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Melatonin, a key regulator of circadian rhythms and sleep-wake cycles, is implicated in the pathophysiology of major depressive disorder (MDD). Emerging evidence supports its anti-inflammatory, cytoprotective, and neuroprotective roles, including promotion of neuroplasticity. This study aims to investigate alterations in serum melatonin, interleukin-6 (IL-6), and brain-derived neurotrophic factor (BDNF) levels in first-episode MDD patients, and explores their clinical correlations. A total of 74 first-episode patients diagnosed with MDD and 72 healthy controls were enrolled in this study. The severity of depressive symptoms was assessed using the 24-item Hamilton Depression Rating Scale (HAMD-24). All blood samples were collected in the morning, and serum levels of melatonin, IL-6, and BDNF were quantified via enzyme-linked immunosorbent assay (ELISA). Baseline serum concentrations of melatonin, IL-6, and BDNF were compared between the MDD group and the control group. Additionally, the discriminative ability of these biomarkers (melatonin, IL-6, and BDNF) in distinguishing MDD patients from healthy controls was evaluated using receiver operating characteristic (ROC) curve analysis. Pearson correlation analysis or Spearman's rank correlation analysis was performed to explore the relationships between serum melatonin levels and clinical disease severity, as well as with IL-6 and BDNF levels, in patients with MDD. Compared with the control group, the MDD group showed significantly higher serum levels of melatonin (Z = -3.861, P < 0.001) and IL-6 (Z = -4.240, P < 0.001), but significantly lower serum BDNF levels (t = 9.537, P < 0.001). Moreover, the combined panel of BDNF, IL-6, and melatonin achieved high accuracy in distinguishing MDD patients from healthy controls, with an area under the curve (AUC) of 0.905. Additionally, no significant correlations were found between serum melatonin levels and clinical disease severity (assessed by HAMD-24 scores), IL-6 levels, or BDNF levels in MDD patients (all P > 0.05). These findings suggest that dysregulation of melatonin, IL-6, and BDNF may contribute to the pathophysiology of first-episode MDD, with their combined measurement offering strong diagnostic potential. Show less

Prenatal stress may lead to cognitive and behavioral dysfunction in the offspring. Large evidence has shown the deleterious effects of maternal stress on cognitive and behavioral functions of the offspring; however, the effect of paternal stress has not been well documented. In the present study, we aimed to investigate the effect of paternal stress (chronic electrical footshocks, post-traumatic stress disorder or PTSD-like model) on cognitive and behavioral functions, and brain-derived neurotrophic factor (BDNF) hippocampal level in both male and female offspring during adolescence. The father rat (stress-exposed) was exposed to three consecutive shocks in a fear conditioning apparatus for ten times during four weeks, in an uncertain and unpredictable schedule. Saline (0.5 mL) or lithium chloride (50 mg/kg) was intraperitoneally injected to male and female offspring during 21-41 postnatal day (PND). The results showed that paternal stress decreased locomotor activity in female offspring, and increased anxiety-like behavior in both male and female offspring, with more effect on females. Paternal stress also decreased pain subthreshold only in female offspring and impaired passive avoidance and spatial memory in both male and female offspring. Paternal stress also decreased BDNF expression level only in female offspring. However, lithium reversed most of the behavioral dysfunctions in rats' offspring with a history of paternal stress. We concluded that paternal stress significantly impairs cognitive and behavioral function in the offspring during adolescence, with more effect on females. Also, chronic lithium treatment may reverse the deleterious effects of paternal stress. Show less

