Monoallelic de novo AJAP1 loss-of-function variants disrupt trans-synaptic control of neurotransmitter release.

Adherens junction-associated protein 1 (AJAP1) has been implicated in brain diseases; however, a pathogenic mechanism has not been identified. AJAP1 is widely expressed in neurons and binds to γ-aminobutyric acid type B receptors (GBRs), which inhibit neurotransmitter release at most synapses in the brain. Here, we show that AJAP1 is selectively expressed in dendrites and trans-synaptically recruits GBRs to presynaptic sites of neurons expressing AJAP1. We have identified several monoallelic AJAP1 variants in individuals with epilepsy and/or neurodevelopmental disorders. Specifically, we show that the variant p.(W183C) lacks binding to GBRs, resulting in the inability to recruit them. Ultrastructural analysis revealed significantly decreased presynaptic GBR levels in Ajap1-/- and Ajap1W183C/+ mice. Consequently, these mice exhibited reduced GBR-mediated presynaptic inhibition at excitatory and inhibitory synapses, along with impaired synaptic plasticity. Our study reveals that AJAP1 enables the postsynaptic neuron to regulate the level of presynaptic GBR-mediated inhibition, supporting the clinical relevance of loss-of-function AJAP1 variants.

Hematological and neurological impact studies on the exposure to naturally occurring radioactive materials.

Naturally Occurring Radioactive Materials (NORM) contribute to everyone's natural background radiation dose. The technologically advanced activities of the gas and oil sectors produce considerable amounts of radioactive materials as industrial by-products or waste products. The goal of the current study is to estimate the danger of long-term liability to Technologically Enhanced Naturally Occurring Radioactive Materials (TE-NORM) on blood indices, neurotransmitters, oxidative stress markers, and ß-amyloid in the cerebral cortex of rats' brains. Twenty adult male albino rats were divided into two equal groups (n = 10): control and irradiated. Irradiated rats were exposed to a total dose of 0.016 Gy of TE-NORM as a whole-body chronic exposure over a period of two months. It should be ''The results showed no significant changes in RBC count, Hb concentration, hematocrit percentage (HCT%), and Mean Corpuscular Hemoglobin Concentration (MCHC). However, there was a significant increase in the Mean Corpuscular Volume of RBCs (MCV) and a significant decrease in cell distribution width (RDW%) compared to the control. Alteration in neurotransmitters is noticeable by a significant increase in glutamic acid and significant decreases in serotonin and dopamine. Increased lipid peroxidation, decreased glutathione content, superoxide dismutase, catalase, and glutathione peroxidase activities indicating oxidative stress were accompanied by increased ß-amyloid in the cerebral cortex of rats' brains. The findings of the present study showed that chronic radiation liability has some harmful effects, that may predict the risks of future health problems in occupational radiation exposure in the oil industries. Therefore, the control of exposure and application of sample dosimetry is recommended for health and safety.

The neurotransmitter calcitonin gene-related peptide shapes an immunosuppressive microenvironment in medullary thyroid cancer.

Neurotransmitters are key modulators in neuro-immune circuits and have been linked to tumor progression. Medullary thyroid cancer (MTC), an aggressive neuroendocrine tumor, expresses neurotransmitter calcitonin gene-related peptide (CGRP), is insensitive to chemo- and radiotherapies, and the effectiveness of immunotherapies remains unknown. Thus, a comprehensive analysis of the tumor microenvironment would facilitate effective therapies and provide evidence on CGRP's function outside the nervous system. Here, we compare the single-cell landscape of MTC and papillary thyroid cancer (PTC) and find that expression of CGRP in MTC is associated with dendritic cell (DC) abnormal development characterized by activation of cAMP related pathways and high levels of Kruppel Like Factor 2 (KLF2), correlated with an impaired activity of tumor infiltrating T cells. A CGRP receptor antagonist could offset CGRP detrimental impact on DC development in vitro. Our study provides insights of the MTC immunosuppressive microenvironment, and proposes CGRP receptor as a potential therapeutic target.

Neurobehavioral, neurotransmitter and redox modifications in Nauphoeta cinerea under mixed heavy metal (silver and mercury) exposure.

