Search Results (113)

Prader–Willi syndrome (PWS) is a rare imprinting-related neurodevelopmental disorder caused by loss of paternally expressed genes within the chromosome 15q11–q13 region, including SNORD116, MAGEL2, and NDN. It provides a natural model for examining how genomic imprinting disruptions shape neural development and psychiatric vulnerability. This review synthesizes current evidence to clarify the mechanistic pathways linking imprinting defects and epigenetic dysregulation to neuropsychiatric outcomes in PWS. Published studies—including patient-derived induced pluripotent stem cell (iPSC) models, animal knockout systems (e.g., Magel2-null models), transcriptomic and DNA methylation datasets, and human neuroimaging research—were identified through targeted searches of PubMed and Web of Science and integrated narratively rather than through systematic procedures. Across these data sources, deletion-type PWS is primarily associated with impaired neuronal maturation, altered serotonergic signaling, and locus-specific transcriptional dysregulation. Maternal uniparental disomy (mUPD) is characterized by broader epigenetic alterations within the imprinted domain, genome-wide transcriptional effects, dopaminergic pathway alterations, and disrupted prefrontal–limbic connectivity linked to increased psychosis risk. Importantly, available evidence supports substantial phenotypic and mechanistic overlap between PWS subtypes, with genotype–phenotype associations reflecting probabilistic tendencies rather than categorical distinctions. Collectively, convergent findings across molecular, neurochemical, and systems-level studies support a mechanistic continuum extending from imprinting defects to behavioral phenotypes. These insights position PWS as a translational model for understanding how epigenetic dysregulation contributes to psychiatric risk and highlight the need for genotype-informed, mechanistically grounded research to advance biomarker development and targeted therapeutic strategies. Full article

Background: Several studies have attempted to identify the initiating drivers of small intestinal neuroendocrine tumor (SI-NET) development and the molecular mechanisms underlying their progression and metastatic spread. Previous gene expression studies have used bulk microarrays or RNA sequencing to compare tumor tissue with normal intestinal mucosa. However, the intestine comprises multiple distinct cell types, and bulk analyses are limited by this cellular heterogeneity, which can confound tumor-specific signals. Methods: We performed single-cell RNA sequencing on primary SI-NETs and paired normal mucosa from two patients to directly compare tumor cells with their cells of origin, the enterochromaffin (EC) cells. To minimize type I errors, we applied a two-step validation strategy by overlapping differentially expressed genes with an external single-cell dataset and cross-referencing candidate genes for enteroendocrine expression in the Human Protein Atlas. Results: For further distinction and characterization, ECs were subdivided into serotonergic and non-serotonergic clusters. This analysis revealed that the SI-NET cells are transcriptionally more similar to serotonergic ECs, consistent with serum metabolite profiles derived from clinical parameters. Our analyses uncovered a loss-of-expression program characterized by regulators of epithelial differentiation and in parallel, a gain-of-expression program displayed neuronal signaling gene induction, implicating functional reprogramming toward neuronal-like properties. Together, these specific losses and gains suggest that our patient-derived SI-NETs undergo adaptation through both loss of enteroendocrine functions and acquisition of neurobiological-promoting signaling pathways. Conclusions: These findings nominate candidate drivers for further functional validation and highlight potential therapeutic strategies in our patient cohort, including restoring suppressed Notch signaling and targeting aberrant neuronal signaling networks. However, even with a two-step validation procedure, the modest cohort size limits statistical power and generalizability, particularly for the proposed association to a serotonergic phenotype. Larger, multi-patient single-cell studies are required to confirm these mechanisms and establish their clinical relevance. Full article