Paclitaxel (PTX) is a potent taxane widely used in the treatment of solid tumors and can cause dose-limiting peripheral neuropathy. This study evaluated the therapeutic potential of selenium in a paclitaxel-induced peripheral neuropathy model. A total of 30 male Sprague-Dawley rats were divided into five groups (n=6): Control, SE1, PTX, PTX+SE0.5, and PTX+SE1. PTX (2mg/kg, i.p., days 1-5) was administered followed by SE (0.5 or 1mg/kg, i.g., days 6-15); sciatic nerve tissues were analyzed on day 16. In addition to molecular and histopathological analyses, behavioral assessments were performed to evaluate mechanical nociception, locomotor activity, and anxiety-like behavior. PTX significantly reduced mechanical pain threshold, impaired locomotor performance, and decreased exploratory behavior. At the molecular level, PTX increased oxidative stress by elevating MDA levels while decreasing SOD and GSH; it also increased TNF-α, IL-1β, and IL-6, and reduced IL-10 levels. Histopathologically, marked axonal degeneration and demyelination, along with reduced myelin fiber area, were observed. SE treatment, particularly at 1mg/kg, restored mechanical pain threshold, improved locomotor parameters, and attenuated anxiety-like behavior. SE also brought oxidative stress markers closer to control levels, suppressed pro-inflammatory cytokines, increased IL-10, reduced histopathological damage, and improved myelin integrity. Immunostaining revealed that SE attenuated PTX-induced increases in BAX, caspase-3, and 8-OHdG, while partially reversing the decrease in Bcl-2. In qPCR analyses, PTX decreased BDNF and increased GFAP expression, which were normalized by SE. SE suppressed the PTX-induced increase in Keap-1 and enhanced Nrf-2 expression. In addition, SE treatment partially restored HO-1 expression, with statistically significant increases observed compared to the PTX group, although levels did not fully return to control values. Show less

Triclocarban (TCC), an antimicrobial agent used in personal care products, has been widely detected in aquatic ecosystems and has raised significant concerns for aquatic organisms and human health. This study aimed to investigate the neurotoxic effects of TCC exposure, a broad-spectrum bactericide, through behavioral, molecular, pathological, and metabolomic analyses. For this purpose, adult zebrafish were exposed to TCC at doses of 3, 10, and 30 μg/L for 96 h, and their brain tissues were removed. Subsequently, behavioral (anxiety and circadian rhythm tests), molecular (qPCR), histopathological, and metabolomic analyses were performed on these fish. The data obtained showed that TCC treatment increased anxiety-like behaviors in zebrafish and caused disruptions in the circadian rhythm. Additionally, it was determined that the expression levels of both core clock genes (Bmal and Gnat2) and genes associated with neuroplasticity, stress response, and neurotransmission (Bdnf, Crhr, 5-ht4, Ache) changed significantly in a dose-dependent manner compared to the control group. Additionally, it was observed that TCC increased degeneration and necrosis in the brain in parallel with the dose increase, while raising 8-OHdG and BDNF protein levels and decreasing NRF2 and SIRT1 protein levels. When metabolomic analysis data were evaluated, it was determined that TCC, especially at the highest dose, significantly altered metabolite levels. These results reveal that TCC, beyond being an environmental pollutant, may cause behavioral disorders and neurotoxic effects. Show less

Acute physical exercise (PE) is known to influence the expression of many neurobiological markers and cognitive functions, but the time course and domain-specificity of such effects remain under debate. This study investigated whether a single bout of maximal incremental exercise can increase serum brain-derived neurotrophic factor (BDNF) levels, improving cognitive performance in healthy adults. Twenty-eight physically active males underwent a maximal incremental cycling test. BDNF serum concentrations were measured at three timepoints: before exercise, 15 min after, and 24 h post-exercise. Cognitive performance in verbal and visuo-spatial memory and convergent creative thinking was assessed before and 24 h post-exercise. Results showed a significant increase in serum BDNF 24 h after exercise, while no significant change was observed 15 min post-exercise. Cognitive assessments revealed improvements in verbal immediate recall and visuo-spatial working memory, but not in long-term verbal memory, visuo-spatial short-term memory, and convergent creative thinking. No significant correlations emerged between BDNF changes and cognitive performance changes. The dissociation between BDNF and behavior points to complex and likely time-dependent mechanisms underlying exercise-induced cognitive enhancements. These results support the effectiveness of acute PE as stimulus for BDNF neurotrophin production and as a non-pharmacological tool to boost specific cognitive functions, with implications for optimizing learning and cognitive performance in healthy populations. Show less

