Search Results (377)

Despite the abundant expression of the microRNA-degrading Translin (TN)/Trax (TX) complex in midbrain dopaminergic (DA) neurons and its implication in neuropsychiatric disorders, its cell-autonomous roles in metabolic and behavioral responses remain unclear. To address this, we generated DA neuron-specific conditional knockout (cKO) mice for Tsn (TN) or Tsnax (TX) using DAT-Cre. Immunostaining confirmed efficient TX loss in Tsnax cKO DA neurons without affecting TN, while Tsn deletion abolished TX expression, revealing asymmetric protein dependency. Body composition analysis showed no alterations in adiposity in either cKO model. Locomotor responses to acute or repeated administration of cocaine (20 mg/kg) or amphetamine (2.5 mg/kg) were unchanged in Tsn or Tsnax cKO mice. Furthermore, amphetamine-induced conditioned place preference (1 mg/kg) was unaffected. These results demonstrate that the TN/TX complex within DA neurons is dispensable for regulating adiposity, psychostimulant-induced locomotion (both acute and sensitized), or amphetamine reward-related behavior, suggesting its critical functions may lie outside these specific domains. Full article

The neurobiology of chronic pain is complex and multifaceted, intertwining with the mesocorticolimbic system to regulate the behavioral and perceptional response to adverse stimuli. Specifically, the ventral tegmental area (VTA), the dopaminergic hub of the reward pathways located deep within the midbrain, is crucial for regulating the release of dopamine (DA) throughout the central nervous system (CNS). To better understand the nuances among chronic pain, VTA response, and therapeutics, implementing progressive approaches for mapping and visualizing the deep brain in real time during nociceptive stimulation is crucial. In this study, we utilize a fluorescence imaging platform with a genetically encoded calcium indicator (GCaMP6s) to directly visualize activity in the VTA during acute nociceptive stimulation in both healthy adult mice and adult mice with partial nerve ligation (PNL)-induced neuropathic pain. We also investigate the visualization of the analgesic properties of morphine. Deep brain imaging using our self-fabricated µ-complementary metal–oxide–semiconductor (CMOS) imaging device allows the tracking of the VTA’s response to adverse stimuli. Our findings show that nociceptive stimulation is associated with a reduction in VTA fluorescence activity, supporting the potential of this platform for visualizing pain-related responses in the central nervous system. Additionally, treatment with morphine significantly reduces the neuronal response caused by mechanical stimuli and is observable using the CMOS imaging platform, demonstrating a novel way to potentially assess and treat neuropathic pain. Full article

Clinicopathological studies and the effectiveness of dopaminergic replacement therapy establish that dopamine loss is the key pathology causing motor symptoms in Parkinson’s disease. The dopamine neurons that are impaired in Parkinson’s disease reside in the substantia nigra and ventral tegmental area in the midbrain. These neurons project into the striatum, where dopamine axons bifurcate repeatedly and form dense axon networks (the striatum is separated into the caudate nucleus and putamen by the internal capsule). Midbrain dopamine neurons also innervate many other areas of the brain, including the cerebral cortex. Therefore, there are preclinical and clinical studies investigating extrastriatal dopamine mechanisms in motor control and Parkinson’s disease pathophysiology and treatment. While extrastriatal dopamine can contribute, this contribution needs to be compared with the contribution of the striatal dopamine system. An isolated view of the extrastriatal dopamine system is like examining only the ear of an elephant and may lead to distorted assessments for preclinical and clinical research and diagnostic work. Thus, photographs of the whole brain dopamine system are important. For these reasons, we photographed the dopamine systems in whole mouse brain sagittal sections, showing clearly that, under identical imaging conditions, dopamine innervation is highly concentrated and intense in the striatum but sparse and weak in the cerebral cortex. Full article

