Journal of Neuroscience Research最新文献

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.

This study explores whether ultrasound can induce short-term synaptic plasticity (STP)-like effects at the systems level by modulating cortical excitability and sensory responsiveness. We designed a temporally shifted sensory paradigm to test how ultrasound frequency (1, 2, and 4 MHz), inter-stimulus interval (10, 25, and 100 ms), and stimulation order (ultrasound–whisker vs. whisker–ultrasound) affect cortical responses in the rat barrel cortex. Thirty Sprague–Dawley rats underwent an identical experimental protocol. Electrocorticography (ECoG) signals were recorded from the C2 barrel column, and neural responses were assessed by peak amplitude, latency, and power spectral density. Whisker stimulation alone evoked strong cortical responses, significantly greater than ultrasound stimulation. Notably, when ultrasound preceded whisker stimulation by 25 ms, subsequent whisker responses were significantly enhanced, suggesting the existence of a cortical “excitability window” for neuromodulation. This facilitation effect was absent with time intervals of 10 and 100 ms. Mechanistically, ultrasound may modulate membrane tension and activate mechanosensitive ion channels to transiently lower the activation threshold of cortical neurons. These findings reveal that ultrasound can temporally enhance cortical excitability and sensory responsiveness in a frequency- and timing-dependent manner. Our results provide systems-level evidence of STP-like neuromodulation and provide the potential of ultrasound as a noninvasive method for dynamic control of sensory processing.

Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (CT) has been explored as a potential novel method to improve response inhibition, but its neural mechanisms remain unclear. This study investigated the effects of rTMS + CT on oscillatory activity across different frequency bands and theta-gamma phase-amplitude coupling during the Stroop task. Sixty healthy participants were randomly assigned to receive four sessions of either active or sham prolonged intermittent theta burst stimulation (iTBS) + CT. Each session involved iTBS over both the right inferior frontal cortex and the pre-supplementary motor area, with participants completing the Stop Signal training task first, followed by the Go/No-Go training task. The Stroop task was administered before and immediately after the intervention while electroencephalography was recorded. There was a significant group effect on the change in beta desynchronization during incongruent trials (t = −2.03, p = 0.048), with a significant decrease observed in the active group (p = 0.03) and no change in the sham group (p = 0.83). Additionally, changes in gamma synchronization differed between groups for congruent trials (t = 2.28, p = 0.03), though neither group showed a significant pre-post change (p > 0.05). Our study suggests that four sessions of iTBS + CT may modulate beta and gamma oscillations during the Stroop task, potentially enhancing motor inhibition and processing speed in response inhibition. These results provide neurophysiological insights into the neural mechanisms through which rTMS + CT may enhance response inhibition.