Pharmacological profile of agmatine: An in-depth overview.

Agmatine, a naturally occurring polyamine derived from arginine via arginine decarboxylase, has been shown to play multifaceted roles in the mammalian body, impacting a wide range of physiological and pathological processes. This comprehensive review delineates the significant insights into agmatine's pharmacological profile, emphasizing its structure and metabolism, neurotransmission and regulation, and pharmacokinetics and function. Agmatine's biosynthesis is highly conserved across species, highlighting its fundamental role in cellular functions. In the brain, comparable to established neurotransmitters, agmatine acts as a neuromodulator, influencing the regulation, metabolism, and reabsorption of neurotransmitters that are key to mood disorders, learning, cognition, and the management of anxiety and depression. Beyond its neuromodulatory functions, agmatine exhibits protective effects across various cellular and systemic contexts, including neuroprotection, nephroprotection, cardioprotection, and cytoprotection, suggesting a broad therapeutic potential. The review explores agmatine's interaction with multiple receptor systems, including NMDA, α2-adrenoceptors, and imidazoline receptors, elucidating its role in enhancing cell viability, neuronal protection, and synaptic plasticity. Such interactions underpin agmatine's potential in treating neurological diseases and mood disorders, among other conditions. Furthermore, agmatine's pharmacokinetics, including its absorption, distribution, metabolism, and excretion, are discussed, underlining the complexity of its action and the potential for therapeutic application. The safety and efficacy of agmatine supplementation, demonstrated through various animal and human studies, affirm its potential as a beneficial therapeutic agent. Conclusively, the diverse physiological and therapeutic effects of agmatine, spanning neurotransmission, protection against cellular damage, and modulation of various receptor pathways, position it as a promising candidate for further research and clinical application. This review underscores the imperative for continued exploration into agmatine's mechanisms of action and its potential in pharmacology and medicine, promising advances in the treatment of numerous conditions.

scRNA-seq data from the larval Drosophila ventral cord provides a resource for studying motor systems function and development.

The Drosophila larval ventral nerve cord (VNC) shares many similarities with the spinal cord of vertebrates and has emerged as a major model for understanding the development and function of motor systems. Here, we use high-quality scRNA-seq, validated by anatomical identification, to create a comprehensive census of larval VNC cell types. We show that the neural lineages that comprise the adult VNC are already defined, but quiescent, at the larval stage. Using fluorescence-activated cell sorting (FACS)-enriched populations, we separate all motor neuron bundles and link individual neuron clusters to morphologically characterized known subtypes. We discovered a glutamate receptor subunit required for basal neurotransmission and homeostasis at the larval neuromuscular junction. We describe larval glia and endorse the general view that glia perform consistent activities throughout development. This census represents an extensive resource and a powerful platform for future discoveries of cellular and molecular mechanisms in repair, regeneration, plasticity, homeostasis, and behavioral coordination.

Microbiota profiling reveals alteration of gut microbial neurotransmitters in a mouse model of autism-associated 16p11.2 microduplication.

The gut-brain axis is evident in modulating neuropsychiatric diseases including autism spectrum disorder (ASD). Chromosomal 16p11.2 microduplication 16p11.2dp/+ is among the most prevalent genetic copy number variations (CNV) linked with ASD. However, the implications of gut microbiota status underlying the development of ASD-like impairments induced by 16p11.2dp/+ remains unclear. To address this, we initially investigated a mouse model of 16p11.2dp/+, which exhibits social novelty deficit and repetitive behavior characteristic of ASD. Subsequently, we conducted a comparative analysis of the gut microbial community and metabolomic profiles between 16p11.2dp/+ and their wild-type counterparts using 16S rRNA sequencing and liquid chromatography-mass spectrometry (LC/MS). Our microbiota analysis revealed structural dysbiosis in 16p11.2dp/+ mice, characterized by reduced biodiversity and alterations in species abundance, as indicated by α/ß-diversity analysis. Specifically, we observed reduced relative abundances of Faecalibaculum and Romboutsia, accompanied by an increase in Turicibacter and Prevotellaceae UCG_001 in 16p11.2dp/+ group. Metabolomic analysis identified 19 significantly altered metabolites and unveiled enriched amino acid metabolism pathways. Notably, a disruption in the predominantly histamine-centered neurotransmitter network was observed in 16p11.2dp/+ mice. Collectively, our findings delineate potential alterations and correlations among the gut microbiota and microbial neurotransmitters in 16p11.2dp/+ mice, providing new insights into the pathogenesis of and treatment for 16p11.2 CNV-associated ASD.

