Search Results (904)

In recent years, significant progress has been made in understanding that Parkinson’s disease (PD) is associated not only with the dopamine (DA) but also with the norepinephric (NE) system. In order to investigate the potential involvement of NE in the development of the early motor symptoms of PD, we studied the effects of reducing its levels in a norepinephrine transporter knockout mouse (NET-KO). Due to the absence of NET, all the norepinephrine needed must be synthesized de novo. NET-KO mice were injected intraperitoneally with α-methyl-p-tyrosine (AMPT), a blocker of tyrosine hydroxylase, to induce a hyponoradrenergic state. Changes in tissue NE content in the frontal cortex and DA content in the striatum were evaluated using HPLC. We also measured the motor activity parameters of NET-KO mice after AMPT injection. The hyponorepinephric state induced by AMPT administration in NET-KO mice did not lead to severe motor impairments, as occurs in PD models. However, NET-KO mice did exhibit abnormal hindlimb extension, which began three hours after AMPT administration. This symptom may be interpreted as an early symptom preceding PD. These results suggest that the potential involvement of different neurotransmitter systems in motor abnormalities relevant to Parkinson’s disease warrants further investigation. Full article

Background: In Parkinson’s disease (PD), changes in the brain begin before clinical symptoms. We have previously shown that VGF precursor levels were reduced in a presymptomatic PD animal model. Objectives: In the present study, we investigated whether two VGF precursor-derived products, namely NAPP-129 protein and TLQP-62 peptide, also exhibit alterations using the same PD animal model. Methods: Specifically, rats were unilaterally injected in the substantia nigra with a viral vector overexpressing green fluorescent protein (N = 12) or α-synuclein (N = 13), the latter resulting in mild dopaminergic alterations without overt motor deficits. Results: NAPP-129 and TLQP-62 were investigated in the substantia nigra, striatum, and plasma by Western blotting or immunoassays using specific antibodies against NAPP and TLQP sequences, alongside other NERP-1- and AQEE-related products. Plasma samples of a Huntington’s disease mouse model were also analyzed. We found reductions in NAPP-129 and TLQP-62 levels in the substantia nigra along with a decrease in NAPP- and TLQP-like plasma immunoreactivity in α-synuclein-overexpressed rats, while the striatum was not affected. NERP-1- and AQEE-related products were not altered. No changes were found in the Huntington’s disease model. Conclusions: These findings indicate that NAPP-129 and TLQP-62 may enhance the sensitivity and specificity of biomarker-based strategies for PD. Full article

Brain-Derived Neurotrophic Factor (BDNF), a key member of the neurotrophin family, is critically involved in neuronal survival, synaptic plasticity, learning, and memory. While its roles in mammals have been extensively documented, the molecular regulatory mechanisms governing BDNF expression and its causal contributions to complex cognitive behaviors remain poorly understood in non-mammalian vertebrates—particularly for the domestic pigeon (Columba livia domestica), a species distinguished by its remarkable spatial navigation and homing capabilities. This review synthesizes the current evidence on BDNF in the pigeon central nervous system across five thematic domains: molecular structure and isoform diversity, transcriptional and epigenetic regulatory networks, involvement in neural development, associations with cognitive and navigational behaviors, and potential translational applications. A particular emphasis is placed on the region-specific and activity-dependent expression patterns of BDNF in brain structures such as the hippocampal formation (HF), optic tectum, and striatum, and their functional relevance to visual processing, homing behavior, and stress adaptation. To date, most findings remain correlational; therefore, establishing a mechanistic understanding necessitates the integration of advanced methodologies—including single-cell omics, CRISPR-based gene editing, and high-resolution behavioral phenotyping—to causally link BDNF dynamics, neural circuit modulation, and spatial cognition. This synthesis aims to bridge gaps in comparative neurobiology, inform molecular approaches to avian cognitive enhancement, and support evidence-based strategies for racing pigeon breeding and welfare assessment. Full article

Substance use disorder (SUD) is a chronic neuropsychiatric condition characterized by persistent drug seeking and impaired behavioral control. Dopaminergic signaling has long been recognized as a central regulator of reinforcement learning, motivation, and habit formation. Addictive substances profoundly alter dopamine transmission through multiple mechanisms. These drug-induced changes contribute to the initiation, escalation, and persistence of addictive behaviors. In addition to dopamine, the cholinergic system has emerged as an important modulator of striatal circuit function. Acetylcholine and its receptors interact extensively with dopaminergic pathways, shaping striatal signaling dynamics and influencing learning and action selection, with particularly strong relevance for nicotine dependence. In this review, we discuss how striatal dopamine and acetylcholine contribute to learning, habit formation, and addiction-related behaviors, as well as how these systems interact at the circuit level. By integrating these findings, we propose a framework for understanding how dopamine–acetylcholine interactions may influence behavioral regulation relevant to substance use disorders. Full article

