Journal of Neuroscience Research最新文献

Ischemic stroke remains a major global health burden, consistently ranking among the leading causes of mortality and long-term disability. Although rodent models are widely utilized for ischemic stroke research, their limited translational success has driven the pursuit of alternative experimental systems. This review underscores the growing significance of non-mammalian models, particularly zebrafish and Drosophila melanogaster, in advancing ischemic stroke research. Zebrafish offer notable advantages, including high genetic homology with humans, optical transparency, a pronounced capacity for neural regeneration, in vivo live real-time imaging, and behavioral analyses. Photothrombotic and systemic hypoxia paradigms in zebrafish enable detailed investigation of neurovascular injury and recovery processes. Drosophila, characterized by a rapid life cycle and sophisticated genetic toolkit, serves as a valuable model for elucidating hypoxia-induced neuronal damage and stroke-related comorbidities such as sleep disturbances. These models are cost-efficient, ethically advantageous, and well-suited for high-throughput applications. Despite inherent anatomical and physiological disparities, non-mammalian systems provide critical complementary insights into stroke pathogenesis and therapeutic innovation, reinforcing their integration into multi-model research frameworks.

Protein function is influenced by multiple factors including cell type and subcellular localization. The cystic fibrosis transmembrane conductance regulator (CFTR) is well investigated in epithelial tissues, where life threatening symptoms stem from its dysfunction. A postsynaptic neuronal role was previously established by the Gleason lab where CFTR regulation of cytosolic Cl^– in retinal amacrine cells was shown. Other work from our lab showed that disruption of the synaptic vesicle cycle reduced action of CFTR, suggesting CFTR associates with synaptic vesicles. Here, we evaluate the hypothesis that CFTR localizes to the synapse with possible presynaptic function. To address this, the cellular and subcellular CFTR localization in mature chicken retina was examined using fluorescence light microscopy and immunogold-labeled transmission electron microscopy. CFTR labeling was detected throughout the retina, including photoreceptor outer segments and in the mitochondria rich region of the photoreceptor inner segment termed the ellipsoid. Synaptic labeling was found in both synaptic plexiform layers, pre-and post-synaptically. A subset of amacrine cells were strongly labeled and labeling was also found in Müller cells and in axons of the nerve fiber layer. Addressing whether the activity of CFTR plays a role in presynaptic function, amacrine cells were recorded using the whole cell voltage clamp method. Spontaneous postsynaptic quantal currents were recorded and found to increase in frequency upon pharmacological inhibition of CFTR suggesting that under normal circumstances, CFTR serves to limit the rate of spontaneous synaptic vesicle fusion. This work provides evidence CFTR might have multiple functions in the retina including synaptic transmission regulation.

Tryptophan hydroxylase (TPH) is a key enzyme in the biosynthesis of serotonin, a neurotransmitter involved in the regulation of mood, emotional state, sleep, appetite, digestion, and cognitive functions. It plays a key role in the creation of a sense of well-being, reduction of anxiety and control of the response to stress. Imbalances in its levels are associated with many disorders, notably depression, anxiety disorders and migraines. This review examines the structural and functional aspects of the regulation of TPH activity with an emphasis on its isoforms, TPH1 and TPH2, which are responsible for serotonin synthesis in peripheral tissues and in neurons, respectively. Approaches to TPH regulation at the gene, protein, and enzymatic activity levels are discussed. The role of TPH in the pathogenesis of affective disorders such as depression, anxiety, attention deficit hyperactivity disorder and posttraumatic stress disorder is also discussed. Approaches to modulating TPH activity are proposed, including, for example, using calpain inhibitors.