Social media addiction has become a global public health challenge, and understanding its mechanism’s complexity requires the integration of the transitional characteristics of addiction development stages and breaking through the traditional single-reinforcement-path explanatory framework. This study is based on the dual pathway of positive and negative emotional reinforcement, integrating multidisciplinary evidence from neuroscience, psychology, and computational behavioral science to propose an independent and dynamic interaction mechanism of positive reinforcement (driven by social rewards) and negative reinforcement (driven by emotional avoidance) in social media addiction. Through a review, it was found that early addiction is mediated by the midbrain limbic dopamine system due to immediate pleasurable experiences (such as liking), while late addiction is maintained by negative emotional cycles due to the dysfunction of the prefrontal limbic circuit. The transition from early addiction to late addiction is characterized by independence and interactivity. Based on this, a phased intervention strategy is proposed, which uses reward competition strategies (such as cognitive behavioral therapy and alternative rewards) to weaken dopamine sensitization in the positive reinforcement stage, enhances self-control by blocking emotional escape (such as through mindfulness training and algorithm innovation) in the negative reinforcement stage, and uses cross-pathway joint intervention in the interaction stage. This study provides a theoretical integration framework for interdisciplinary research on social media addiction from a dynamic perspective for the first time. It is recommended that emotional reinforcement variables are included in addiction diagnosis, opening up new paths for precise intervention in different stages of social media addiction development. Full article

Background: Behavioral, social, and physical characteristics are posited to distinguish the sexes, yet research on transcription-level sexual differences in the brain is limited. Here, we investigated sexually divergent brain transcriptomics in pre-pubertal cynomolgus macaques, a commonly used surrogate species to humans. Methods: A transcriptomic profile using RNA sequencing was generated for the temporal lobe, ventral midbrain, and cerebellum of three female and three male cynomolgus macaques previously treated with an adeno-associated virus vector mix. Statistical analyses to determine differentially expressed protein-coding genes in all three lobes were conducted using DeSeq2 with a false-discovery-rate-corrected p-value of 0.05. Results: We identified target genes in the temporal lobe, ventral midbrain, and cerebellum with functions in translation, immunity, behavior, and neurological disorders that exhibited statistically significant sexually divergent expression. Conclusions: We provide potential mechanistic insights into the epidemiological differences observed between the sexes with regard to mental health and infectious diseases, such as COVID-19. Our results provide pre-pubertal information on sexual differences in non-human primate brain transcriptomics and may provide insight into health disparities between the biological sexes in humans. Full article

Brain stem cavernomas are exceedingly rare in pediatric populations, with limited literature addressing their natural history, treatment guidelines, and counseling. We report the case of a 5-year-old girl presenting with acute neurological symptoms, including diplopia, gait ataxia, headache, and altered consciousness. Initial imaging revealed obstructive hydrocephalus caused by a hemorrhagic lesion near the pineal region. After emergency external ventricular drainage (EVD), most symptoms resolved except for diplopia. A subsequent MRI suggested a space-occupying hemorrhagic cyst in the tectal lamina, leading to endoscopic third ventriculostomy (ETV). During ETV, a large hemorrhagic mass at the aqueduct entrance was identified but not removed due to its fragility. Following ETV, the patient improved rapidly and was discharged. However, she was readmitted with recurrent symptoms and altered consciousness. An emergency MRI indicated a progressive hemorrhagic mass lesion compressing the midbrain, necessitating surgical intervention. The patient underwent suboccipital craniotomy using a telovelar approach. The intraoperative findings included cavernoma-like tissue within the aqueduct, which was successfully resected. Histopathology confirmed hemorrhagic and angiomatous tissue, excluding a primary brain tumor. Postoperatively, the patient showed significant, progressive neurological improvement, with mild internuclear strabism, trunk ataxia, and fatigue at the last follow-up. Six months later, a follow-up MRI and cerebral angiography showed no cavernoma remnants but identified a midbrain deep venous anomaly. This case underscores the feasibility of the microsurgical resection of midbrain cavernomas in symptomatic pediatric patients, highlighting the importance of the thorough assessment of atypical hemorrhagic midbrain lesions to exclude rare vascular malformations from differential diagnoses. Full article