The regulation of sensory processing by centralized neuromodulatory systems can alter behavioral responses to social cues. Neuromodulatory systems such as the serotonergic neurons in the dorsal raphé nucleus (DRN) show heterogenous responses to different types of sensory stimuli or to stimulus qualities such as reward, valence, or salience. Sensory neuromodulation could therefore be related to a broader quality of the behavioral context or to specific types of social cues. We assessed this issue by presenting male mice with either playback of female vocal signals associated with defensive aggression (squeaks) or silence, and the presence or absence of a female. Activity in regions of the DRN that project to the auditory midbrain was assessed through co-labeling with antibodies to the serotonin synthetic enzyme tryptophan hydroxylase (TPH) and the immediate early gene product c-Fos. Female presence or absence had the largest effect, decreasing the co-localization of TPH and c-Fos, while the playback of squeaks had effects that were condition-dependent, increasing co-label only when females were absent. Squeak playback further decreased the correlation in the numbers of co-labeled neurons between two dorsal subdivisions of the DRN, the DRD and DRL. These results are inconsistent with an auditory-exclusive feedback loop. Instead, cues associated with female presence heavily influence raphé activity, with squeaks playing a modifying and context-dependent role. Because the elevation of serotonin in the IC causes males to become more responsive to female squeaks, these findings suggest that a nuanced interaction of positive and negative cues during social interaction may fine-tune male responses to the vocalization of social partners, in part through the serotonergic system. Full article

Depression is a heterogeneous neuropsychiatric disorder with variable clinical presentation and response to treatment. This variability has motivated interest in neuroimaging biomarkers capable of disease characterization and therapeutic prediction. Positron emission tomography (PET) enables in vivo assessment of cerebral glucose utilization, neurochemical targets, inflammatory markers, and cerebral blood flow. This narrative review synthesizes PET studies conducted predominantly in adults with major depressive disorder diagnosed using DSM-based criteria, with bipolar disorder included only when imaging was performed during a depressive episode. Studies were identified through a structured, non-systematic literature search of major databases. Depression is consistently associated with regionally specific PET alterations within cortico-limbic and cortico-striatal circuits; studies most frequently report reduced glucose-derived PET measures in prefrontal and anterior cingulate regions at baseline, with treatment responders showing relative increases or redistribution of these measures following interventions. Neurochemical PET studies demonstrate altered receptor, transporter, or enzyme-related binding in serotonergic, dopaminergic, and noradrenergic systems, while neuroinflammatory and perfusion studies reveal regionally increased PET signals in subsets of patients. Overall, PET findings indicate convergent, region-specific and neurochemical alterations associated with depressive episodes and treatment response. Interpretation is constrained by methodological and clinical heterogeneity, underscoring the need for harmonized, longitudinal PET studies. Full article

Serotonergic signaling is traditionally conceived as a transient, vesicle-mediated process restricted to the synaptic cleft. Here, we propose an expanded model in which serotonin can also be inserted into the plasma membrane of neurons and glial cells, forming a stable, membrane-associated reservoir that prolongs its availability beyond classical synaptic timescales. In this framework, the synapse emerges not as a simple neurotransmitter–receptor interface but as a dynamic, multiscale medium where membrane order, hydration, and quantum-level processes jointly govern information flow. Two temporal “tunnels” appear to regulate serotonin bioavailability: its aggregation in synaptic vesicles during exocytosis, and its cholesterol-dependent insertion into neuronal and glial membranes at the tripartite synapse. Lipid raft microdomains enriched in cholesterol and gangliosides thus act as active regulators of a continuum between transient and constitutive serotonin signaling. This extended serotonergic persistence prompts a reconsideration of current pharmacological models and the action of antidepressants such as fluoxetine, which not only inhibits the serotonin transporter (SERT) but also accumulates in lipid rafts, perturbs raft organization, and alters serotonin–cholesterol equilibria, contributing to SERT-independent effects. Grounded in the recently established fundamental parameters of biological systems, this model invites a broader, quantum-informed rethinking of synaptic transmission. Full article