Heavy metals are encountered in nature, and are used in several human endeavors, including in dental fillings. It is well known that the safety of metals depends on their chemical form, as well as the dose and route through which biological systems are exposed to them. Here, we used the Nauphoeta cinerea model to examine the mechanism by which salts of the heavy metals used in dental fillings - silver and mercury - exert their neurotoxicity. Nymphs exposed to heavy metals presented with reduced motor and exploratory abilities as they spent more time immobile, especially in the periphery of a novel object, and covered less distance compared with control nymphs. Exposure to AgNO3 and HgCl2 also exacerbated levels of oxidative stress markers (MDA & ROS) and the neurotransmitter regulators - AChE and MAO, while reducing antioxidant activity markers, both in biochemical (thiol & GST) and RT-qPCR (TRX, GST, SOD, Catalase) examinations, in neural tissues of the cockroach. The observed disruptions in neurolocomotor control, synaptic transmission and redox balance explain how heavy metal salts may predispose organisms to neurological disorders.

Correlation between Neurotransmitters (Dopamine, Epinephrine, Norepinephrine, Serotonin), Prognostic Nutritional Index, Glasgow Prognostic Score, Systemic Inflammatory Response Markers, and TNM Staging in a Cohort of Colorectal Neuroendocrine Tumor Patients.

Neuroendocrine tumors are uncommon in the gastrointestinal system but can develop in the majority of the body's epithelial organs. Our goal was to examine the presence and clinical application of serum dopamine (DA), serotonin (ST), norepinephrine (NE), and epinephrine (EPI), in addition to determining the significance of the Prognostic Nutritional Index (PNI), Glasgow Prognostic Score (GPS), and systemic inflammatory response (SIR) markers as a prognostic factor for patients with colorectal neuroendocrine tumors (CR-NETs), in various tumor-node-metastasis (TNM) stages. We also wanted to identify the possible connection between them. This study included 25 consecutive patients who were diagnosed with CR-NETs and a control group consisting of 60 patients with newly diagnosed colorectal cancer (CRC). We used the Enzyme-Linked Immunosorbent Assay (ELISA) technique. This study revealed that CR-NET patients showed significantly higher serum levels of DA compared to CRC patients. We showed that serum DA was present in the early stages of CR-NETs, with increasing levels as we advanced through the TNM stages. Moreover, we found a close relationship between the levels of DA and the inflammation and nutritional status of the CR-NET patients in this study. CR-NET patients from the PNI < 47.00 subgroup had a higher level of DA than those from the PNI ≥ 47.00 subgroup. Pearson's correlation analysis revealed correlations between DA, PNI, and the neutrophil/lymphocyte ratio (NLR) and the platelet/lymphocyte ratio (PLR). Both hematological indices were negatively correlated with albumin (ALB). Our investigation's findings relating to the PNI, GPS, SIR, and DA indicate that these tools can be markers of nutritional and systemic inflammatory status, are simple to use, and are repeatable. Further research on this topic could provide valuable insights into which biomarkers to incorporate into clinical practice for the management of CR-NET patients.

Brain Networks, Neurotransmitters and Psychedelics: Towards a Neurochemistry of Self-Awareness.

PURPOSE OF REVIEW: Self-awareness can be defined as the capacity of becoming the object of one's own awareness and, increasingly, it has been the target of scientific inquiry. Self-awareness has important clinical implications, and a better understanding of the neurochemical basis of self-awareness may help clarifying causes and developing interventions for different psychopathological conditions. The current article explores the relationship between neurochemistry and self-awareness, with special attention to the effects of psychedelics. RECENT FINDINGS: The functioning of self-related networks, such as the default-mode network and the salience network, and how these are influenced by different neurotransmitters is discussed. The impact of psychedelics on self-awareness is reviewed in relation to specific processes, such as interoception, body ownership, agency, metacognition, emotional regulation and autobiographical memory, within a framework based on predictive coding. Improved outcomes in emotional regulation and autobiographical memory have been observed in association with the use of psychedelics, suggesting higher-order self-awareness changes, which can be modulated by relaxation of priors and improved coping mechanisms linked to cognitive flexibility. Alterations in bodily self-awareness are less consistent, being potentially impacted by doses employed, differences in acute/long-term effects and the presence of clinical conditions. Future studies investigating the effects of different molecules in rebalancing connectivity between resting-state networks may lead to novel therapeutic approaches and the refinement of existing treatments.