Parkinson’s disease (PD) is a neurodegenerative disorder caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Lipid metabolism, especially phospholipids, has been reported to be altered in PD. The purpose of this study is to investigate the temporal expression and spatial distribution of phospholipids in the motor cortex and striatum at different time points of PD using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mouse model. Mice were injected with saline (NSS) or MPTP at two different time points to create acute and subacute models. Motor analysis was performed at 0, 3, 7, 14, and 21 days post-injection. Tyrosine hydroxylase (TH) staining revealed progressive damage of neurons in the substantia nigra compacta (SNc) and reduced striatal fibers in MPTP-treated animals. By using MALDI-MSI, we identified changes in phosphatidylcholine (PC) profiles in the brains of MPTP-treated animals. Polyunsaturated PCs, including PC 36:4 (16:0/20:4), PC 38:6 (16:0/22:6), and PC 40:8 (18:2/22:6), were decreased in the MPTP-treated groups. These reductions were time-dependent and were more pronounced in the subacute MPTP-treated group. The loss of dopamine neurons caused by MPTP may be associated with the selective loss of polyunsaturated PCs in brain membranes, indicating that lipid metabolism and membrane structural alterations may contribute to the pathology of PD. Full article

Low-count positron emission tomography (PET) is inherently affected by Poisson-dominated noise, which degrades image contrast, structural delineation, and quantitative reliability. This study systematically evaluated residual learning-based deep neural networks to investigate the influence of residual block depth on PET image restoration performance under low-count conditions. We employed a physically controlled striatum phantom, fabricated using 3D printing technology, to ensure reproducible acquisition conditions and controlled physical variability. PET images were acquired using a clinical PET/computed tomography (CT) system with list-mode acquisition. Low-count images reconstructed from short-duration acquisition were paired with high-count reference images reconstructed from extended acquisitions. We compared conventional filtering techniques, including median, Wiener, and modified median Wiener filters, with residual network (ResNet)-based models incorporating 8, 16, and 32 residual blocks. Image quality was quantitatively assessed using contrast-to-noise ratio (CNR), coefficient of variation (COV), line profile analysis, universal quality index (UQI), and perceptual image patch similarity (LPIPS). The results demonstrated that ResNet-based restorations substantially outperformed conventional filtering techniques in contrast recovery, signal stability, and structural preservation. The ResNet-16 model achieved the most balanced performance, yielding the highest CNR (9.02) and lowest COV (0.105), while also demonstrating superior structural and perceptual similarity, as indicated by UQI (0.9224) and LPIPS (0.0174), relative to the high-count reference images. Deeper network configurations exhibited diminishing returns and reduced structural consistencies. These findings indicate that an intermediate residual block depth is optimal for low-count PET image restoration and highlight the importance of architectural optimization in deep learning-based PET image enhancement with phantom-based evaluation frameworks. Full article

Pharmacological antidepressant treatments alter the molecular and functional reactivity of stress-sensitive neural networks. However, how classical versus rapid-acting antidepressants differentially modulate acute stress-induced transcriptional responses across brain regions remains unclear. Here, we compared imipramine and ketamine in mice exposed to acute swim stress, assessing transcriptional adaptations across the frontal cortex, hippocampus, and striatum. Swim stress induced significant widespread activation of cFOS, which led to drug-specific modulations: imipramine primarily significantly dampened cortical and striatal cFOS expression, whereas ketamine preserved stress-evoked neuronal activation. In contrast, hippocampal activation was significantly robust but largely unaffected, indicating that acute antidepressant drug effects during stress coping preferentially target cortical and striatal plasticity mechanisms. In contrast, BDNF expression was altered only within the striatal region, where imipramine attenuated the stress-related increase in BDNF expression. Statistical analysis of behavioral outcomes during the swim stress confirmed a shared facilitation of active coping, yet these similar outcomes emerged from distinct molecular programs. Together, the data demonstrate that the treatment effects of the two substances diverge mechanistically, revealing cortical and striatal transcriptional signatures of classical versus rapid-acting antidepressant action. While these findings suggest potential translational relevance for understanding distinct mechanisms, further studies in humans are required to validate these signatures and their clinical implications. Full article

