder (AUD) is essential to manage complex patients, following an evidence-based approach. The aim of this narrative review is to provide a clear and practical summary to support and assist healthcare professionals in the Italian context. Approved pharmacological treatments for AUD include oral naltrexone and acamprosate, sodium oxybate, disulfiram, and nalmefene. Off-label therapies include baclofen, topiramate, gabapentin, pregabalin, ondansetron, and cytisine. A more informed clinical and practical approach that understands the altered neuronal signaling pathways is essential for offering effective, efficient, appropriate, and safe therapeutic algorithms for complex patients with alcohol use disorder. A comprehensive framework should include integrated treatments with a personalized approach. Full article

Background/Objectives: Contextual memory associated with methamphetamine (METH) use contributes to relapse and persistence of addiction. Angiotensin II type 1 receptor (AT1R) signaling has been implicated in drug reinforcement. LCZ696, a clinically used combination of sacubitril (a neprilysin inhibitor) and valsartan (an AT1R antagonist), may interfere with METH-associated memory through the modulation of dopaminergic pathways. Methods: Male C57BL/6J mice were tested in a conditioned place preference (CPP) paradigm to assess the effects of LCZ696, sacubitril (AHU377), and valsartan on METH-induced memory expression and reinstatement. Synaptic plasticity in the nucleus accumbens (NAc) was examined by assessing the levels of synaptophysin (Syp) and postsynaptic density protein 95 (Psd95), as well as dendritic spine density. Dopaminergic signaling in the ventral tegmental area (VTA) was evaluated via ELISA, Western blotting, and chromatin immunoprecipitation (ChIP), targeting cAMP response element-binding protein (Creb) binding to the tyrosine hydroxylase (Th) promoter. To further assess the role of Th, an adeno-associated virus (AAV9) carrying a CRISPR-Cas9-based sgRNA targeting Th (AAV9-Th-sgRNA) was microinjected into the VTA. Results: LCZ696 and valsartan significantly reduced METH-induced CPP and reinstatement. LCZ696 reversed METH-induced synaptic and dopaminergic alterations and suppressed Creb-mediated Th transcription. Th knockdown attenuated both CPP acquisition and relapse. Conclusions: LCZ696 disrupts METH-associated contextual memory by modulating dopaminergic signaling and Creb-dependent Th expression, supporting its potential as a treatment for METH use disorder. Full article

The area postrema (AP) is a circumventricular organ (CVO) at the base of the fourth ventricle. It has a crucial role in regulating nausea and vomiting due to its unique blood–brain barrier (BBB)-permeability and extensive neural connectivity. Here, we present two cases of area postrema syndrome (APS), a rare condition of intractable nausea and vomiting resulting from direct AP injury. Our cases each occurred in the context of infratentorial neoplasms or their treatment. Using these cases as a framework, we review the literature on central emetic pathways and propose a treatment algorithm for managing refractory nausea and vomiting of central origin. We also highlight other targets beyond conventional serotonergic, dopaminergic, or histaminergic blockade and their roles in central hyperemesis. Our literature review suggests that APS is due to the disruption of the baseline inhibitory tone of outgoing AP signals. When other options fail, our algorithm culminates in the off-label use of combined serotonergic and neurokinin-1 blockade, which is otherwise used to manage chemotherapy-induced nausea and vomiting (CINV). We believe multimodal CNS receptor blockade is efficacious in APS because it addresses the underlying central neural dysregulation, rather than solely targeting peripheral emetic triggers. Full article

Background: Personality traits, particularly Conscientiousness, are recognised as crucial psychological factors contributing to success in elite-level athletes. Emerging evidence suggests that individual differences in these traits are influenced by environmental exposure and genetic variation, especially within the dopaminergic system. The DRD2 promoter polymorphism rs1799732, which affects dopamine D2 receptor expression, may modulate goal-directed behaviour and self-regulation traits. Methods: This study included 323 participants (141 elite mixed martial arts (MMA) athletes and 182 non-athlete controls). Participants completed the NEO Five-Factor Inventory (NEO-FFI). Genotyping for the DRD2 rs1799732 polymorphism was conducted using real-time PCR. Group comparisons and two-way ANOVA were used to assess genotype–phenotype associations and gene × environment interactions. Results: Athletes scored significantly higher on Conscientiousness than controls. A significant main effect of the DRD2 rs1799732 genotype and a genotype × group interaction were observed for Conscientiousness. Specifically, athletes with the ins/ins genotype exhibited the highest levels of Conscientiousness, whereas individuals with the del/del genotype showed the lowest scores. No significant associations were found for other personality traits. Conclusions: These findings suggest that the DRD2 promoter polymorphism rs1799732 moderates the expression of Conscientiousness, particularly under the structured and demanding conditions experienced by elite athletes. Our results support a gene × environment interaction model, highlighting the importance of considering genetic predispositions in high-performance environments. These insights may inform personalised psychological support strategies tailored to athletes’ genetic profiles, enhancing motivation, self-regulation and long-term athletic development. Full article