Psychotomimetic compensation versus sensitization.

It is a paradox that psychotomimetic drugs can relieve symptoms that increase risk of and cooccur with psychosis, such as attention and motivational deficits (e.g., amphetamines), pain (e.g., cannabis) and symptoms of depression (e.g., psychedelics, dissociatives). We introduce the ideas of psychotomimetic compensation and psychotomimetic sensitization to explain this paradox. Psychotomimetic compensation refers to a short-term stressor or drug-induced compensation against stress that is facilitated by engagement of neurotransmitter/modulator systems (endocannabinoid, serotonergic, glutamatergic and dopaminergic) that mediate the effects of common psychotomimetic drugs. Psychotomimetic sensitization occurs after repeated exposure to stress and/or drugs and is evidenced by the gradual intensification and increase of psychotic-like experiences over time. Theoretical and practical implications of this model are discussed.

Multimodal neuroimaging fusion unravel structural-functional-neurotransmitter change in Parkinson's disease with impulse control disorders.

BACKGROUND: Impulse control disorders (ICD) in Parkinson's disease (PD) is highly multifactorial in etiology and has intricate neural mechanisms. Our multimodal neuroimaging study aimed to investigate the specific patterns of structure-function-neurotransmitter interactions underlying ICD. METHODS: Thirty PD patients with ICD (PD-ICD), 30 without ICD (PD-NICD) and 32 healthy controls (HCs) were recruited. Gyrification and perivascular spaces (PVS) were computed to capture the alternations of cortical surface morphology and glymphatic function. Seed-based functional connectivity (FC) were performed to identify the corresponding functional changes. Further, JuSpace toolbox were employed for cross-modal correlations to evaluate whether the spatial patterns of functional alterations in ICD patients were associated with specific neurotransmitter system. RESULTS: Compared to PD-NICD, PD-ICD patients showed hypogyrification and enlarged PVS volume fraction in the left orbitofrontal gyrus (OFG), as well as decreased FC between interhemispheric OFG. The interhemispheric OFG connectivity reduction was associated with spatial distribution of µ-opioid pathway (r = -0.186, p = 0.029, false discovery rate corrected). ICD severity was positively associated with the PVS volume fraction of left OFG (r = 0.422, p = 0.032). Furthermore, gyrification index (LGI) and percent PVS (pPVS) in OFG and their combined indicator showed good performance in differentiating PD-ICD from PD-NICD. CONCLUSIONS: Our findings indicated that the co-altered structure-function-neurotransmitter interactions of OFG might be involved in the pathogenesis of ICD.

Unveiling of a messenger: Gut microbes make a neuroactive signal.

Gut microbes are known to impact host physiology in several ways. However, key molecular players in host-commensal interactions remain to be uncovered. In this issue of Cell, McCurry et al. reveal that gut bacteria perform 21-dehydroxylation to convert abundant biliary corticoids to neurosteroids using readily available H2 in their environment.

Neurotransmitters: Impressive regulators of tumor progression.

In contemporary times, tumors have emerged as the primary cause of mortality in the global population. Ongoing research has shed light on the significance of neurotransmitters in the regulation of tumors. It has been established that neurotransmitters play a pivotal role in tumor cell angiogenesis by triggering the transformation of stromal cells into tumor cells, modulating receptors on tumor stem cells, and even inducing immunosuppression. These actions ultimately foster the proliferation and metastasis of tumor cells. Several major neurotransmitters have been found to exert modulatory effects on tumor cells, including the ability to restrict emergency hematopoiesis and bind to receptors on the postsynaptic membrane, thereby inhibiting malignant progression. The abnormal secretion of neurotransmitters is closely associated with tumor progression, suggesting that focusing on neurotransmitters may yield unexpected breakthroughs in tumor therapy. This article presents an analysis and outlook on the potential of targeting neurotransmitters in tumor therapy.