Growing evidence has revealed that gut dysbiosis is associated with the development of anxio-depressive disorders through mechanisms that involve neuroimmune signaling, neurotransmitter changes, and neuroplasticity in the brain. This study investigated the effects of gingerol-enriched ginger (GEG) on specifically anxiety-related neuroinflammation-, neuroimmunity-, neuroplasticity-, neurotransmission-, and neurotoxicity-associated genes in different brain regions, as well as on alterations linked to colonic microflora-driven dysbiosis, in the spinal nerve ligation (SNL) rat model of neuropathic pain (NP). Twenty-seven male rats were assigned to 3 groups: sham, SNL, and SNL-treated with GEG at 200 mg/kg body weight (SNL+200GEG) via oral gavage for 5 weeks. Anxiety-like behavior was assessed on the elevated plus maze (EPM). mRNA expression was assessed by qRT-PCR using respective primers. Correlation between behavioral parameters and colonic microbiome composition was analyzed using the Spearman rank correlation. The SNL+200GEG group demonstrated decreased anxiety-like behavior in the SNL model. Compared to the SNL group, the SNL+200GEG group had increased mRNA expression of NRF2 (amygdala: left), LXRα (amygdala: both sides), and CX3CR1 (amygdala: both sides, hippocampus: right). GEG modulated neuroplasticity as shown by increased gene expression of PGK1 (amygdala: right, hippocampus: both sides), MEK1 (frontal cortex: both sides), LDHA (frontal cortex: both sides), GPM6A (frontal cortex: both sides, amygdala: right, hippocampus: right, and hypothalamus), and GLUT1 (amygdala: right) as well by decreased gene expression of HIF1α (in all brain regions except for the hypothalamus). GEG modulated neurotransmission via clearance of excessive glutamate release as suggested by increased gene expression of SLC1A3 (frontal cortex: both sides, hippocampus: right) and via augmenting mGluR5 signaling as shown by increased gene expression of GRM5 (hippocampus: both sides, hypothalamus) as well as downregulation of KMO, HAAO, GRIN2B, and GRIN2C influencing downstream serotonergic neurotransmission and NMDA receptor-mediated glutamatergic pathways in different brain regions. GEG further alleviated neurotoxicity through downregulated gene expression of SIRT1, KMO, IDO1, and HAAO in different brain regions. Moreover, the increased relative abundance of Bilophila spp., accompanied by decreased time spent in the EPM open arms, suggests that increased Bilophila abundance increases anxiety-like behavior. GEG supplementation mitigated anxiety-like behavior in male rats with NP, at least in part, by reducing SNL-induced inflammatory sequelae-related mRNA gene expression in different brain regions. In addition, there is a positive correlation between the abundance of Bilophila wadsworthia and the degree of anxiety-like behavior. Full article

Background/Objectives: The therapeutic potential of selective trace amine-associated receptor 1 (TAAR1) agonists has been established in multiple animal models of depression and anxiety. PTSD is a debilitating psychiatric disorder frequently characterized by anxiety and often comorbid with major depressive disorder. Complex PTSD represents an even more severe clinical presentation, emerging from prolonged or repeated exposure to traumatic events. Recent studies indicate that TAAR1 agonists can attenuate anxiety-like behaviors in experimental models of PTSD; however, the molecular mechanisms underlying this effect remain poorly understood. In this study, we evaluated whether TAAR1 agonism modulates PTSD-related neurochemical and molecular changes within the hippocampus and striatum. Methods: Post-traumatic stress was modeled using predator stress, a validated experimental paradigm relevant to complex PTSD. Treatment consisted of intraperitoneal administration of the TAAR1 agonist LK00764. Monoamine neurotransmitters and their metabolites were quantified, and the expression of genes implicated in noradrenergic, dopaminergic, and serotonergic signaling pathways was assessed. In addition, gene network reconstruction was performed using artificial intelligence to identify TAAR1-dependent regulatory interactions. Results: Treatment with a TAAR1 agonist fully prevented behavioral abnormalities in the experimental model of complex PTSD. Neurochemical analyses revealed decreased 5-HT levels in the hippocampus and reduced dopamine and metabolite concentrations in the striatum following TAAR1 agonism. Moreover, TAAR1 activation was associated with increased expression of the neurotrophic factor BDNF in the striatum. Gene network reconstruction identified a distinct molecular hub within the PTSD network, comprising TAAR1-coexpressed genes, their encoded proteins, and interconnected signaling pathways, suggesting a tightly regulated feedback loop. Conclusions: These findings provide novel evidence that TAAR1 agonists exert protective effects against complex PTSD-related behavioral and neurochemical abnormalities. The reconstructed TAAR1-centered gene network offers mechanistic insight into receptor-dependent regulation of monoaminergic signaling and neuroplasticity, supporting further exploration of TAAR1 agonists as promising therapeutic candidates for PTSD. Full article