To determine candidate key proteins involved in synaptic transmission in the thalamus in tinnitus, we used bioinformatic methods by analyzing protein–protein interaction networks under different conditions of acoustic activity. The motor system was used to analyze the specificity of the response reaction in the auditory system. The databases GeneCard, STRING-, DAVID-, and Cytoscape version 3.9.1 were applied to identify the top three high-degree proteins, their high-score interaction proteins and the gene ontology—biological processes (GO-BPs) associated in the thalamus with synaptic transmission in tinnitus. Under normal hearing conditions, a balanced state of functional connectivity was observed for both systems, the auditory system and the motor system of the thalamus. Under conditions of acoustic stimulation, the GO-BP-enrichment analyses suggest that in the auditory system, tinnitus-related proteins may be involved in responses typically associated with “xenobiotic stimuli”; in the motor system, the activation of the dopaminergic system was observed. Under conditions of tinnitus in the auditory system, key proteins and the GO-BPs indicate the regulation of different developmental processes and regulation by microRNA transcription; in the motor system, tinnitus is also identified as “xenobiotic” but responded with GO-BPs, corresponding to various signaling systems, e.g., tachykinin. Key proteins and their interactions with neurotransmitter receptors may be useful indicators for tinnitus-associated changes in synaptic transmission in the thalamic auditory system. Full article

Prenatal cannabis exposure (PCE) has been associated with altered prefrontal cortex (PFC) activity and connectivity in adulthood, potentially increasing the risk of psychopathology later in life. This risk is thought to involve a complex interplay between the endocannabinoid and dopaminergic systems. We investigated the transcriptional regulation of genes associated with these systems in an animal model of PCE during adolescence, focusing on DNA methylation and specific microRNAs (miRNAs). Our study revealed increased mRNA levels of dopamine D1 and D2 receptors (Drd1 and Drd2) in the PFC, with a notable effect on Drd2 in male offspring. Notably, we observed a consistent reduction in Drd2 DNA methylation levels in PCE male rats. Both Drd1 and Drd2 expressions were regulated by selective miRNAs. Accordingly, we found changes in the excitability of PFC pyramidal neurons in male adolescent PCE offspring, along with alterations in the Netrin-1/DCC guidance cue system. Our findings highlight PCE-induced modifications of the PFC dopaminergic system while maintaining stable gene expression of the endocannabinoid system in male offspring. Changes in this complex interaction during sensitive developmental periods like adolescence might lead to sex-dependent divergent behavioral outcomes induced by PCE. Full article

Objective:Burning mouth syndrome (BMS) is a chronic, intractable orofacial pain condition characterized by a burning sensation in the oral mucosa without discernible lesions. The syndrome predominantly affects menopausal and postmenopausal women and is considered a form of nociplastic pain, where the processing of pain stimuli is altered. Given the significant sex disparity, it is crucial to consider underlying neurobiological differences that may inform treatment. This review explores potential pharmacological targets by examining the pathological mechanisms of BMS. Method of Research: A narrative review approach was utilized to systematically explore and synthesize literature regarding the pathophysiology of BMS and to identify receptors implicated in the enhancement of sensory transmission and the altered processing of pain stimuli. Results: The mechanism of enhanced sensory transmission points to receptors such as TRPV1, P2X3, and CB2 as potential targets. However, considering the nociplastic nature of BMS and its prevalence in women, mechanisms involving altered central pain processing are paramount. Research indicates significant sex differences in glutamate transmission and plasticity within reward-related brain regions. This suggests that the N-methyl-D-aspartate (NMDA) receptor, a cornerstone of glutamate signaling and synaptic plasticity, is a primary therapeutic target. Furthermore, the altered processing of pain and reward, which is a key feature of chronic pain, implicates the brain’s dopaminergic system. A decrease in dopamine D2 receptor function within this system is believed to contribute to the pathology of BMS. Estrogen receptors are also considered relevant due to the menopausal onset. Conclusions: Based on the evidence, the most promising targets for pharmacotherapy in BMS are likely the NMDA receptor and the dopamine D2 receptor. The high prevalence of BMS in women, coupled with known sex differences in the glutamate and dopamine pathways of the reward system, provides a strong rationale for this focus. Effective treatment strategies should therefore aim to modulate these specific systems, directly or indirectly controlling NMDE receptor hyperactivity and addressing the decreased D2 receptor function. Further research into therapies that specifically target this sex-linked neurobiology is essential for developing effective pharmacotherapy for BMS. Full article