Pulmonary fibrosis is a common and life-threatening complication of Parkinson's disease (PD), yet the molecular mechanisms linking the two diseases remain unclear, creating a critical gap in targeted therapeutic strategies for comorbid patients. Angiotensin-converting enzyme 2 (ACE2) plays a key role in neuroprotection and lung homeostasis; its deficiency exacerbates PD-related neuroinflammation and α-synuclein aggregation, while also promoting pulmonary inflammation and fibrotic remodeling. Clarifying how ACE2 deficiency drives PD-exacerbated pulmonary fibrosis is therefore an urgent unmet need. This study explored the underlying mechanisms using MPTP-induced PD mouse models and bioinformatics analyses of PD/idiopathic pulmonary fibrosis (IPF) datasets from the GEO database. In MPTP-induced PD mice, ACE2 deficiency significantly worsened motor/non-motor dysfunction, dopaminergic neuron loss, microglial/astrocytic activation, and lung fibrosis (evidenced by elevated α-SMA/TGF-β and increased collagen deposition). Bioinformatics identified 41 overlapping differentially expressed genes (DEGs) between PD and IPF, enriched in critical pathways: downregulated FoxO1 (impairing antioxidant defense) and upregulated TNF, JAK1-STAT3, and AGE-RAGE (amplifying inflammation/fibrosis). ROC analysis validated hub genes (e.g., BDNF, FOSL2) with good diagnostic value (AUC > 0.7), and molecular docking identified Smilagenin, Fostamatinib, Olopatadine, and Amlexanox as potential therapeutics. This study confirms ACE2 deficiency is a central driver of PD-exacerbated pulmonary fibrosis via the FoxO1/TNF/JAK1-STAT3/AGE-RAGE pathways, providing novel biomarkers and drug candidates to address the clinical need for managing this comorbidity. Show less

Signal peptides (SPs) are short N-terminal sequences that direct proteins to the endoplasmic reticulum (ER). After cleavage of the SP, these proteins are mostly trafficked to the Golgi apparatus for secretion. Lipocalin-2 (LCN2), a neurotoxic secretory protein, was recently identified as a target of autophagy. The presence of an SP is a prerequisite for secretion and autophagic degradation. Based on these observations, we investigated whether the SP of LCN2 is sufficient to enable proteins to be secreted or degraded via autophagy. We fused the SP of LCN2 to a non-secretory green fluorescent protein (GFP) and found that this ER-generated GFP was either secreted or degraded via autophagy. These results indicate that the LCN2-derived SP alone is sufficient to direct proteins to the ER and subsequent secretion or autophagic degradation. This dual regulation was abolished when the SP was deleted from LCN2. Notably, the effect was preserved even when the LCN2 SP was replaced with the SP from brain-derived neurotrophic factor, another secretory protein. These results suggest that SPs with different sequences can similarly direct proteins to the ER and subsequent secretion or autophagic degradation. Furthermore, we found that even when LCN2 reached the Golgi apparatus for secretion, it could also be degraded via autophagy. Thus, we propose that SP-directed and ER-generated secretory proteins can undergo autophagic degradation during ER-Golgi transport, including at the ER, the ER-Golgi intermediate compartment, or the Golgi apparatus. Taken together, degradation of secretory proteins via autophagy suggests implications for the potential control of secretory protein homeostasis. Show less

Suicidal behavior in children and adolescents is a major global public health issue, and suicide is one of the leading causes of death in this age group. While psychosocial determinants of suicidality are well established, understanding its biological risk factors is crucial for targeted prevention and treatment. This review presents a narrative synthesis of recent literature examining current evidence on the biological mechanisms that contribute to youth suicidality. Genetic liability plays a substantial role, often interacting with environmental stressors. Key neurobiological factors include dysfunction of the serotonin system and impaired neuroplasticity, characterized by a glutamate-gamma-aminobutyric acid imbalance and reduced brain-derived neurotrophic factor. Psychosocial stress appears linked to these changes through several pathways, including dysregulation of the hypothalamic-pituitary-adrenal axis, chronic low-grade inflammation, oxidative stress, and activation of the kynurenine pathway. Neurodevelopmental conditions like autism spectrum disorders and attention deficit hyperactivity disorder, as well as sleep disturbances, may further increase risk. While therapeutic agents such as ketamine and lithium target these neurobiological systems, evidence for their anti-suicidal efficacy in youth remains limited, with only a small number of randomized controlled trials conducted in pediatric populations. Biological research offers valuable insights, but the use of varied study methods and a lack of longitudinal data complicate its translation into clinical practice. Future studies should employ integrative, developmentally informed models to elucidate causal mechanisms and inform more effective interventions. Show less