Molecular mechanism underlying SNARE-mediated membrane fusion enlightened by all-atom molecular dynamics simulations.

The SNAP receptor (SNARE) proteins syntaxin-1, SNAP-25, and synaptobrevin mediate neurotransmitter release by forming tight SNARE complexes that fuse synaptic vesicles with the plasma membranes in microseconds. Membrane fusion is generally explained by the action of proteins on macroscopic membrane properties such as curvature, elastic modulus, and tension, and a widespread model envisions that the SNARE motifs, juxtamembrane linkers, and C-terminal transmembrane regions of synaptobrevin and syntaxin-1 form continuous helices that act mechanically as semirigid rods, squeezing the membranes together as they assemble ("zipper") from the N to the C termini. However, the mechanism underlying fast SNARE-induced membrane fusion remains unknown. We have used all-atom molecular dynamics simulations to investigate this mechanism. Our results need to be interpreted with caution because of the limited number and length of the simulations, but they suggest a model of membrane fusion that has a natural physicochemical basis, emphasizes local molecular events over general membrane properties, and explains extensive experimental data. In this model, the central event that initiates fast (microsecond scale) membrane fusion occurs when the SNARE helices zipper into the juxtamembrane linkers which, together with the adjacent transmembrane regions, promote encounters of acyl chains from both bilayers at the polar interface. The resulting hydrophobic nucleus rapidly expands into stalk-like structures that gradually progress to form a fusion pore, aided by the SNARE transmembrane regions and without clearly discernible intermediates. The propensity of polyunsaturated lipids to participate in encounters that initiate fusion suggests that these lipids may be important for the high speed of neurotransmitter release.

Cell-specific extracellular vesicle-encapsulated exogenous GABA controls seizures in epilepsy.

BACKGROUND: Epilepsy affects ∼60 million people worldwide. Most antiseizure medications in the market act on voltage-gated sodium or calcium channels, indirectly modulating neurotransmitter GABA or glutamate levels or multiple targets. Earlier studies made significant efforts to directly deliver GABA into the brain with varied success. Herein, we have hypothesized to directly deliver exogenous GABA to the brain with epilepsy through extracellular vesicles (EVs) from human GABA-producing cells and their progenitors as EVs largely mimic their parent cell composition. METHODS: Human neural stem cells (NSCs), medial ganglionic eminence (MGE) cells, and GABAergic interneurons (INs) were generated from induced pluripotent stem cells (iPSCs) and characterized. EVs were isolated from NSCs, MGE cells, and INs and characterized for size and distribution, morphological features, and molecular markers. Exogenous GABA was passively loaded to the isolated EVs as a zwitterion at physiological pH, and the encapsulated dose of GABA was quantified. Epilepsy was developed through status epilepticus induction in Fisher rats by administration of repeated low doses of kainic acid. The extent of the seizures was measured for 10 h/ day for 3-6 months by video recording and its evaluation for stage III, IV and V seizures as per Racine scale. EVs from INs, MGE cells, and NSCs encapsulated with exogenous GABA were sequentially tested in the 4th, 5th, and 6th months by intranasal administration in the rats with epilepsy for detailed seizure, behavioral and synapse analysis. In separate experiments, several controls including exogenic GABA alone and EVs from INs and MGE cells were evaluated for seizure-controlling ability. RESULTS: Exogenic GABA could enter the brain through EVs. Treatment with EVs from INs and MGE cells encapsulated with GABA significantly reduced total seizures, stage V seizures, and total time spent in seizure activity. EVs from NSCs encapsulated with GABA demonstrated limited seizure control. Exogenic GABA alone and EVs from INs and MGE cells individually failed to control seizures. Further, exogenic GABA with EVs from MGE cells improved depressive behavior while partially improving memory functions. Co-localization studies confirmed exogenous GABA with presynaptic vesicles in the hippocampus, indicating the interaction of exogenous GABA in the brain with epilepsy. CONCLUSION: For the first time, the study demonstrated that exogenous GABA could be delivered to the brain through brain cell-derived EVs, which could regulate seizures in temporal lobe epilepsy. It is identified that the cellular origin of EVs plays a vital role in seizure control with exogenous GABA.