Retinal dysfunction is emerging as a potential early marker of neurodegenerative diseases. Within the retina, the dopaminergic circuit, comprising dopaminergic amacrine cells, dopamine synthesis and turnover, and dopamine receptor signalling, is essential for visual processing, particularly colour contrast perception. Disruption of this circuit may underline early retinal alterations observed in Huntington’s disease (HD) and Alzheimer’s disease (AD). In this study, we systematically analysed retinal dopaminergic dysfunction in murine models of HD (genetic origin) and AD (sporadic), across different disease stages. We assessed dopamine levels, turnover, tyrosine hydroxylase expression, D1 and D2 receptor gene expression, and neurotransmitter balance. HD mice showed early and marked alterations: reduced dopamine content, decreased tyrosine hydroxylase, increased turnover, and downregulation of D1 receptor expression—all preceding motor symptoms and detectable brain pathology. In contrast, AD mice showed only mild changes at later stages; however, clinical evidence suggests that similar dysfunction may occur earlier in human AD. These findings position retinal dopaminergic disruption as a potential early biomarker in HD and possibly in AD. While the current study relies on invasive techniques in animal models, it lays the groundwork for non-invasive retinal assessments, such as electroretinography or optical coherence tomography, as promising tools for early diagnosis and disease monitoring in neurodegeneration. Full article

Background/Objectives: G protein-coupled trace amine-associated receptors (TAARs) belong to a family of biogenic amine-sensing receptors. TAAR1 is the best-investigated receptor of this family, and TAAR1 agonists are already being tested in clinical studies for the treatment of schizophrenia, anxiety, and depression. Meanwhile, other TAARs (TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9 in humans) are mostly known for their olfactory function, sensing innate odors. At the same time, there is growing evidence that these receptors may also be involved in brain function. TAAR8 is the least studied TAAR family member, and currently, there is no data on its function in the mammalian central nervous system. Methods: We generated triple knockout (tTAAR8-KO) mice lacking all murine Taar8 isoforms (Taar8a, Taar8b, and Taar8c) using CRISPR-Cas9 technology. In this study, we performed the first phenotyping of tTAAR8-KO mice for behavioral, electrophysiological, and neurochemical characteristics. Results: During the study, we found a number of alterations specific to tTAAR8-KO mice compared to controls. tTAAR8-KO mice demonstrated better short-term memory, more depressive-like behavior, and higher body temperature. Also, we observed changes in the dopaminergic system, brain electrophysiological activity, and adult neurogenic functions in mice lacking Taar8 isoforms. Conclusions: Based on the data obtained, it can be assumed that the physiological TAAR8 role is not limited only to the innate olfactory function, as previously proposed. TAAR8 could be involved in brain function, in particular in dopamine function regulation. Full article

The 5-HT_1A and 5-HT₇ receptors play a key role in regulating cognitive processes and have been widely linked to the pathophysiology of depression, anxiety, and schizophrenia—disorders often associated with memory impairment. Recently, interest has grown in understanding how the coexpression of these receptors contributes to cognitive decline. This review explores the individual roles of 5-HT_1A and 5-HT₇ receptors, as well as their coexpression, in memory regulation. The heterodimerization of these receptors at both pre- and postsynaptic levels, along with their colocalization in serotonergic, glutamatergic, GABAergic, and dopaminergic neurons, adds to the complexity of this interaction and may help explain the paradoxical effects of selective serotonergic drugs (agonists and antagonists). These findings underscore the need for further research into the 5-HT_1A and 5-HT₇ receptor relationship in cognitive decline through diverse approaches, including targeted gene silencing, electrophysiology, and cell culture studies. Full article

We tried to synthesize the possibilities of predicting the response to clozapine treatment, which can significantly improve the efficacy of the active substance and reduce adverse reactions, and how the active substance acts at the D1 dopaminergic receptors D2, D3, D4, and D5, muscarinic M1, M2, M3, and M5, and the histamine and alpha 1 adrenergic receptor, as well as how it contributes to increased cerebral blood flow, the effect on ribosomal protein S6 function, or the effect on kynurenine 3-monooxygenase function. Clozapine is one of the most effective antipsychotics, and there is potential to improve performance by combining it with different compounds to limit adverse effects or by augmenting it with other antipsychotics (amisulpride, paliperidone), other active substances with different properties (minocycline, N-acetylcysteine, memantine), or alternative therapies (electroconvulsive therapy, repetitive transcranial magnetic stimulation). There are also significant steps in optimizing clozapine efficacy by predicting treatment response, which could be determined by testing the following: plasma levels of clozapine N-oxide and N-desmethylclozapine, serum levels of neurotrophins and glutamate, genetic testing, the polygenic risk score, morphometry, or even the identification and accurate determination of persistent negative symptoms. Full article