Chronic stress induces sensorimotor, cognitive, and neuroendocrine alterations, particularly in females who exhibit heightened vulnerability to stress-related disorders. This study tested the hypothesis that chronic quetiapine administration during ongoing unpredictable chronic mild stress (UCMS) would attenuate stress-induced impairments in sensorimotor gating, recognition memory, and HPA-axis–related biochemical markers in female rats. Adult female Wistar rats were exposed to a 9-week UCMS paradigm, with quetiapine (10 mg/kg/day, i.p.) administered during the final 3 weeks. Behavioral outcomes were assessed using prepulse inhibition (PPI), startle reactivity, and the Novel Object Recognition (NOR) test. Serum and hippocampal corticosterone and BDNF levels were quantified by ELISA. Chronic stress significantly reduced PPI and recognition memory performance and increased serum and hippocampal corticosterone levels. Quetiapine treatment improved PPI and startle responsiveness, restored NOR discrimination index values, and partially attenuated stress-induced corticosterone elevations. Hippocampal BDNF levels were elevated in stressed animals and were modulated toward intermediate levels following quetiapine treatment. These findings indicate that chronic quetiapine administration mitigates behavioral and neuroendocrine alterations induced by prolonged stress in female rats. [Image: see text] The online version contains supplementary material available at 10.1007/s11011-026-01834-8. Show less

According to neuropsychiatric sequelae for cardiovascular pathology, carotid artery disease (CAD) represents a significant medical, social, and economic burden. Numerous efforts have been made to define reliable markers that can reflect the principal pathological event and the effect of employed therapeutic protocols, prognoses, and clinical outcomes of CAD. However, the potential role of the neurotrophin (NT) system has not yet been confirmed. This narrative review was conducted following a literature search of PubMed, which included all studies on NT system elements and CAD published over the last two decades, encompassing both animal and clinical investigations, regarding the potential use of NT system elements as biomarkers for neurotoxicity manifestations and therapeutic effectiveness in CAD. Still, the analysis presented in this review is not sufficient to reveal whether NT system elements can be considered as exploratory or standard biomarkers for the evaluation of CAD. Further research is essential to elucidate this dilemma. Show less

Major depressive disorder (MDD) is a highly prevalent psychiatric illness for which rapid-acting antidepressants such as ketamine provide only transient benefit. Because κ-opioid receptor (KOR) signaling contributes to stress-related dysphoria and impaired neuroplasticity, we examined whether KOR antagonism could prolong ketamine's antidepressant-like effects in a mouse model of adolescent chronic unpredictable stress (CUS). Male Show less

Pituitary macroadenomas often cause visual pathway impairment due to optic chiasm compression. The association between systemic neurotrophic factors and visual recovery remains insufficiently explored. This prospective observational cohort study included 53 patients (106 eyes); 36 patients (72 eyes) completed a 12-month follow-up. Patients were assigned to a treatment group (surgical and/or pharmacological; Show less

Affective disorders, such as major depressive disorder and anxiety disorders, represent a major global health burden, with current treatments proving inadequate for a substantial proportion of patients. Emerging research highlights the microbiota-gut-brain (MGB) axis as a crucial bidirectional communication system influencing brain function and neuroplasticity through neural, endocrine, immune, and metabolic pathways. This narrative review examines probiotics-live beneficial microorganisms-as modulators of adult neurogenesis and synaptic plasticity, two processes fundamentally implicated in the pathophysiology of affective disorders. Preclinical evidence demonstrates that specific strains, particularly from the Show less

Ketamine has emerged as a promising rapid-acting antidepressant with distinct advantages for the treatment of treatment-resistant depression (TRD). Its therapeutic effects are mediated through multi-target modulation of the glutamatergic system. Unlike conventional antidepressants, ketamine exerts a markedly faster onset of action; however, its long-term safety profile and potential risk of dependence require rigorous evaluation. This scoping review aims to systematically summarize recent advances in research on ketamine's role in depression treatment. This review synthesizes current evidence regarding ketamine's molecular mechanisms of action, neuroimaging correlates, pharmacological characteristics, and associated ethical considerations. By primarily antagonizing N-methyl-D-aspartate (NMDA) receptors, ketamine rapidly disinhibits the mesolimbic dopamine reward pathway and upregulates brain-derived neurotrophic factor (BDNF) expression via eukaryotic elongation factor 2 kinase (eEF2K) suppression, thereby activating the mammalian target of rapamycin (mTOR) pathway and enhancing synaptic plasticity. Neuroimaging studies further reveal that ketamine induces rapid remodeling of prefrontal-limbic functional connectivity, modulates default mode network activity, and promotes the normalization of cerebral metabolism and structure. Pharmacologically, ketamine exhibits a rapid onset of action and a relatively broad therapeutic window, though notable pharmacodynamic and pharmacokinetic differences exist between its enantiomers and active metabolites, which warrants further investigation. Ketamine displays rapid onset and high efficacy in the management of TRD; nevertheless, its long-term safety, risk of dependence, and potential cognitive effects necessitate close clinical monitoring. Future research should prioritize the exploration of synergistic treatment regimens and the development of novel ketamine derivatives with improved target specificity and safety profiles to advance the application of precision psychiatry. Collectively, this review provides a foundational reference to guide clinical practice and inform subsequent mechanistic studies on ketamine-based antidepressant therapies. Show less