The 3-nitropropionic acid (NPA) promotes neurological alterations in the striatum, hippocampus and vicinal motor and pre-motor cortical areas, and in the cerebellum. The neurological alterations induced by systemic NPA administration resemble those found in Huntington’s disease. In previous works, we have shown that intraperitoneal (i.p.) administration of kaempferol can efficiently protect against striatum degeneration and against motor neurological dysfunctions induced by NPA. In this work, we show that i.p. administration of kaempferol also protects against the increase in pro-inflammatory cytokines that potentiate the activation of complement C3 protein (a biomarker of A1-type reactive astrocytes generation) and overproduction of neurotoxic amyloid β (Aβ) peptides in the cerebellum of rats treated with acute i.p. administration of NPA. In NPA-treated rats, large multipolar neurons of cerebellar nuclei and Purkinje neurons of the cerebellar cortex are the cells that are most intensely stained by anti-C3 and by anti-Aβ antibodies. In addition, we found that kaempferol also protects against the NPA-induced increase in phospho-tau 217 and phospho-tau 181 in the cerebellum, and our results pointed out that the NPA-induced phospho-tau 217 colocalizes with Aβ(1-42) more closely than phospho-tau 181, both in dentate nucleus and cerebellar cortex. Also, our results unveil another novel brain-protective action of i.p. kaempferol co-administration: namely, its ability to prevent microhemorrhages induced in the cerebellar nuclei area by acute NPA administration. In conclusion, the results of this work show a potent protection of kaempferol against the NPA-induced increase in degeneration biomarkers in the cerebellum. Full article

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 C57BL/6J mice (n = 10 per group for behavioral analyses) were exposed to CUS during adolescence and developed persistent depression-like behavior in adulthood. Mice with depressive-like behavior received a single injection of ketamine, the selective KOR antagonist norbinaltorphimine (nBNI), or their combination. Behavioral testing showed that all treatments reduced immobility in the tail suspension test (TST) 24 h post-administration; however, only the combined ketamine/nBNI treatment maintained antidepressant-like effects one week post-treatment. Molecular analyses (n = 4–8 per group) were conducted at this single time point, one week post-treatment, to characterize region-specific signaling states in the prefrontal cortex, hippocampus, and striatum, focusing on ERK, AKT, JNK, mTOR, and BDNF pathways. These molecular findings represent correlates of sustained behavioral effects rather than evidence of causal mechanisms. Together, the data indicate that concurrent KOR antagonism is associated with prolonged antidepressant response to ketamine in stress-exposed male mice and with distinct region-dependent signaling profiles at one week post-treatment. Further studies are needed to establish mechanistic causality and confirm the possible applicability of these findings. Full article

Methamphetamine (METH) use is highly prevalent among people with HIV (PWH) and those at risk and may contribute to overall worse health outcomes. Poorer health-related problems may be mediated by METH enhancing risky decision-making among PWH. While both METH and HIV are known to have overlapping and deleterious effects on the frontostriatal neural circuitry essential for decision-making, few studies have examined their combined effects. Eighty-eight participants stratified by HIV and a history of METH use disorder completed a risky decision-making paradigm, which involved choosing among safe (20¢) and risky (40¢/80¢ win or loss) choices, during blood-oxygen level-dependent functional magnetic resonance imaging (fMRI). Linear mixed-effects models were used to assess voxelwise differences in group and choice constrained to the anterior cingulate cortex (ACC), insula, and striatum. Despite similar choice behavior across groups, PWH and a history of METH use disorder had greater activation of the ACC and caudate than either condition alone (i.e., HIV+/METH− and HIV−/METH+), which was similar to seronegative, non-using controls. Within the ACC in particular, these differences may have been driven by safe choices. A longer estimated duration of HIV infection was associated with greater ACC activation to risky choices for PWH regardless of METH use history. These findings suggest that PWH and a history of METH use disorder may exhibit compensatory activation of regions associated with decision-making in the context of rewards and that the effects of HIV and past METH use might not be additive. Full article