Lycium barbarum polysaccharides attenuate nonylphenol and octylphenol-induced oxidative stress and neurotransmitter disorders in PC-12 cells.

Nonylphenol (NP) and octylphenol (OP) are environmental contaminants with potential endocrine disrupting effects. However, there is limited research on the mechanisms and intervention of combined NP and OP exposure-induced neurotoxicity. This study aims to explore the cytotoxicity of combined NP and OP exposure and evaluate the potential of Lycium barbarum polysaccharides (LBP) in mitigating the aforementioned toxicity. In present study, LBP (62.5, 125 and 250µg/mL) were applied to intervene rat adrenal pheochromocytoma (PC-12) cells treated with combined NP and OP (NP: OP = 4:1, w/w; 1, 2, 4 and 8µg/mL). The results showed that NP and OP induced oxidative stress, disrupted the 5-hydroxytryptamine (5-HT) and cholinergic systems in PC-12 cells. Additionally, they activated the p38 protein kinase (p38) and suppressed the expression of silent information regulation type 1 (SIRT1), monoamine oxidase A (MAOA), phosphorylated cyclic-AMP response binding protein (p-CREB), brain-derived neurotrophic factor (BDNF) and phosphorylated tropomyosin-related kinase receptor type B (p-TrkB). However, N-acetyl-L-cysteine (NAC) treatment counteracted the changes of signalling molecule p38, SIRT1/MAOA and CREB/BDNF/TrkB pathways-related proteins induced by NP and OP. LBP pretreatment ameliorated combined NP and OP exposure-induced oxidative stress and neurotransmitter imbalances. Furthermore, the application of LBP and administration of a p38 inhibitor both reversed the alterations in the signaling molecule p38, as well as the proteins associated to the SIRT1/MAOA and CREB/BDNF/TrkB pathways. These results implied that LBP may have neuroprotective effects via p38-mediated SIRT1/MAOA and CREB/BDNF/TrkB pathways.

Electroacupuncture regulates gut microbiota to reduce depressive-like behavior in rats.

Background and objectives: Growing studies show that gut microbiota is closely associated with depression. Acupuncture treatment could regulate the gut microbiota of many diseases. Here, we aim to observe the effect of electroacupuncture (EA) on gut microbiota in rats that showed depressive-like behavior. Materials and methods: The rats were randomly divided into normal group, chronic unpredictable mild stress model (CUMS) group, CUMS + electroacupuncture (EA) group, and CUMS + sham-electroacupuncture (Sham) group. The CUMS+EA rats were treated with EA stimulation at bilateral Zusanli (ST36) and Tianshu (ST25) acupoints for 2 weeks (0.7 mA, 2/100 Hz, 30 min/day). The rats in the sham EA group were treated with the same conditions without inserting needles and electrical stimulation. Behavioral tests were conducted by forced swimming test (FST), open field test (OFT), and sucrose preference test (SPT) to assess depression-like behavior in rats. The relative abundance of intestinal bacteria in rat feces was detected by 16S rRNA analysis. The expression of calcitonin-gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), somatostatin (SST), and adrenocorticotropic hormone (ACTH) in serum was detected by ELISA kit, and VIP, CGRP, and SST in the colon were detected by qRT-PCR and Western blot. Results: Chronic unpredictable mild stress model rats exhibited depressive-like behaviors and had differential abundance vs. control rats. CUMS significantly decreased the relative abundance of Bifidobacterium and Streptococcus at the genus level, CGRP in plasma (p < 0.05), and significantly increased the intestine propulsion rate, the mRNA and protein expression of VIP, SST, and mRNA in the colon, and ATCH in plasma (p < 0.05). EA rats with microbial profiles were distinct from CUMS rats. EA markedly reduced the depressive-like behaviors, significantly increased the intestine propulsion rate, the relative abundance of Bacteroidetes, Proteobacteria, and Actinobacteria at the phylum level, Bifidobacterium and Streptococcus at the genus level, and VIP and CGRP in plasma (p < 0.05), and significantly decreased Firmicutes, the ratio of Firmicutes to Bacteroidetes at the phylum level, ACTH and SST in plasma, and SST mRNA in the colon (p < 0.05). Conclusion: The antidepressant effect of EA at ST36 and ST25 is related to regulating intestinal flora and the neurotransmitter system. Our study suggests that EA contributes to the improvement of depression, and gut microbiota may be one of the mechanisms of EA effect.