Effects of electroacupuncture combined with paliperidone palmitate long-acting injection on withdrawal symptoms and neurotransmitters in methamphetamine addicts.

OBJECTIVE: To investigate the effects of electroacupuncture combined with paliperidone palmitate long-acting injection (PP-LAI) on withdrawal symptoms and neurotransmitters in methamphetamine (MA) addicts. MATERIALS AND METHODS: A total of 109 methamphetamine addicts, who were treated in the hospital from October 2021 to October 2022, were selected. According to the random number table, the patients were divided into the study group (n=54) and the control group (n=55), in which the control group was treated with PP-LAI and the study group was treated with electroacupuncture on the basis of the control group; the methamphetamine withdrawal symptom score scale was used to assess the therapeutic effect before treatment and within 12 months after treatment; the changes of brain neurotransmitters dopamine, γ-aminobutyric acid, serotonin, acetylcholine values were compared between the two groups. RESULTS: 1) There was no statistical difference in MA withdrawal symptom scores between the two groups before treatment (p>0.05); 2) MA withdrawal symptom scores have a statistically significant difference between the study group and the control group after 3 and 6 months of treatment; 3) dopamine levels in the study group were significantly higher than those in the control group after 6 months of completion of treatment, and γ-aminobutyric acid values and 5- serotonin values in the study group were significantly lower than those in the control group (p<0.05). CONCLUSIONS: Electroacupuncture combined with PP-LAI can partially improve the withdrawal symptoms and anxiety of methamphetamine addicts. This is a potential treatment for preventing relapse of withdrawal symptoms.

Effects of nanoplastic exposure during pregnancy and lactation on neurodevelopment of rat offspring.

Microplastics have emerged as a prominent global environmental contaminant, and they have been found in both human placenta and breast milk. However, the potential effects and mechanisms of maternal exposure to microplastics at various gestational stages on offspring neurodevelopment remain poorly understood. This investigation delves into the potential neurodevelopmental ramifications of maternal exposure to polystyrene nanoplastics (PS-NPs) during distinct phases of pregnancy and lactation. Targeted metabolomics shows that co-exposure during both pregnancy and lactation primarily engendered alterations in monoamine neurotransmitters within the cortex and amino acid neurotransmitters within the hippocampus. After prenatal exposure to PS-NPs, fetal rats showed appreciably diminished cortical thickness and heightened cortical cell proliferation. However, this exposure did not affect the neurodifferentiation of radial glial cells and intermediate progenitor cells. In addition, offspring are accompanied by disordered neocortical migration, typified by escalated superficial layer neurons proliferation and reduced deep layer neurons populations. Moreover, the hippocampal synapses showed significantly widened synaptic clefts and diminished postsynaptic density. Consequently, PS-NPs culminated in deficits in anxiolytic-like behaviors and spatial memory in adolescent offspring, aligning with concurrent neurotransmitter and synaptic alterations. In conclusion, this study elucidates the sensitive windows of early-life nanoplastic exposure and the consequential impact on offspring neurodevelopment.

Quantitative susceptibility mapping of multiple system atrophy and Parkinson's disease correlates with neurotransmitter reference maps.