Introduction: Neurodegenerative diseases like progressive supranuclear palsy (PSP) present challenges concerning their diagnosis. Neuroimaging using magnetic resonance (MRI) may add diagnostic value. However, modern techniques such as volumetric assessment using Voxel-Based Morphometry (VBM), although proven to be more accurate and superior compared to MRI, have not gained popularity among scientists in the investigation of neurological disorders due to their higher cost and time-consuming applications. Conventional brain MRI methods may present a quick, practical, and easy-to-use imaging rating tool for the differential diagnosis of PSP. The purpose of this study is to evaluate a string of existing visual MRI rating scales and signs regarding their impact for the diagnosis of PSP. Materials and Methods: The population study consisted of 30 patients suffering from PSP and 72 healthy controls. Each study participant underwent a brain MRI, which was subsequently examined by two independent researchers in a double-blinded fashion. Fifteen visual rating scales and signs were evaluated, including pontine atrophy, cerebellar atrophy, midbrain atrophy, aqueduct of Sylvius enlargement, cerebellar peduncle hyperintensities, enlargement of the fourth ventricle (100% sensitivity and 71% specificity) and left temporal lobe atrophy (97% sensitivity and 78% specificity). Conclusions: Enlargement of the Sylvius aqueduct, enlargement of the fourth ventricle and atrophy of both temporal lobes together with the presence of morning glory and hummingbird signs can be easily and quickly distinguished and identified by an experienced radiologist without involving any complex analysis, making them useful tools for PSP diagnosis. MRI visual scale measurements could be added to the diagnostic criteria of PSP and may serve as an alternative to highly technical and more sophisticated quantification methods. Full article

Background: This paper investigates the effect of intranasal insulin administration on brain glutathione (GSH) levels and elucidates the potential mechanism by which insulin enhances antioxidant defenses in the brain. Methods: C57BL/6J mice were intranasally administered insulin (2 IU/day) or saline for 7 days. GSH levels were measured in the brain and liver. Blood glucose concentrations and daily food intake were also monitored. Protein levels of excitatory amino acid carrier-1 (EAAC1), its interaction with glutamate transport-associated protein 3-18(GTRAP3-18), and activated AMP-activated protein kinase (AMPK) were assessed. Results: Insulin-treated mice exhibited significantly higher GSH levels in the hippocampus and midbrain compared to saline-treated controls, while no significant differences were found in liver GSH levels, blood glucose concentrations, or food intake. EAAC1 expression increased in both the cytosolic and plasma membrane fractions of insulin-treated mouse brains. Furthermore, the interaction between EAAC1 and its negative regulator, GTRAP3-18, along with activated AMPK levels, was reduced in insulin-treated mice. Conclusions: Intranasal insulin administration enhances brain GSH levels through a mechanism involving EAAC1 upregulation and reduced AMPK activation. These findings suggest that intranasal insulin could be a promising strategy for enhancing antioxidant defenses against neurodegeneration in the brain. Full article

Parkinson’s disease (PD) is a neurodegenerative disorder affecting nearly 10 million people worldwide, and for which no cure is currently known. Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene, age, as well as environmental factors such as neurotoxin exposure and stress, are known to increase the risk of developing the disease in humans. To investigate the role of a specific Asian variant of the LRRK2 gene to induce susceptibility to stress and trigger PD phenotypes with time, knock-in (KI) mice bearing the human LRRK2 R1628P risk variant have been generated and studied from 2 to 16 months of age in the presence (or absence) of stress insults, including neurotoxin injections and chronic mild stress applied at 3 months of age. Pathophysiological and behavioural phenotypes have been measured at different ages and primary neurons and fibroblast cells were cultured from the KI mouse line and treated with H₂O₂ to study susceptibility towards oxidative stress in vitro. KI mice displayed specific PD features and these phenotypes were aggravated by environmental stresses. In particular, KI mice developed locomotion impairment and increased constipation. In addition, dopamine-related proteins were dysregulated in KI mice brains: Dopamine transporter (DAT) was decreased in the midbrain and striatum and dopamine levels were increased. Primary fibroblast cells and cortical neurons from KI mice also displayed increased susceptibility to oxidative stress. Therefore, the LRRK2 R1628P KI mice are an excellent model to study the progressive development of PD. Full article