Neuroinflammatory Response and Redox-regulation Activity of Hyperoside in Manganese-induced Neurotoxicity Model of Wistar Rats.

BACKGROUND: Excessive manganese exposure can lead to neurotoxicity with detrimental effects on the brain. Neuroinflammatory responses and redox regulation play pivotal roles in this process. Exploring the impact of hyperoside in a Wistar rat model offers insights into potential neuroprotective strategies against manganese-induced neurotoxicity. OBJECTIVE: The study investigated the neuroprotective efficacy of hyperoside isolated from the ethanol leaf extract of Gongronema latifolium (HELEGL), in the brain tissue of Wistar rats following 15 consecutive days of exposure to 30 mg/L of MnCl2. METHODS: Control animals in Group 1 had access to regular drinking water, while animals in groups 2-4 were exposed to MnCl2 in their drinking water. Groups 3 and 4 also received additional HELEGL at doses of 100 mg/kg and 200 mg/kg of body weight, respectively. In Group 5, HELEGL at a dose of 100 mg/kg of body weight was administered alone. Treatment with HELEGL commenced on day 8 via oral administration. RESULTS: HELEGL effectively mitigated MnCl2-induced memory impairment, organ-body weight discrepancies, and fluid intake deficits. Exposure to MnCl2 increased the activities or levels of various markers such as acyl peptide hydrolase, tumour necrosis factor-α, dipeptidyl peptidase IV, nitric oxide, IL-1ß, prolyl oligopeptidase, caspase-3, myeloperoxidase, H2O2, and malondialdehyde, while it decreased the activities or levels of others, including AChE, BChE, DOPA, serotonin, epinephrine, norepinephrine, GST, GPx, CAT, SOD, GSH, and T-SH (p < 0.05). In contrast, HELEGL effectively counteracted the adverse effects of MnCl2 by alleviating oxidative stress, inflammation, apoptosis, mitochondrial dysfunction, cognitive deficits, and bolstering the antioxidant status. Moreover, HELEGL restored the normal histoarchitecture of the brain, which had been distorted by MnCl2. CONCLUSION: In summary, HELEGL reversed the causative factors of neurodegenerative diseases induced by MnCl2 exposure, suggesting its potential for further exploration as a prospective therapeutic agent in the management of Alzheimer's disease and related forms of dementia.

Experimentally monitored calcium dynamics at synaptic active zones during neurotransmitter release in neuron-muscle cell cultures.

Ca2+ -dependent K+ (BK) channels at varicosities in Xenopus nerve-muscle cell cultures were used to quantify experimentally the instantaneous active zone [Ca2+ ]AZ resulting from different rates and durations of Ca2+ entry in the absence of extrinsic buffers and correlate this with neurotransmitter release. Ca2+ tail currents produce mean peak [Ca2+ ]AZ ~ 30 µM; with continued influx, [Ca2+ ]AZ reaches ~45-60 µM at different rates depending on Ca2+ driving force and duration of influx. Both IBK and release are dependent on Ca2+ microdomains composed of both N- and L-type Ca channels. Domains collapse with a time constant of ~0.6 ms. We have constructed an active zone (AZ) model that approximately fits this data, and depends on incorporation of the high-capacity, low-affinity fixed buffer represented by phospholipid charges in the plasma membrane. Our observations suggest that in this preparation, (1) some BK channels, but few if any of the Ca2+ sensors that trigger release, are located within Ca2+ nanodomains while a large fraction of both are located far enough from Ca channels to be blockable by EGTA, (2) the IBK is more sensitive than the excitatory postsynaptic current (EPSC) to [Ca2+ ]AZ (K1/2 -26 µM vs. ~36 µM [Ca2+ ]AZ ); (3) with increasing [Ca2+ ]AZ , the IBK grows with a Hill coefficient of 2.5, the EPSC with a coefficient of 3.9; (4) release is dependent on the highest [Ca2+ ] achieved, independent of the time to reach it; (5) the varicosity synapses differ from mature frog nmjs in significant ways; and (6) BK channels are useful reporters of local [Ca2+ ]AZ .