Background/Objectives: Baihe Dihuang Tang (BDT), a classical herbal formula from Zhang Zhongjing’s Han Dynasty work Jin Gui Yao Lue, is widely used to treat depressive disorder by nourishing Yin, clearing heat, and tonifying the heart and lungs. However, its pharmacological mechanisms remain unclear. This study aims to explore BDT’s antidepressant effects via MAOA-regulated serotonin (5-HT) metabolism and synaptic plasticity, supported by experimental validation, while using network pharmacology to predict MAOA-targeting active components. Methods: Active components and targets of BDT were screened using TCMSP, TCMID, and other databases, and then a component-target-pathway network was constructed. A chronic restraint stress (CRS)-induced depressive mouse model was established. Behavioral tests, including open field test (OFT), elevated plus maze (EPM), forced swimming test (FST) and tail suspension test (TST), were conducted to evaluate antidepressant effects. ELISA, qRT-PCR, and Western blot were employed to assess hippocampal 5-HT metabolism (MAOA, 5-HT/5-HIAA ratio) neurotrophic signaling (BDNF, TrkB) and synaptic plasticity-related proteins (PSD-95, SYN1). Results: BDT significantly reduced FST/TST immobility time and improved anxiety-like behaviors in OFT/EPM. BDT treatment downregulated MAOA expression, elevated hippocampal 5-HT/5-HIAA ratio, activated BDNF/TrkB pathway, and upregulated PSD-95/SYN1. Network pharmacology confirmed MAOA’s central role, identifying MAOA/serotonergic synapse modulation as BDT’s main mechanism and pinpointing Ferulic acid, Caffeate, Stigmasterol, (−)-nopinene, Eugenol, and cis-Anethol as MAOA-targeting bioactive components. Conclusions: BDT ameliorates depressive-like behaviors. This effect is mechanistically linked to suppression of MAOA-mediated 5-HT catabolism—a key validated target. This suppression elevates hippocampal 5-HT bioavailability, thereby activating BDNF/TrkB signaling and promoting synaptic plasticity. Network pharmacology confirmed MAOA as a primary target and identified specific modulatory bioactive components. Full article

Phototaxis, the movement toward or away from light, is a fundamental behavior with ecological and evolutionary relevance. In Drosophila melanogaster, phototactic choice shows individual variability and has been linked to serotonergic signaling. Using a high-throughput FlyVac assay to test single flies in parallel, we reared w¹¹¹⁸ flies on (1) standard food (Control), (2) aMW (a serotonin-synthesis inhibitor), (3) 5-HTP (a serotonin precursor), or (4) escitalopram (a selective serotonin reuptake inhibitor, SSRI). Light-choice probability (LCP) did not differ between Control and aMW. LCP was lower in 5-HTP and escitalopram than in Control and aMW, and lower with escitalopram than with 5-HTP. Between-fly variability (MAD_n) differed across treatments: escitalopram exhibited higher dispersion than Control and aMW, whereas 5-HTP did not differ reliably from Control. These findings support the hypothesis that serotonin modulates behavioral predictability and mean choice bias; variability effects were compound-specific (escitalopram modestly increased MAD_n, whereas 5-HTP did not differ from Control). Given the rising costs and ethical constraints of vertebrate models, our results highlight Drosophila and FlyVac as a powerful, cost-effective system for investigating SSRI effects on decision phenotypes. Full article

Background: Chronic pain affects nearly one in five adults worldwide and remains a major healthcare burden due to its persistence, multidimensional impact, and resistance to conventional therapies. The opioid crisis has further highlighted the urgent need for safer and more effective alternatives. Psilocybin, a serotonergic psychedelic compound, has re-emerged as a potential therapeutic option for chronic pain given its effects on neuroplasticity, neuroinflammation, and emotional regulation. Methods: This narrative review synthesized evidence from published preclinical and clinical studies. The focus was on the mechanisms of action of psilocybin, animal models of neuropathic and inflammatory pain, and early human trials exploring its effects on pain, mood, and quality of life. Results: Preclinical studies demonstrated that psilocybin promotes synaptogenesis via BDNF-TrkB signalling, modulates 5-HT2A receptor activity, and reduces neuroinflammatory processes, leading to persistent analgesic and anxiolytic effects. Animal models of chemotherapy-induced neuropathy and inflammatory pain showed long-lasting antinociceptive responses. Clinical studies, though limited, reported improvements in depression, anxiety, resilience, and quality of life in patients with advanced cancer and chronic conditions, with preliminary evidence of analgesic benefit. Conclusions: Psilocybin shows promise as a multidimensional therapy for chronic pain, addressing both sensory and affective components. However, ethical issues, safety concerns, and regulatory barriers necessitate careful management, and robust randomized controlled trials are essential to confirm efficacy and guide clinical translation. Full article