Prolonged occupational exposure to oil mist particulate matter (OMPM) poses health risks, yet its neurotoxic effects and underlying mechanisms remain poorly understood. Here, OMPM generated from turbine oil commonly used in occupational labor environments was used to expose rats. The rats were divided into the control and OMPM groups. Following 42 days of exposure, a multidimensional assessment was performed using untargeted metabolomics, phosphoproteomics, behavioral testing, hematoxylin–eosin (HE) staining, transmission electron microscopy (TEM), colorimetric assays, enzyme-linked immunosorbent assay, and Western blotting (WB) to evaluate metabolic alterations, protein phosphorylation, and tissue integrity in the striatum. Integrated omics analyses revealed that differentially phosphorylated proteins and metabolites were remarkably enriched in dopaminergic synapse, Parkinson’s disease, and amphetamine addiction pathways (FDR < 0.05), with a regulatory axis involving L-tyrosine, tyrosine hydroxylase (TH), and dopamine (DA) identified. OMPM-exposed rats exhibited depression- and anxiety-like behaviors, alongside striatal pathological and ultrastructural damage. Biochemical analyses showed elevated malondialdehyde and reactive oxygen species levels; reduced superoxide dismutase, glutathione, and glutathione peroxidase activities and total antioxidant capacity; increased glutathione disulfide and inducible nitric oxide synthase expression; and decreased DA and L-tyrosine levels. Additionally, proinflammatory mediators (IL-1β, IL-6, TNF-α, MCP-1, and PGD₂) were significantly upregulated in the striatum. WB analysis further confirmed significant reductions in the relative phosphorylation levels of key regulators in dopaminergic and calcium signaling pathways, including CALM3, CaMK2b, GSK-3β, PRKCG, and TH. Collectively, these findings reveal critical molecular and biochemical alterations in the rat striatum following OMPM exposure and provide a mechanistic basis for understanding depression-like behaviors associated with prolonged OMPM exposure in occupational workers. Full article

Background/Objectives: Hepatic encephalopathy (HE) is characterized by hyperammonemia, neuroinflammation, oxidative stress, and blood–brain barrier (BBB) dysfunction, with brain endothelial cells being highly vulnerable to ammonia-induced damage. Adiponectin is a cytoprotective adipokine that may enhance endothelial resilience; however, its specific role under hyperammonemic conditions remains unclear. This study aims to investigate the protective effects of adiponectin on brain endothelial function and BBB integrity. Methods: In vivo, male C57BL/6J mice underwent bile duct ligation (BDL) surgery and received daily intraperitoneal adiponectin injections (10 μg/kg/day) for 6 days, starting 5 days post-surgery. On day 11, brain tissues and serum were collected for molecular and cytokine analyses. In vitro, mouse brain endothelial cells (bEnd.3) were pretreated with adiponectin before exposure to ammonia. Assays for tight junction preservation, mitochondrial membrane potential, reactive oxygen species (ROS) generation, and total RNA sequencing were performed. Results: In BDL mice, adiponectin increased the expression of the tight junction protein claudin-5 and synaptic marker PSD95 across the cortex, hippocampus, and striatum, while reducing pro-oxidant (Cyp2e1, Cyp4a1) and apoptotic (Caspase-9) markers. In vitro, adiponectin pretreatment maintained tight junction proteins, suppressed inflammatory markers, restored mitochondrial membrane potential, and decreased ROS generation in ammonia-exposed bEnd.3 cells. Transcriptomic profiling revealed that adiponectin modulates stress-related gene expression under hyperammonemic conditions. Conclusions: Adiponectin enhances cellular stress resistance and maintains BBB structural integrity under ammonia-induced toxicity. These findings suggest that adiponectin serves as a promising therapeutic target for mitigating neurovascular unit dysfunction in hepatic encephalopathy. Full article

Huntington’s disease (HD) is characterized by progressive striatal atrophy and complex proteomic changes in the central nervous system. Using the ultrasensitive Next-Gen Ultra-Sensitive Immunoassay (NULISA) proteomic platform, we analyzed cerebrospinal fluid (CSF) from 88 persons with HD to dissect the biological correlates of gray matter loss. Our findings reveal a distinct “Two-Track” model of pathology. The first track, marked by the axonal damage protein neurofilament light chain (NEFL), showed a strong inverse correlation with putamen volume (Pearson r = −0.53, p < 0.001), reinforcing its utility as a proxy for structural neurodegeneration. The second track was defined by a positive association between the immune regulator TNFRSF8 (CD30) and putamen volume (Pearson r = 0.36, p < 0.001), reflecting a decline in active immune-regulatory signaling as striatal atrophy advances. Given its established role in immune modulation, TNFRSF8 was pre-specified for follow-up to further interrogate this neuro-immune axis. Crucially, TNFRSF8 maintained an independent association with striatal volume (Beta = 0.24, p = 0.008) even after controlling for NEFL, genetic burden (CAG-Age Product score), and sex. Supplementary analyses confirmed that this structural–immune axis is localized specifically to the striatum—showing no association with generic structural control regions—and is driven by CAG repeat length rather than chronological aging. Furthermore, bidirectional mediation analysis supported an atrophy-driven model, where striatal volume statistically mediates the relationship between genetic burden and downstream immune dysregulation (p = 0.010). These results demonstrate that maladaptive immune signaling is a distinct pathological correlate in HD, separable from general cytoskeletal damage. This dual-axis framework warrants evaluation in larger longitudinal and interventional studies to guide future biomarker-driven patient stratification and target engagement. Full article