Huanglian-banxia promotes gastric motility of diabetic rats by modulating brain-gut neurotransmitters through MAPK signaling pathway.

BACKGROUND: Gastric motility disorder is an increasingly common problem among people with diabetes. Neurotransmitters have been recognized as critical regulators in the process of gastric motility. Previous study has shown that herb pair huanglian-banxia (HL-BX) can improve gastric motility, but the underlying mechanism is still unclear. The aim of this study was to further investigate the role of HL-BX in modulating brain-gut neurotransmission to promote gastric motility in diabetic rats, and to explore its possible mechanism. METHODS: The diabetic rats were divided into five groups. Gastric emptying rate, intestinal propulsion rate, body weight, and average food intake were determined. Substance P (SP), 5- hydroxytryptamine (5-HT), and glucagon-like peptide -1 (GLP-1) in the serum were measured by enzyme-linked immunosorbent assay. Dopamine (DA) and norepinephrine (NE) in the brain were analyzed by high-pressure liquid chromatography with a fluorescence detector. Protein expression of the tissues in the stomach and brain was determined by Western blot. KEY RESULTS: HL-BX reduced average food intake significantly, increased body weight, and improved gastric emptying rate and intestinal propulsion rate. HL-BX administration caused a significant increase in SP, GLP-1, and 5-HT, but a significant decrease in DA and NE. Interestingly, HL-BX regulated simultaneously the different expressions of MAPK and its downstream p70S6K/S6 signaling pathway in the stomach and brain. Moreover, berberine exhibited a similar effect to HL-BX. CONCLUSIONS: These results indicated that HL-BX promoted gastric motility by regulating brain-gut neurotransmitters through the MAPK signaling pathway. HL-BX and MAPK provide a potential therapeutic option for the treatment of gastroparesis.

Electroencephalography connectome changes in chronic insomnia disorder are correlated with neurochemical signatures.

STUDY OBJECTIVES: This study aimed to investigate the alterations in resting-state electroencephalography (EEG) global brain connectivity (GBC) in patients with chronic insomnia disorder (CID) and to explore the correlation between macroscale connectomic variances and microscale neurotransmitter distributions. METHODS: We acquired 64-channel EEG from 35 female CID patients and 34 healthy females. EEG signals were source-localized using individual brain anatomy and orthogonalized to mitigate volume conduction. Correlation coefficients between band-limited source-space power envelopes of the DK 68 atlas were computed and averaged across regions to determine specific GBC values. A support vector machine (SVM) classifier utilizing GBC features was employed to differentiate CID patients from controls. We further used Neurosynth and a 3D atlas of neurotransmitter receptors/transporters to assess the cognitive functions and neurotransmitter landscape associated with CID cortical abnormality maps, respectively. RESULTS: CID patients exhibited elevated GBC within the medial prefrontal cortex and limbic cortex, particularly at the gamma carrier frequency, compared to controls (pFDR<0.05). GBC patterns were found to effectively distinguish CID patients from controls with a precision of 90.8% in the SVM model. The cortical abnormality maps were significantly correlated with meta-analytic terms like "cognitive control" and "emotion regulation." Notably, GBC patterns were associated with neurotransmitter profiles (pspin<0.05), with neurotransmitter systems such as norepinephrine, dopamine, and serotonin making significant contributions. CONCLUSIONS: This work characterizes the EEG connectomic profile of CID, facilitating the cost-effective clinical translation of EEG-derived markers. Additionally, the linkage between GBC patterns and neurotransmitter distribution offers promising avenues for developing targeted treatment strategies for CID.

Dopamine Measurement Using Engineered CNT-CQD-Polymer Coatings on Pt Microelectrodes.