Background: The blood–brain barrier (BBB) plays an important role in regulating homeostasis of the central nervous system (CNS), and it is an obstacle for molecules with a molecular weight higher than 500 Da seeking to reach it, making many drugs ineffective simply because they cannot be delivered to where they are needed. As a result, crossing the BBB remains the rate-limiting factor in brain drug delivery during the treatment of brain diseases, specifically tumors such as diffuse intrinsic pontine glioma (DIPG), a highly aggressive pediatric tumor with onset in the pons Varolii, the middle portion of the three contiguous parts of the brainstem, located above the medulla and below the midbrain. Methods: Currently, radiotherapy (RT) relieves DIPG symptoms but chemotherapy drugs do not lead to significant results as they do not easily cross the BBB. Focused ultrasound (FUS) and microbubbles (MBs) can temporarily open the BBB, facilitating radiotherapy and the entry of drugs into the CNS. A patient-derived xenograft DIPG model exposed to high-intensity focalized ultrasound (HIFU) or low-intensity focalized ultrasound (LIFU) combined with MBs was treated with doxorubicin, panobinostat, olaparib, ONC201 (Dordaviprone^®) and anti-PD1. Panobinostat has also been used in children with diffuse midline glioma, a broad class of brain tumors to which DIPG belongs. Results: Preliminary studies were performed using FUS to temporarily open the BBB and allow a milder use of radiotherapy and facilitate the passage of drugs through the BBB. The data collected show that after opening the BBB with FUS and MBs, drug delivery to the CNS significantly improved. Conclusions: FUS associated with MBs appears safe and feasible and represents a new strategy to increase the uptake of drugs in the CNS and therefore enhance their effectiveness. This review reports pre-clinical and clinical studies performed to demonstrate the usefulness of FUS in patients with DIPG treated with some chemotherapy. The papers reviewed were published in PubMed until the end of 2024 and were found using a combination of the following keywords: diffuse intrinsic pontine glioma (DIPG), DIPG H3K27-altered, blood–brain barrier and BBB, focused ultrasound (FUS) and radiotherapy (RT). Full article

Background: A rat robot can be constructed by electrically stimulating specific brain regions to control rat locomotion and behavior. The rat robot makes full use of the rat’s motor function and energy supply and has significant advantages in motor flexibility, environmental adaptability, and covertness. It can be widely used in disaster search and rescue, terrain survey, anti-terrorism, and explosion-proof tasks. However, the motor control of existing rat robots mainly relies on the virtual whisker touch produced by the electrical stimulation of the barrel area of the somatosensory cortex and the virtual reward generated by the electrical stimulation of the medial forebrain bundle. The methods requires substantial experimental training to encourage the animals to match the virtual sensation with the motor behavior. However, the conditioned reflexes acquired by the animals will gradually disappear after a period of time at the end of the experiments, which will lead to a decrease in the stability of the motor control system. Methods: In this study, we developed a new method to gain control of inclined movement in rats by the electrical stimulation of the ventral tegmental area (VTA) of the midbrain and motor control of steering in rats by the electrical stimulation of nigrostriatal (NS) pathway. Results: The results showed that the electrical stimulation of the rat VTA could induce stable inclined movement in rats and that the neuromodulatory effect significantly correlated with the electrical stimulation parameters. In addition, the electrical stimulation of the NS pathway was able to directly and stably induce the steering movements of the head and trunk to the contralateral side of the stimulated side of the rat. Conclusions: These findings are of great importance for the motor control of rat robots, especially in the field environment with many slopes. In addition, the rat robot constructed based on this method does not need pre-training while ensuring reliability, which greatly improves the preparation efficiency and has certain practical application value. Full article

Background and Objectives: Zinc finger proteins are important transcription factors that regulate gene expression and play a critical role in neurodevelopment including autism spectrum disorders (ASDs). They are involved in a variety of cellular processes, including cell proliferation, differentiation, and apoptosis. Materials and Methods: Whole-exome sequencing (WES) analysis on a patient diagnosed with ASD. Results: Sequencing identified a homozygous insertion causing a stop codon, resulting in the removal of several functional domains including the zinc finger C2HC/C3H type of the ZC2HC1C protein. To date, no MIM entry has been assigned to the detected gene. In silico predictions described the variant as likely pathogenic, indicating an autosomal recessive inheritance pattern. In this study, we hypothesize that this homozygous mutation disrupts protein function and may represent a susceptibility gene for autism. The parents and the patient’s sister were healthy and carry the variant in the heterozygous condition. This gene is expressed in brain tissues showing high expression in both the choroid plexus (ChP) and midbrain, whose dysfunctions, as reported, may lead to ASD. Moreover, predictive pathway analyses indicated the probable involvement of this gene in primary cilia development. This process has been frequently linked to neurodevelopmental impairments, such as autism, as documented in previous studies. Conclusions: Further analyses are needed via in vitro functional assays or by ZC2HC1C gene knockout to validate its functional role. Full article

