Generative Modelling of Cortical Receptor Distributions from Cytoarchitectonic Images in the Macaque Brain.

Neurotransmitter receptor densities are relevant for understanding the molecular architecture of brain regions. Quantitative in vitro receptor autoradiography, has been introduced to map neurotransmitter receptor distributions of brain areas. However, it is very time and cost-intensive, which makes it challenging to obtain whole-brain distributions. At the same time, high-throughput light microscopy and 3D reconstructions have enabled high-resolution brain maps capturing measures of cell density across the whole human brain. Aiming to bridge gaps in receptor measurements for building detailed whole-brain atlases, we study the feasibility of predicting realistic neurotransmitter density distributions from cell-body stainings. Specifically, we utilize conditional Generative Adversarial Networks (cGANs) to predict the density distributions of the M2 receptor of acetylcholine and the kainate receptor for glutamate in the macaque monkey's primary visual (V1) and motor cortex (M1), based on light microscopic scans of cell-body stained sections. Our model is trained on corresponding patches from aligned consecutive sections that display cell-body and receptor distributions, ensuring a mapping between the two modalities. Evaluations of our cGANs, both qualitative and quantitative, show their capability to predict receptor densities from cell-body stained sections while maintaining cortical features such as laminar thickness and curvature. Our work underscores the feasibility of cross-modality image translation problems to address data gaps in multi-modal brain atlases.

Genes related to neurotransmitter receptors as potential biomarkers for Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a leading cause of dementia and is rapidly emerging as one of the costliest and most burdensome diseases. Neurotransmitter receptors play a vital role in many neuronal processes, primarily regulating signal inhibition within the brain to facilitate cell communication. OBJECTIVES: Our research aims to identify potential biomarkers associated with AD and how these biomarkers impact immune infiltration. METHODS: We extracted mRNA expression data from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were employed to identify hub genes as biomarkers in AD. The Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Gene Set Variation Analysis (GSVA) were used for functional enrichment. Furthermore, we examined 22 immune cell types infiltration using "CIBERSORT". RESULTS: In this study, we identified 70 neurotransmitter receptor genes showing differential expression in AD: 22 were up-regulated, and 48 were down-regulated. Functional analyses indicated these genes were involved in essential biochemical pathways, including G protein-coupled receptors, neurotransmitter receptor activity, and ion channel interactions. WGCNA generated three co-expression modules, with one demonstrating the strongest association with AD. Five key NRGs (HTR3C, HTR3E, ADRA2A, HTR3A, and ADRA1D) were identified using a combination of differential genes. These genes have better diagnostic value by ROC analysis. Immune infiltration analysis showed that these genes were closely associated with the levels of resting mast cells, activated natural killer (NK) cells, and plasma cells in AD compared to controls. CONCLUSION: Our study identified five NRGs (ADRA1D, ADRA2A, HTR3A, HTR3C, and HTR3E) with significant associations with AD. These findings may offer promising sights for further studies.

Decreased inter-hemispheric cooperation in major depressive disorder and its association with neurotransmitter profiles.

BACKGROUND: Inter-hemispheric cooperation is a prominent feature of the human brain, and previous neuroimaging studies have revealed aberrant inter-hemispheric cooperation patterns in patients with major depressive disorder (MDD). Typically, inter-hemispheric cooperation is examined by calculating the functional connectivity (FC) between each voxel in one hemisphere and its anatomical (structurally homotopic) counterpart in the opposite hemisphere. However, bilateral hemispheres are actually asymmetric in anatomy. METHODS: In the present study, we utilized connectivity between functionally homotopic voxels (CFH) to investigate abnormal inter-hemispheric cooperation in 96 MDD patients compared to 173 age- and sex-matched healthy controls (HCs). In addition, we analyzed the spatial correlations between abnormal CFH and the density maps of 13 neurotransmitter receptors and transporters. RESULTS: The CFH values in bilateral orbital frontal gyri and bilateral postcentral gyri were abnormally decreased in patients with MDD. Furthermore, these CFH abnormalities were correlated with clinical symptoms. In addition, the abnormal CFH pattern in MDD patients was spatially correlated with the distribution pattern of 5-HT1AR. LIMITATIONS: drug effect; the cross-sectional research design precludes causal inferences; the neurotransmitter atlases selected were constructed from healthy individuals rather than MDD patients. CONCLUSION: These findings characterized the abnormal inter-hemispheric cooperation in MDD using a novel method and the underlying neurotransmitter mechanism, which promotes our understanding of the pathophysiology of depression.

Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis.

Fibrotic diseases impose a major socioeconomic challenge on modern societies and have limited treatment options. Adropin, a peptide hormone encoded by the energy homeostasis-associated (ENHO) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize adropin as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent down-regulation of adropin/ENHO in skin across multiple cohorts of patients with SSc. The prototypical profibrotic cytokine TGFß reduced adropin/ENHO expression in a JNK-dependent manner. Restoration of adropin signaling by therapeutic application of bioactive adropin34-76 peptides in turn inhibited TGFß-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices. Knockdown of GPR19, an adropin receptor, abrogated the antifibrotic effects of adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of adropin34-76 were functionally linked to deactivation of GLI1-dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo, and ex vivo using cultured human dermal fibroblasts, a sclGvHD mouse model, and precision-cut human skin slices. ChIP-seq confirmed adropin34-76-induced changes in TGFß/GLI1 signaling. Our study characterizes the TGFß-induced down-regulation of adropin/ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling.