This study aims to develop a microelectrode array-based neural probe that can record dopamine activity with high stability and sensitivity. To mimic the high stability of the gold standard method (carbon fiber electrodes), the microfabricated platinum microelectrode is coated with carbon-based nanomaterials. Carboxyl-functionalized multi-walled carbon nanotubes (COOH-MWCNTs) and carbon quantum dots (CQDs) were selected for this purpose, while a conductive polymer like poly (3-4-ethylene dioxythiophene) (PEDOT) or polypyrrole (PPy) serves as a stable interface between the platinum of the electrode and the carbon-based nanomaterials through a co-electrodeposition process. Based on our comparison between different conducting polymers and the addition of CQD, the CNT-CQD-PPy modified microelectrode outperforms its counterparts: CNT-CQD-PEDOT, CNT-PPy, CNT-PEDOT, and bare Pt microelectrode. The CNT-CQD-PPy modified microelectrode has a higher conductivity, stability, and sensitivity while achieving a remarkable limit of detection (LOD) of 35.20 ± 0.77 nM. Using fast-scan cyclic voltammetry (FSCV), these modified electrodes successfully measured dopamine's redox peaks while exhibiting consistent and reliable responses over extensive use. This electrode modification not only paves the way for real-time, precise dopamine sensing using microfabricated electrodes but also offers a novel electrochemical sensor for in vivo studies of neural network dynamics and neurological disorders.

Copines, a Family of Calcium Sensor Proteins and Their Role in Brain Function.

The Copines are a family of evolutionary conserved calcium-binding proteins found in most eukaryotic organisms from protists to humans. They share a unique architecture and contain tandem C2 domains and a Von Willebrand factor type A (VWA) domain. C2 domains in Copines bind calcium, phospholipids, and other proteins and mediate the transient association of these proteins with biological membranes at elevated calcium levels. The VWA domain also binds calcium and is involved in protein-protein interactions. Here, we provide a comprehensive review of the sequences, structures, expression, targeting, and function of the entire family of known Copine proteins (Copine 1-9 in mammals) with a particular emphasis on their functional roles in the mammalian brain. Neuronal Copines are implicated in a wide array of processes from cell differentiation to synaptic transmission and plasticity and are also linked to several pathological conditions from cancers to brain diseases. This review provides the most up-to-date insights into the structure and function of Copines, with an emphasis on their role in brain function.

The Relative Contribution of Glycine-GABA Cotransmission in the Core of the Respiratory Network.

The preBötzinger complex (preBötC) and the Bötzinger complex (BötC) are interconnected neural circuits that are involved in the regulation of breathing in mammals. Fast inhibitory neurotransmission is known to play an important role in the interaction of these two regions. Moreover, the corelease of glycine and GABA has been described in the respiratory network, but the contribution of the individual neurotransmitter in different pathways remains elusive. In sagittal brainstem slices of neonatal mice, we employed a laser point illumination system to activate glycinergic neurons expressing channelrhodopsin-2 (ChR2). This approach allowed us to discern the contribution of glycine and GABA to postsynaptic currents of individual whole-cell clamped neurons in the preBötC and BötC through the application of glycine and GABA receptor-specific antagonists. In more than 90% of the recordings, both transmitters contributed to the evoked IPSCs, with the glycinergic component being larger than the GABAergic component. The GABAergic component appeared to be most prominent when stimulation and recording were both performed within the preBötC. Taken together, our data suggest that GABA-glycine cotransmission is the default mode in the respiratory network of neonatal mice with regional differences that may be important in tuning the network activity.

Zhumian Granules improves PCPA-induced insomnia by regulating the expression level of neurotransmitters and reducing neuronal apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Sleep problems, according to Traditional Chinese medicine (TCM) philosophy, are attributed to the imbalance between yin and yang. Zhumian Granules, also known as Sleep-aid Granules or ZG, are a traditional Chinese herbal remedy specifically designed to alleviate insomnia. This formula consists of many components, including Wu Wei Zi (Schisandrae Chinensis Fructus), Suan Zao Ren (Ziziphi Spinosae Semen), and other medicinal plants. According to the pharmacology of Traditional Chinese Medicine (TCM), Wu Wei Zi and Suan Zao Ren have the ability to relax the mind and promote sleep. When taken together, they may balance the opposing forces of yin and yang. Therefore, ZG may potentially be used as a therapeutic treatment for insomnia. AIM OF THE STUDY: This research was specifically developed to establish a strong empirical basis for the subsequent advancement and utilization of ZG in the management of insomnia. This research aimed to gather empirical data to support the effectiveness of ZG, thereby providing useful insights into its potential therapeutic advantages for persons with insomnia. MATERIALS AND METHODS: This study utilized Zhumian Granules (ZG), a traditional Chinese herbal decoction, to examine its sedative and hypnotic effects on mice with PCPA-induced insomnia. The effects were assessed using the pentobarbital-induced sleep test (PIST), Morris water maze test (MWM), and autonomic activity test. The levels of neurotransmitters in each group of mice were evaluated using UPLC-QQQ-MS. The impact of ZG on the quantity and structure of hippocampal neurons was seen in brain tissue slices using immunofluorescence labeling. RESULTS: ZG was shown to possess active sedative properties, effectively lowering the distance of movement and lengthening the duration of sleep. ZG mitigated the sleeplessness effects of PCPA by elevating the levels of 5-hydroxytryptamine (5-HT), 4-aminobutyric acid (GABA), and 5-hydroxyindoleacetic acid (5-HIAA), while reducing the levels of dopamine (DA) and norepinephrine (NE), as well as decreasing neuronal death. CONCLUSIONS: This research confirmed the sedative and hypnotic properties of ZG and elucidated its probable mechanism involving neurotransmitters.