BACKGROUND: Multiple system atrophy (MSA) and Parkinson's disease (PD) are neurodegenerative disorders characterized by α-synuclein pathology, disrupted iron homeostasis and impaired neurochemical transmission. Considering the critical role of iron in neurotransmitter synthesis and transport, our study aims to identify distinct patterns of whole-brain iron accumulation in MSA and PD, and to elucidate the corresponding neurochemical substrates. METHODS: A total of 122 PD patients, 58 MSA patients and 78 age-, sex-matched health controls underwent multi-echo gradient echo sequences and neurological evaluations. We conducted voxel-wise and regional analyses using quantitative susceptibility mapping to explore MSA or PD-specific alterations in cortical and subcortical iron concentrations. Spatial correlation approaches were employed to examine the topographical alignment of cortical iron accumulation patterns with normative atlases of neurotransmitter receptor and transporter densities. Furthermore, we assessed the associations between the colocalization strength of neurochemical systems and disease severity. RESULTS: MSA patients exhibited increased susceptibility in the striatal, midbrain, cerebellar nuclei, as well as the frontal, temporal, occipital lobes, and anterior cingulate gyrus. In contrast, PD patients displayed elevated iron levels in the left inferior occipital gyrus, precentral gyrus, and substantia nigra. The excessive iron accumulation in MSA or PD correlated with the spatial distribution of cholinergic, noradrenaline, glutamate, serotonin, cannabinoids, and opioid neurotransmitters, and the degree of this alignment was related to motor deficits. CONCLUSIONS: Our findings provide evidence of the interaction between iron accumulation and non-dopamine neurotransmitters in the pathogenesis of MSA and PD, which inspires research on potential targets for pharmacotherapy.

Optimizing neurotransmitter pathway detection by IR-MALDESI-MSI in mouse brain.

Mass spectrometry imaging (MSI) platforms such as infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) are advantageous for a variety of applications, including elucidating the localization of neurotransmitters (NTs) and related molecules with respect to ion abundance across a sample without the need for derivatization or organic matrix application. While IR-MALDESI-MSI conventionally uses a thin exogenous ice matrix to improve signal abundance, it has been previously determined that sucrose embedding without the ice matrix improves detection of lipid species in striatal, coronal mouse brain sections. This work considers components of this workflow to determine the optimal sample preparation and matrix to enhance the detection of NTs and their related metabolites in coronal sections from the striatal region of the mouse brain. The discoveries herein will enable more comprehensive follow-on studies for the investigation of NTs to enrich biological pathways and interpretation related to neurodegenerative diseases and ischemic stroke.

ERß activation improves nonylphenol-induced depression and neurotransmitter secretion disruption via the TPH2/5-HT pathway.

The aim of this study is to investigate the role of estrogen receptor ß (ERß) in nonylphenol (NP) - induced depression - like behavior in rats and its impact on the regulation of the TPH2/5-HT pathway. In the in vitro experiment, rat basophilic leukaemia cells (RBL-2H3) cells were divided into the four groups: blank group, NP group (20 µM), ERß agonist group (0.01 µM), and NP＋ERß agonist group (20 µM＋0.01 µM). For the in vivo experiment, 72 adult male Sprague-Dawley rats were randomly divided into following six groups: the Control, NP (40 mg/kg) group, ERß agonist (2 mg/kg, Diarylpropionitrile (DPN)) group, ERß inhibitor (0.1 mg/kg, 4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl) phenol (PHTPP)) group, NP+ERß agonist (40 mg/kg NP ＋ 2 mg/kg DPN) group, and NP+ERß inhibitor (40 mg/kg NP + 0.1 mg/kg PHTPP) group, with 12 rats in each group. Each rat in drug group were given NP by gavage and/or received a single intraperitoneal injection of DPN 2 mg/kg or PHTPP 0.1 mg/kg. Both in vivo and in vitro, NP group showed a decrease in the expression levels of ERß, tryptophan hydroxylase (TPH1), and tryptophan hydroxylase-2 (TPH2) genes and proteins, and reduced levels of DA, NE, and 5-hydroxytryptophan (5-HT) neurotransmitters. RBL-2H3 cells showed signs of cell shrinkage, with rounded cells, increased suspension and more loosely arranged cells. The effectiveness of the ERß agonist stimulation exhibited an increase exceeding 60% in RBL-2H3 cells. The application of ERß agonist resulted in an alleviation the aforementioned alterations. ERß agonist activated the TPH2/5-HT signaling pathways. Compared to the control group, the NP content in the brain tissue of the NP group was significantly increased. The latency to eat for the rats was longer and the amount of food consumed was lower, and the rats had prolonged immobility time in the behavioral experiment of rats. The expression levels of ERß, TPH1, TPH2, 5-HT and 5-HITT proteins were decreased in the NP group, suggesting NP-induced depression-like behaviours as well as disturbances in the secretion of serum hormones and monoamine neurotransmitters. In the NP group, the midline raphe nucleus showed an elongated nucleus with a dark purplish-blue colour, nuclear atrophy, displacement and pale cytoplasm. ERß might ameliorate NP-induced depression-like behaviors, and secretion disorders of serum hormones and monoamine neurotransmitters via activating TPH2/5-HT signaling pathways.