Psilocybin-containing mushrooms, commonly known as magic mushrooms, strongly affect mood, cognition, and behavior. Psilocybe azurescens is a species of psilocybin mushrooms that contains the main active compounds psilocybin and psilocin. Psilocybin mushrooms have been used since ancient times to improve the quality of life. However, their adverse effects have been less studied. This study aimed to investigate, for the first time, the effect of oral consumption of P. azurescens on social behavior, anxiety- and depressive-like behaviors in rats. The underlying mechanisms of these behaviors were also studied. Male Wistar rats received three doses of P. azurescens (10, 100, and 250 mg/kg) by gavage every other day for 14 days. Social interaction, anxiety- and depressive-like behaviors were assessed using the three-chamber, elevated plus maze, and forced swimming tests, respectively. Protein levels of neurotrophic (BDNF and GDNF), neuroinflammatory (IL-6 and TNFα), and oxidative stress (ROS and SOD) factors were measured in the hippocampus, prefrontal cortex (PFC), and amygdala by ELISA technique. The results showed that P. azurescens significantly increased anxiety- and depressive-like behaviors and disrupted social interaction behavior in rats. These effects were accompanied by increased neuroinflammation and oxidative stress and decreased neurotrophic factors in the hippocampus, PFC, and amygdala. This study suggests that the high doses of P. azurescens can cause mood disorders by increasing inflammatory responses and oxidative stress and decreasing the expression of neurotrophic factors.

Ketamine has emerged as a highly effective intervention for treatment-resistant depression (TRD). Though it acts as a non-competitive antagonist of excitatory N-methyl-D-aspartate receptors (NMDAR), widely expressed in the brain, including on inhibitory γ-aminobutyric acid (GABA)-ergic cells, the mechanisms of its antidepressant action are less clear. To investigate the links between glutamate and GABA neurotransmission and the clinical benefits of ketamine, we used proton magnetic resonance spectroscopy (¹H-MRS) to measure both glutamate and GABA levels in the dorsal anterior cingulate cortex (dACC) in 60 participants with TRD before (~within 1 week), and 24 h after a 40-min intravenous infusion with 0.5 mg/kg of racemic (R,S)-ketamine. The 17-item Hamilton Depression Rating Scale (HDRS₁₇) was used as the primary measure of clinical improvement, and a 50% or greater improvement in HDRS₁₇ ratings was used to define treatment responders. Ketamine increased mean dACC glutamate levels in responders only 24 h after treatment (n = 25, p = 0.01). Further, lower glutamate levels at baseline predicted greater improvements in HDRS₁₇ scores at 24 h post treatment (p < 0.0001). However, GABA levels remained stable after treatment irrespective of response status (p = 0.90). Metabolites associated with neuronal integrity (tNAA), metabolic function (tCr), and membrane turnover (tCho), which may serve as complementary biological evidence of ketamine-induced plasticity, also increased with treatment (all p < 0.01). Results provide evidence of sustained enhancements of neurotransmission or other glutamate-related metabolic effects following subanesthetic ketamine in responders and a potential role of ACC glutamate levels as a biomarker of responsivity to ketamine.

This investigation centered on Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by memory impairment and cognitive decline. Functional connectome gradient analysis was utilized to investigate alterations in the hierarchical architecture of brain networks in AD. The study cohort consisted of 222 subjects, encompassing 111 AD patients and 111 normal controls (NC). Connectome gradients were computed via a dimensionality reduction technique based on diffusion map embedding and analyzed at both the region of interest (ROI) and network levels. Additional connectome gradient metrics, including network median distance and gradient eccentricity, were calculated, and the relationship between connectome gradients and rich-club organization was assessed. These connectome gradient values were subsequently correlated with clinical cognitive scores. The results demonstrated a significant reduction in the principal gradient range in AD patients. At the network level, gradient values exhibited an increase in the somatomotor (SMN) and visual networks (VIS), while decreasing in the default mode (DMN) and frontoparietal networks (FPN) relative to controls. Analyzes of network mean distance and gradient eccentricity further revealed compression of the brain cortical hierarchy in AD patients. Furthermore, rich-club analyzes indicated a reduction in the gradient value difference between hub and peripheral nodes in AD patients. Finally, clinical correlation analysis revealed a positive correlation between the degree of cognitive impairment and the degree of compression of the brain cortical hierarchy. These findings provide a novel perspective on the study of brain network organization in AD patients, contributing to a more comprehensive understanding of the neural mechanisms underlying Alzheimer's disease.