Forebrain EAAT3 Overexpression Increases Susceptibility to Amphetamine-Induced Repetitive Behaviors.

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder characterized by intrusive obsessive thoughts and compulsive behaviors. Multiple studies have shown the association of polymorphisms in the SLC1A1 gene with OCD. The most common of these OCD-associated polymorphisms increases the expression of the encoded protein, excitatory amino acid transporter 3 (EAAT3), a neuronal glutamate transporter. Previous work has shown that increased EAAT3 expression results in OCD-relevant behavioral phenotypes in rodent models. In this study, we created a novel mouse model with targeted, reversible overexpression of Slc1a1 in forebrain neurons. The mice do not have a baseline difference in repetitive behavior but show increased hyperlocomotion following a low dose of amphetamine (3 mg/kg) and increased stereotypy following a high dose of amphetamine (8 mg/kg). We next characterized the effect of amphetamine on striatal cFos response and found that amphetamine increased cFos throughout the striatum in both control and Slc1a1-overexpressing (OE) mice, but Slc1a1-OE mice had increased cFos expression in the ventral striatum relative to controls. We used an unbiased machine classifier to robustly characterize the behavioral response to different doses of amphetamine and found a unique response to amphetamine in Slc1a1-OE mice, relative to controls. Lastly, we found that the differences in striatal cFos expression in Slc1a1-OE mice were driven by cFos expression specifically in D1 neurons, as Slc1a1-OE mice had increased cFos in D1 ventral medial striatal neurons, implicating this region in the exaggerated behavioral response to amphetamine in Slc1a1-OE mice.

Light-dependent regulation of neurotransmitter release from rod photoreceptor ribbon synapses involves an interplay of Complexin 4 and Transducin with the SNARE complex.

Adaptation of photoreceptor sensitivity to varying light intensities is a fundamental requirement for retinal function and vision. Adaptive mechanisms in signal transduction are well described, but little is known about the mechanisms that adapt the photoreceptor synapse to changing light intensities. The SNARE complex regulators Complexin 3 and Complexin 4 have been proposed to be involved in synaptic light adaptation by limiting synaptic vesicle recruitment and fusion. How this Complexin effect is exerted is unknown. Focusing on rod photoreceptors, we established Complexin 4 as the predominant Complexin in the light-dependent regulation of neurotransmitter release. The number of readily releasable synaptic vesicles is significantly smaller in light than in dark at wildtype compared to Complexin 4 deficient rod photoreceptor ribbon synapses. Electrophysiology indicates that Complexin 4 reduces or clamps Ca2+-dependent sustained synaptic vesicle release, thereby enhancing light signaling at the synapse. Complexin 4 deficiency increased synaptic vesicle release and desensitized light signaling. In a quantitative proteomic screen, we identified Transducin as an interactor of the Complexin 4-SNARE complex. Our results provide evidence for a presynaptic interplay of both Complexin 4 and Transducin with the SNARE complex, an interplay that may facilitate the adaptation of synaptic transmission to light at rod photoreceptor ribbon synapses.

Nonketotic hyperglycemia hemichorea and hemiballismus: a case report.