Background: We previously established that striatal, but not cortical, dopaminergic activation stimulates movement, indicating that the crucial and original site of dopaminergic stimulation of motor function is the striatum, not the motor cortex. In the present study, we have further investigated the potential effects of the cortical and striatal dopaminergic activity on cortical pyramidal neuron physiology. Methods and Results: First, under a constant fluorescence imaging condition, we established that DA innervation and D1R and D2R expression were very low in the cerebral cortex but very high in the striatum. Second, we performed cellular neurophysiological experiments on layer 2/3 pyramidal neurons in the primary motor cortex (M1) in tyrosine hydroxylase gene knockout (TH-KO) DA-depleted mice that have hyperfunctional DA receptors. Using brain slice–whole-cell patch-clamping techniques, we found that M1 layer 2/3 pyramidal neurons had lower input resistance, stronger inward rectification, more negative RMP, and fired fewer spikes in DA-depleted TH-KO mice than in DA-intact WT mice; M1 layer 2/3 pyramidal neurons also had a diminished synaptic release function with reduced frequencies for spontaneous and miniature excitatory synaptic currents in TH-KO mice compared to WT mice. Third, we also found that when TH-KO mice were treated with L-dopa before brain slice preparation, these neurophysiological deficits of M1 layer 2/3 pyramidal neurons were reversed, but 30 min incubation of cortical brain slices with 10–20 μM DA produced no detectable effect in M1 layer 2/3 pyramidal neurons in TH-KO mice and WT mice. Fourth, Golgi staining showed that cortical pyramidal neuron morphology was indistinguishable between WT mice and TH-KO mice. Conclusions: Our results indicate that DA loss in the striatum, not in the cortex, indirectly reduces cortical pyramidal neuron membrane excitability and weakens synaptic function. Our data also indicate that (1) the normal direct effects of the cortical DA system on cortical pyramidal neurons are weak, (2) the striatal DA system is the dominant DA system in the brain, and (3) striatal DA activity can indirectly increase cortical neuron activity (spike firing and synaptic activity) and thus critically contribute to brain function. Additionally, our data suggest that in DA depletion rodent PD models, DA loss-induced effects on cortical pyramidal neurons and other neurons are functional rather than structural, such that DA replenishment restores motor function almost instantaneously. These findings provide important insights into how the brain’s dopaminergic system controls our motor and cognitive functions and indicate that the striatum is the main therapeutic target of dopaminergic drugs. Full article

Background: Decreased dopaminergic cells and tyrosine hydroxylase (TH) in the substantia nigra (SN) lead to Parkinson’s disease (PD); but its cause remains unknown. PD is characterized by α-synuclein (α-syn) accumulation in Lewy bodies; most of which is phosphorylated at Ser129 (pSer129 α-syn). Serping1 is an important gene for controlling blood vessel maintenance; including the process of inflammation. Methods: Increased expression of Serping1 affects dopaminergic cell death in the SN of a chronic PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); and Serping1 siRNA treatment has a therapeutic effect in this model. Results: We demonstrated that this treatment shows a normal status in the motor ability test and TH level in the SN and striatum. Serping1 siRNA was found to react to decreased Serping1 levels in the SN. In the pSer129-α-syn level of the SN region; Serping1 siRNA had a greater positive effect on PD than N-acetylcysteine by inhibiting pSer129-α-syn formation. Cyclooxygenase-2 and inducible nitric oxide synthase levels were decreased by Serping1 siRNA treatment; thereby indicating its effect on inflammation. Conclusions: Our findings suggest that Serping1 siRNA may represent a potential therapeutic approach for PD; warranting further investigation. Full article