Irritable Bowel Syndrome (IBS) is a prevalent and heterogeneous functional gastrointestinal disorder with a complex and multifactorial pathophysiology. Traditional treatment approaches have focused on symptom relief, often overlooking the underlying biological mechanisms driving the disease. Τhis review summarizes the current evidence linking core pathophysiological pathways of IBS with mechanism- and diet- based therapeutic strategies to guide personalized treatment. Serotonergic signaling, microbial dysbiosis, immune activation, epithelial barrier dysfunction, and bile acid malabsorption interact to shape the diverse phenotypes of IBS, contributing to altered motility, visceral hypersensitivity, and gut-brain axis dysregulation. Increasing evidence supports that targeted dietary and biological interventions including low-FODMAP and Mediterranean low-FODMAP diets, targeted use of probiotics and psychobiotics, and vitamin D supplementation can modulate microbial composition, reduce luminal irritants, support barrier integrity, and attenuate immune system activation. Similarly, pharmacologic therapies including serotonergic receptor modulators, bile acid sequestrants and neuroimmune agents act on specific mechanistic pathways, reflecting a shift from symptom-based to mechanism-driven management. Collectively, these findings highlight that integrating dietary, microbial, neuroimmune, and serotonergic modulation within a unified therapeutic framework can support a more rational and individualized approach to IBS management and long term symptom control. Full article

Background/Objectives: Thermoregulation is essential for survival, with the hypothalamic preoptic area integrating peripheral signals to maintain core body temperature. While fever enhances immune responses, excessive hyperthermia causes cellular damage. Previous work has shown that central glucagon-like peptide-1 (GLP-1) receptor antagonism intensifies lipopolysaccharide (LPS)-induced fever, suggesting a role for GLP-1 signaling in temperature regulation. However, the direct effects of GLP-1 receptor agonists on fever remained unexplored. This study investigated the effects of liraglutide (LIRA), a GLP-1 analog used to treat diabetes and obesity, on temperature regulation and fever in rats, with a focus on sex-dependent mechanisms. Methods: Male and female Wistar rats received lipopolysaccharide (LPS, i.p.) to induce fever, followed by LIRA treatment (0.3 mg/kg, i.p.) one hour later. Body temperature was monitored for up to six hours post-LPS injection. Results: LIRA reduced body temperature in both euthermic and febrile rats of both sexes. LPS increased PGE₂ concentration in both sexes, with males showing a twofold increase compared to females. LIRA treatment reduced PGE₂ levels in LPS-challenged males (62%, p < 0.01) but not in female rats. LPS elevated interleukin (IL)-6 levels in both sexes, while LIRA treatment decreased IL-6 only in females (45%, p < 0.05). In males, LPS reduced hypothalamic serotonin (5-HT) levels, and LIRA further decreased 5-HT in saline-treated animals. In females, LIRA increased 5-HT levels (84%, p < 0.01) in LPS-challenged animals. Additionally, LIRA exhibited sex-specific effects on hypothalamic JNK phosphorylation, increasing activation in LPS-treated males and reducing it in LPS-treated females. Conclusions: LIRA demonstrates antipyretic properties through distinct, sex-specific mechanisms. In males, temperature reduction correlates with decreased hypothalamic PGE₂, whereas in females, antipyretic effects are associated with reduced IL-6, decreased JNK phosphorylation, and increased 5-HT. These findings reveal sexually dimorphic GLP-1R-mediated thermoregulatory pathways during inflammation. However, the causal relationships between these molecular changes and temperature regulation require further investigation, particularly regarding whether observed biochemical alterations represent primary mechanisms or secondary consequences of temperature modulation. Future studies should investigate the functional significance of the apparent contradiction in serotonergic responses between sexes. Full article