Ethanol's impact on the brain: a neurobiological perspective on the mechanisms of memory impairment.

Alcohol consumption is known to have detrimental effects on memory function, with various studies implicating ethanol in the impairment of cognitive processes related to memory retention and retrieval. This review aims to elucidate the complex neurobiological mechanisms underlying ethanol-induced memory impairment. Through a thorough search of existing literature using electronic databases, relevant articles focusing on the neurobiological mechanisms of ethanol on memory were identified and critically evaluated. This review focuses on the molecular and neural pathways through which ethanol exerts its effects on memory formation, consolidation, and recall processes. Key findings from the included studies shed light on the impact of ethanol on neurotransmitter systems, synaptic plasticity, and neuroinflammation in relation to memory impairment. This review contributes to a better understanding of the intricate mechanisms by which alcohol impairs memory function, offering insights for future research directions and the development of targeted interventions to alleviate these cognitive impairments.

Implications of Jatropha curcas L. cake feed on swine health: A microbiota-gut-brain axis perspective.

The safety of Jatropha curcas L. cake (JCC) in animal feed remains under scrutiny, despite the advent of low phorbol ester (PE) variants. This study investigates the impact of low PE JCC on swine health when used as a protein feed. Pigs were fed a 5% JCC diet with a PE concentration of 0.98 mg/kg, which surprisingly still induced toxicity. Symptoms included depression, decreased food intake, increased diarrhea, along with hypothalamus and colon lesions. The toxicity was associated with a decrease in antioxidant enzymes, an increase in inflammatory cytokines in the hypothalamus, plasma, and colon, and a rise in pro-inflammatory colon microbes and metabolites. Disturbances in neurotransmitters further suggest that this toxicity is related to disruption of the microbiota-gut-brain axis, indicating that JCC's toxic elements are not solely due to PE. The sensitivity of pigs to JCC underscores the need for thorough detoxification prior to its use as feed. These findings significantly contribute to the discourse on the safety of low PE JCC in animal feed, highlighting implications for both the feed industry and public health.

A comparative study of urinary levels of multiple metals and neurotransmitter correlations between GDM and T2DM populations.

OBJECTIVE: The pathogenesis of GDM and T2DM are closely related to various metals in vivo, and changes in the concentration of these metal exposures can lead to neuropathy through the DNA damage pathway caused by the accumulation of ROS. METHOD: Urine samples were analyzed for heavy metals and trace elements by ICP-MS, neurotransmitter metabolites by HPLC, 8-OH-dG by HPLC-MS and metabolomics by UPLC-MS. RESULT: Cd and Hg were risk factors for T2DM. There was a positive correlation between 8-OH-dG and neurotransmitter metabolites in both two populations. For GDM, the metabolite with the largest down-regulation effect was desloratadine and the largest up-regulation effect was D-glycine. That tyrosine and carbon metabolites were upregulated in the GDM population and downregulated in the T2DM population. CONCLUSION: The BMI, urinary Cd and Hg endo-exposure levels correlated with elevated blood glucose, and the latter may cause changes in the DNA damage marker 8-OH-dG in both study populations and trigger common responses to neurological alterations changes in the neurotransmitter. Tyrosine, carbonin metabolites, alanine, aspartate, and glutamate were signature metabolites that were altered in both study populations. These indicators and markers have clinical implications for monitoring and prevention of neurological injury in patients with GDM and T2DM.

What's the n? On sample size vs. subject number for brain-behavior neurophysiology and neuromodulation.

Neurophysiology and neuromodulation strive to understand the neural basis of behavior through a one-to-one correspondence between a particular brain and its behavioral output. Within this framework, studies with few subjects but sufficient sample sizes can be both rigorous and impactful.