BACKGROUND: Diabetic striatopathy, also known as hyperglycemic hemichorea-hemiballismus, is a rare movement disorder associated with nonketotic hyperglycemia in patients with poorly controlled diabetes mellitus. The pathophysiology is not fully elucidated but may involve hyperviscosity, ischemia, and alterations in basal ganglia neurotransmitters. CASE PRESENTATION: We present a case of a 64-year-old Asian female patient with longstanding poorly controlled type 2 diabetes mellitus who developed abrupt-onset right-sided hemichorea-hemiballismus. Laboratory results showed hyperglycemia without ketoacidosis. Neuroimaging revealed left putaminal hyperdensity on computed tomography and T1 hyperintensity on magnetic resonance imaging. With insulin therapy and tetrabenazine, her movements improved but persisted at 1-month follow-up. DISCUSSION: This case illustrates the typical features of diabetic striatopathy, including acute choreiform movements contralateral to neuroimaging abnormalities in the setting of nonketotic hyperglycemia. While neuroleptics may provide symptomatic relief, prompt glycemic control is critical given the risk of recurrence despite imaging normalization. CONCLUSION: Diabetic striatopathy should be recognized as a rare disorder that can occur with poorly controlled diabetes. Further study of its pathophysiological mechanisms is needed to better guide management. Maintaining tight glycemic control is essential to prevent recurrence of this debilitating movement disorder.

Preening cups in duck housing are associated with an increase in central dopamine activity that suggests a negative affective state.

Preening cups are a form of environmental enrichment that provides Pekin ducks a semi-open water source to express their natural behaviors. We recently observed that preening cups may increase feather pecking behaviors in ducks. Thus, we set out to determine if this form of enrichment can impact the affective state of Pekin ducks. To accomplish this goal, we evaluated the effect of preening cups on serotonin (5-HT) and dopamine (DA) turnover via mass spectrometry and their respective synthetic enzyme gene expression via qRT-PCR. Our study investigated the link between aggressive pecking with levels and activity of brain 5-HT and DA. Brain 5-HT and DA levels and activity have been established for decades to be associated with affective states. Grow-out Pekin ducks (n = 260) were housed at Purdue and raised per industry standards. On day 18, brains were collected from ducks in pens before preening cups were placed (PRE, n = 6) and, again on day 43, in pens with (PC, n = 6) and without (CON, n = 6) preening cups. Brains were dissected into right and left halves, then further microdissected into 4 brain areas: caudal mesencephalon (CM), rostral mesencephalon (RM), diencephalon (DI), and forebrain (FB). The right hemisphere was used for mass spectrometry to determine the neurotransmitter concentration (ng/mg of tissue) and those concentrations were applied to neurotransmitter turnover equations. There were no differences across treatments for 5-HT turnover in any brain area. There were differences in DA turnover across age (P = 0.0067) in the CM and across treatments (P = 0.003) in the RM. The left hemisphere of the brain was used to perform qRT-PCR on the genes of 5-HT and DA production enzymes. Within the CM, day 43 duck brains had increased (P = 0.022) tryptophan hydroxylase and tyrosine hydroxylase relative mRNA levels. All other brain areas showed no differences. Our data suggest that ducks housed with preening cups and that showed increased feather pecking are associated with increased brain DA activity. The increased DA in the brain may lead to a predisposition for increased aggression in the form of feather pecking.

The Role of Dietary Peptides Gluten and Casein in the Development of Autism Spectrum Disorder: Biochemical Perspectives.

This paper examines the role of dietary peptides gluten and casein in modulating brain function in individuals with autism spectrum disorder (ASD) from a biochemical perspective. Neurotransmitter systems and neural networks are crucial for brain function, and alterations at the biochemical level can contribute to the characteristic symptoms and behaviors of ASD. The paper explores how dietary peptides influence neurotransmitter systems and neural networks, highlighting their potential as interventions to improve brain function in ASD. The evidence suggests that dietary peptides can impact neurotransmitter synthesis, release, and receptor interactions, disrupting the balance of neurotransmitter systems and affecting neural network function. The findings underscore the potential of dietary interventions in modulating brain function in ASD and call for further research to elucidate the underlying mechanisms and optimize clinical practice. Considering individual dietary sensitivities and preferences, personalized dietary approaches may be necessary for optimal outcomes. Dietary interventions' timing, duration, and integration with other evidence-based treatments are crucial considerations. Safety considerations and regular monitoring are important to ensure the implementation of dietary interventions safely and effectively.