Serotonergic psychedelics, particularly psilocybin, lysergic acid diethylamide (LSD), and dimethyltryptamine (DMT), are increasingly recognised as powerful tools to advance the understanding of consciousness and its relation to brain activity. Psychedelic research has informed neuroscientific theories that attempt to map neural observations of network connectivity and signal diversity to phenomenological qualities like psychological flexibility. Thus far, however, there have been relatively limited efforts to bridge the gap between psychedelic-informed theory and the experiential differences observed in neurodevelopmental conditions such as autism. In this narrative review and conceptual synthesis, we compare the psychedelic state and autism in adults from a neurophenomenological perspective. Predictive processing is invoked as a unifying framework. This procedure highlights both phenomena as involving a shift towards sensory information relative to prior knowledge, but potentially implicating alterations at opposite ends of the cortical hierarchy. This contrastive approach also reveals opportunities for refining concepts—including psychological flexibility—as well as interpretations of results across fields. However, neurobiological findings, especially in autism, are heterogeneous and there are inherent restrictions in comparing transient state and lifelong trait phenomena. Conclusions of this comparison are primarily conceptual and offer testable hypotheses for the neurophenomenology of the psychedelic state, autism, and their interaction. Full article

Serotonin (5-hydroxytryptamine) is a key neurotransmitter involved in gastrointestinal and central nervous system functions. Given that approximately 90% of serotonin is synthesized in the gut, dietary interventions targeting the gut microbiota have emerged as promising strategies to modulate serotonin homeostasis. Kefir, a fermented milk beverage rich in probiotics and bioactive compounds, has been suggested to influence gut–brain axis signaling, yet its effects in the pediatric period remain insufficiently characterized. This study aimed to investigate the impact of kefir supplementation on serotonin biosynthesis, receptor expression, and metabolic pathways in a pediatric rat model, focusing on molecular markers across brain, jejunum, and serum tissues. Sixteen male Wistar rats (four weeks old) were divided into kefir and control groups. The kefir group received daily oral gavage of kefir (1 mL/100 g) for eight weeks, while controls received saline. Gene and protein expression levels of serotonergic markers (5-HT, TPH1, TPH2, SLC6A4, VMAT2, 5-HTR2B, 5-HTR3A, and 5-HTR4) were analyzed using quantitative PCR, ELISA, and Western blotting. Serotonin turnover was assessed via 5-HIAA levels. Kefir supplementation significantly increased 5-HT and TPH1 expression in both brain and jejunum tissues. In the brain, kefir elevated TPH2 and upregulated 5-HTR3A and 5-HTR2B, while reducing 5-HIAA levels, suggesting decreased serotonin degradation. In the jejunum, 5-HTR4 expression was markedly increased. Serum analyses revealed reduced TPH1/TPH2 expression but elevated 5-HTR4 levels, indicating systemic modulation of serotonergic signaling. Kefir exerts multifaceted effects on the serotonergic system in pediatric rats by enhancing serotonin biosynthesis, modulating receptor expression, and reducing serotonin turnover. These findings highlight kefir as a potential psychobiotic capable of influencing the gut–brain axis during early life, with implications for pediatric neurodevelopment and mental health. Further research, including clinical trials, is warranted to confirm its translational potential. Full article

Treatment-resistant depression (TRD) affects 20–30% of patients with major depressive disorder and presents a significant clinical challenge due to its biological diversity. This review highlights standard mechanisms that contribute to treatment resistance beyond traditional monoaminergic models. Evidence supports serotonergic dysregulation, including 5-HT1A autoreceptor dysfunction and “serotonin flooding” as well as dopaminergic deficits linked to anhedonia and an imbalance between glutamate and GABA that impair synaptic plasticity. Changes in neurotrophic signaling, such as reduced BDNF and VEGF activity, complicate recovery by limiting neural repair and regeneration. Chronic inflammation and oxidative stress contribute to neuronal dysfunction, while HPA axis dysregulation may exacerbate depressive symptoms and resistance to antidepressants. Emerging evidence suggests that obesity and gut microbiota imbalance reduce the production of short-chain fatty acids by bacteria and increase intestinal permeability, thereby influencing neuroinflammatory and neurochemical processes in TRD. Neuroimaging studies reveal hyperconnectivity within the default mode network and impaired reward circuits, both of which are associated with persistent symptoms and a poor treatment response. By combining evidence on inflammation, oxidative stress, neuroendocrine disturbances, microbiome changes, and brain connectivity issues, this review develops a comprehensive framework for understanding TRD. It emphasizes the importance of biomarker-based subtyping to guide personalized future treatments. Full article