Background/Objectives: Parkinson’s disease (PD) is a rapidly growing neurological disorder in the developed world, affecting millions over the age of 60. The decline in motor functions occurs due to a progressive loss of midbrain dopaminergic neurons, resulting in lowered dopamine levels and impaired muscle function. Studies show defective mitochondrial autophagy (or “mitophagy”) links to PD. Rho-associated coiled-coil containing protein kinases (ROCK) 1 and ROCK2 are serine/threonine kinases, and their inhibition can enhance neuroprotection in PD by promoting mitophagy. Methods: We examine the effects of ROCK inhibitor SR3677, delivered via macrophage-derived small extracellular vesicles (sEVs) to Parkin Q311X(A) PD mouse models. sEVs with SR3677, administered intranasally, increased mitophagy gene expression, reduced inflammatory factors, and elevated dopamine levels in brain tissues. Results: ROCK2 expression decreased, showing the drug’s inhibitory effect. sEV-SR3677 treatment was more effective than treatment with the drug alone, although sham EVs showed lower effects. This suggests that EV-SR3677 not only activates mitochondrial processes but also promotes the degradation of damaged mitochondria through autophagy. Mitochondrial functional assays and oxygen consumption in ex vivo glial cultures revealed that sEV-SR3677 significantly improved mitochondrial respiration compared to that in untreated or SR3677-only treated cells. Conclusion: We demonstrated the efficacy of ROCK2 inhibition on mitochondrial function via sEV-SR3677 in the PD mouse model, necessitating further studies to explore design challenges and mechanisms of sEV-SR3677 as mitochondria-targeted therapy for PD Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic (DA) neurons in the midbrain. While dopamine precursor levodopa and D2 receptor agonists are commonly used to alleviate PD symptoms, these treatments do not halt or reverse disease progression. Thus, developing effective neuroprotective strategies remains a critical goal. In this study, we explored neuroprotective mechanisms in a Drosophila primary neuronal culture model of PD, created by administering the environmental toxin rotenone. Using the chemogenetic DREADD (designer receptors exclusively activated by designer drugs) system, we selectively activated cAMP signaling in DA neurons within the rotenone-induced model. Our results demonstrate that increasing cAMP signaling via Gs-coupled DREADD (rM3Ds) is protective against DA neurodegeneration. Furthermore, overexpression of the catalytic PKA-C1 subunit fully rescued DA neurons from rotenone-induced degeneration, with this effect restricted to DA neurons where PKA-C1 was specifically overexpressed. These findings reveal that cAMP-PKA signaling activation is neuroprotective in DA neurons against rotenone-induced degeneration, offering promising insights for developing targeted therapeutic strategies to slow or prevent PD pathology progression. Full article

Background/Objectives: Spinal cord injury (SCI) presents significant challenges in restoring motor function, with limited therapeutic options available. Recent advancements in neuromodulation technologies, such as brain-spine interface (BSI), epidural electrical stimulation (EES), and deep brain stimulation (DBS), offer promising solutions. This review article explores the integration of these approaches, focusing on their potential to restore function in SCI patients. Findings: DBS has shown efficacy in SCI treatment with several stimulation sites identified, including the nucleus raphe magnus (NRM) and periaqueductal gray (PAG). However, transitioning from animal to human studies highlights challenges, including the technical risks of targeting the NRM in humans instead of rodent models. Additionally, several other regions have shown potential for motor rehabilitation, including the midbrain locomotor region (MLR) pathways, cuneiform nucleus (CnF), pedunculopontine nucleus (PPN), and lateral hypothalamic. DBS with EES further supports motor recovery in SCI; however, this approach requires high-DBS amplitude, serotonergic pharmacotherapy, and cortical activity decoding to attenuate stress-associated locomotion. BSI combined with EES has recently emerged as a promising novel therapy. Although human studies are limited, animal models have provided evidence supporting its potential. Despite these advancements, the effectiveness of DBS and combined systems remains limited in cases of complete central denervation. Conclusions: The integration and combination of DBS, BSI, and EES represent a transformational approach to treating and restoring function in patients with SCI. While further research is needed to optimize these strategies, these advancements hold immense potential for improving the quality of life in SCI patients and advancing the field of neuromodulation. Full article