Exercise as a non-pharmacological measure is important to increase the brain plasticity hence improving cognitive performance as well as mental health. This narrative review describes in depth the hierarchical multiscale processes of neuroplasticity to exercise, including the presence of neurotrophic factor regulation, cellular metabolic adaptations and neurotransmitter remodeling, up to the structure and functional reorganization of brain networks as seen through neuroimaging, and concluding with adaptive cognitive and behavioral outcomes. We further investigate the role of personal variations in genetic time and social environments in moderating the neuroplasticity of exercise. Furthermore, the review identifies the importance of combining multimodal visualization methods with computational models in generating accurate workout prescriptions and their potential of translation into clinical and educational practice. Lastly, the research problems and "grand challenges" are addressed, with a focus on the importance of exercise as a pleiotropic behavior-intervention and its general implications to the area of promoting brain health. Show less

Methadone maintenance treatment (MMT) is one of the major pharmacotherapies for opioid use disorder. The underlying mechanisms of addiction and the treatment response are only partially understood. The study's main goal was to identify differential DNA CpG methylation that occurred in response to MMT. Toward this goal, we have conducted a longitudinal epigenome-wide study of blood samples from 64 patients at the beginning and after 1-3 years of MMT, using a linear mixed model. A total of 1881 differentially methylated probes (DMPs) were identified (FDR < 0.05), controlling for sex, age, estimates of blood cell proportions, and the first two principal components based on genome-wide SNP genotypes. Among the genes annotated to the top DMPs are The study provides preliminary insight into the epigenetic effect of MMT. Future studies will have to confirm the DMPs, assess their impact on gene expression, and determine their clinical relevance. Show less

Psilocybin is studied as innovative medication in anxiety, substance abuse and treatment-resistant depression. Animal studies show that psychedelics promote neuronal plasticity by strengthening synaptic responses and protein synthesis. However, the exact molecular and cellular changes induced by psilocybin in the human brain are not known. Here, we treated human cortical neurons derived from induced pluripotent stem cells with the 5-HT2A receptor agonist psilocin - the psychoactive metabolite of psilocybin. We analyzed how exposure to psilocin affects gene expression, neuronal morphology, synaptic markers and neuronal function. Psilocin provoked a 5-HT2A-R-mediated augmentation of BDNF abundance. Transcriptomic profiling identified gene expression signatures priming neurons to neuroplasticity. On a morphological level, psilocin induced enhanced neuronal complexity and increased expression of synaptic proteins, in particular in the postsynaptic compartment. Consistently, we observed an increased excitability and enhanced synaptic network activity in neurons treated with psilocin. In conclusion, exposure of human neurons to psilocin might induce a state of enhanced neuronal plasticity, which could explain why psilocin is beneficial in the treatment of neuropsychiatric disorders where synaptic dysfunctions are discussed. Show less

Primary dysmenorrhea (PDM) involves recurrent pelvic pain (RPP), alongside menstruation and psychological comorbidity, yet existing models inadequately capture its recurrent nature. In this study, we established a pharmacologically induced rat model of RPP, using estradiol benzoate and oxytocin over six 4-day cycles. The RPP model produced robust and sustained writhing responses, with writhing latency dropping from 30 to 4 min ( Show less

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a complex and not fully understood etiology. Increasing evidence suggests that neurotrophic factors involved in neurodevelopment and synaptic plasticity, as well as hormones of the hypothalamic-pituitary-adrenal (HPA) axis that regulate the stress response, may contribute to the pathophysiology of ADHD. This cross-sectional study aimed to compare children diagnosed with ADHD and healthy controls with respect to serum levels of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), neurotrophin-3 (NT-3), adrenocorticotropic hormone (ACTH), and cortisol. A total of 80 children aged 6-18 years with a diagnosis of ADHD and 81 healthy controls were included in the study. The severity of ADHD symptoms was assessed using the Conners' Parent Rating Scale-Short Version (CPRS-SV). Serum levels of biochemical parameters were measured using commercially available electrochemiluminescence immunoassay and enzyme-linked immunosorbent assay kits. Compared with the healthy control group, the ADHD group exhibited significantly higher serum levels of BDNF, GDNF, VEGF, ACTH, and cortisol, whereas NT-3 levels did not differ between the groups. These group differences remained statistically significant after controlling for potential confounding variables. Correlation analyses revealed no significant associations between neurotrophic factors, hypothalamic-pituitary-adrenal (HPA) axis hormones, and CPRS-SV subscale scores. The present findings indicate that neurotrophic factors and hormones related to the hypothalamic-pituitary-adrenal (HPA) axis are altered in medication-naïve children and adolescents with ADHD. The absence of a direct correlation between neurotrophic factors and HPA axis hormones suggests that these systems may contribute to the pathophysiology of ADHD through parallel yet partially independent and complex mechanisms. Future longitudinal and multimodal studies are warranted to elucidate the dynamic interactions between stress-related neuroendocrine processes and neurodevelopmental pathways in ADHD. Show less

Sleep deprivation (SD) impairs information processing through alterations of prefrontal cortex (PFC) function, yet the molecular underpinnings of this process remain poorly understood. We previously showed that SD disrupts sensorimotor gating by elevating prefrontal levels of the neurosteroid allopregnanolone (AP), a positive allosteric modulator of GABA-A receptors. Here we identify a complementary, mechanistically independent process whereby SD alters GABA-A currents in the PFC of mice and rats. SD reduced membrane expression of the chloride exporter KCC2, leading to intracellular chloride accumulation and a depolarizing shift in GABA-A receptor reversal potential that weakened GABAergic inhibition. Pharmacological normalization of chloride homeostasis with bumetanide fully rescued SD-induced deficits in sensorimotor gating and information encoding. SD also upregulated BDNF, and intra-PFC antagonism of its receptor TrkB restored KCC2 expression and normalized information processing, identifying BDNF-TrkB signaling as an upstream driver of chloride dysregulation. Notably, blocking AP synthesis rescued behavioral deficits without correcting chloride imbalance, confirming mechanistic independence. Finally, combined administration of AP and a KCC2 blocker produced information-processing deficits akin to those induced by SD. These findings identify TrkB-dependent disruption of prefrontal chloride homeostasis as a druggable mechanism underlying sleep loss-induced cognitive dysfunction. Show less

Huntington's disease (HD) is characterized by progressive striatal degeneration associated with mutant huntingtin (mHTT)-related proteostatic disruption and chronic neuroinflammation. Although mHTT-lowering approaches hold therapeutic promise, their capacity to restore the degenerating neural microenvironment remains limited. Here, we evaluated the therapeutic potential of human induced pluripotent stem cell (iPSC)-derived neural precursor cells (s513-NPCs) in two complementary HD models, the acute R6/2 transgenic fragment model and the protracted, full-length YAC128 genomic model. Intrastriatal transplantation of s513-NPCs resulted in sustained functional improvement, including stabilization of motor coordination and attenuation of neuromuscular decline, across both disease contexts. These neuroprotective effects were accompanied by efficient donor cell engraftment and integration within the host striatum. At the molecular level, transplantation was associated with coordinated changes in proteostasis-related pathways, reflected by reduced mHTT aggregate burden and modulation of proteasomal and autophagic markers. In parallel, enhanced local BDNF-TrkB signaling was observed in grafted regions, consistent with improved neuronal support. Notably, transplanted NPCs exhibited context-dependent immunological responses, characterized by attenuation of pro-inflammatory signatures in aggressive disease stages and features of a reparative microenvironment in more protracted settings. Collectively, these findings demonstrate that iPSC-derived neural precursor transplantation confers robust neuroprotective effects in HD models, supporting its potential as a stem cell-based strategy to mitigate striatal pathology and functional decline. Show less