Expression of NMU and NMUR1 in tryptase-positive mast cells and PBLs in allergic rhinitis patients' nasal mucosa.

BACKGROUND: The neuropeptide U (NMU) has been proven to elicit the release of mediators from mast cells (MCs) through its receptor NMUR1 in allergic inflammatory models. However, little is known about the correlations between NMU and MCs in human allergic rhinitis (AR). OBJECTIVE: The objective of this study is to investigate the expressions of NMU and NMUR1 in the tryptase + MCs and the peripheral blood leukocytes (PBLs) in human nasal mucosa with AR. METHODS: Specimens of nasal mucosa from patients with AR (n = 10) and control patients without AR (n = 8) were collected and soaked in frozen tissue liquid solution (OCT) in tum. Cryostat sections were prepared for immunofluorescence staining. Tryptase was used as a marker to detect mast cells and other tryptase + immune cells. The expression of NMU and NMUR1 was respectively determined by double staining using a confocal microscope. RESULTS: Neither NMU nor NMUR1 were detected in the tryptase + mast cells in the human nasal mucosa. To our surprise, both NMU and NMUR1 were co-expressed with tryptase in the PBLs within peripheral blood vessels in AR and controls. CONCLUSION: Our findings showed that NMU could not influence human nasal tryptase + mast cells directly through NMUR1 in AR. The co-expression of both NMU and NMUR1 with tryptase in the PBLs provided new insight into the potential roles of NMU and tryptase in the circulation PBLs, and the infiltrated PBLs may promote nasal allergic inflammation by producing tryptase and NMU.

Fármacos glutamatérgicos en tratamiento de la esquizofrenia / Glutamatergic drugs for schizophrenia treatment

Actualmente se considera que tanto los síntomas positivos como en negativos de la esquizofrenia podrían deberse a una hipofunción glutamatérgica que tendría como consecuencia la alteración de la actividad de la neurotransmisión dopaminérgica. Concretamente, podría haber una disminución de la señalización glutamatérgica a nivel de los receptores NMDA, pero los agonistas directos de estos receptores no tienen utilidad clínica por ser inespecíficos y sus muchos efectos indeseables. Dados los problemas de falta de eficacia o de efectos secundarios que presentan los fármacos que actúan directamentesobre los receptores ionotrópicos y mGlu2-3, se han ensayado otros que actúan por otros mecanismos, especialmente indirectos, como es la administración co-agonistas de los receptores NMDA (glicina o D-serina), inhibidores del transportador de la glicina (sarcosina, Bitopertin), AMPAkinas (CX-516) y agonistas de los receptores mGlu5. Sin embargo, a pesar de los constantes fracasos, el enfoque glutamatérgico en el tratamiento de la esquizofrenia no está agotado y es necesario revisar todos los aspectos teóricos que relacionan estos mecanismos neuroquímicos con la compleja sintomatología esta patología hasta que logremos moléculas que sean realmente eficaces y que tengan un perfil de efectos secundarios aceptable

It is accepted that both positive and negative symptoms of schizophrenia may be due to hypofunction of glutamatergic pathways leading to altered dopaminergic neurotransmission activity. Specifically, there may be diminished glutamatergic signaling at the level of the NMDA receptors, but direct receptor agonists have no clinical utility due to their nonspecific actions and undesirable side effects. Given the problems of ineffectiveness or side effects of drugs that act directly on ionotropic and metabotropicmGlu2-3 receptors, clinical trials have been conducted with other drugs that have other mechanisms of action, especially indirect mechanisms, such as the co-administration of NMDA agonists (glycine or D-serine), glycine transporter inhibitors (sarcosine bitopertin), ampakines (CX-516), andmGlu5 receptor agonists. However, despite repeated failures, the glutamatergic approach to the treatment of schizophrenia has not been exhausted and all theoretical aspects that relate these complex neurochemical mechanisms with symptoms of schizophrenia should be reviewed until we find truly effective molecules with an acceptable side effect profile

Depresión: una mirada integrativa / Depression: an integrative view

En este trabajo se revisan las contribuciones de la literatura psicoanalítica al tema de la depresión, en particular los trabajos de Freud, Klein y Bibring y se plantean algunos subtipos de ella. Asimismo, siguiendo el concepto de las series complementarias de Freud, se sugiere una mirada amplia para evaluar los factores etiológicos del paciente depresivo. Se propone el tratamiento integral de la depresión que integre los aportes del psicoanálisis con la farmacoterapia

Overview of molecular mechanisms in chagasic cardioneuromyopathy and achalasia

Evidence accumulated by our investigations over the years give adequate proof for the existence of circulating antibodies in Chagas disease which bind to beta adrenergic and muscarinc cholinergic receptor of myocardium. The interaction of agonist-like antibodies with neurotransmitter receptors, triggers in the cells intracellular signal transductions that alter the physiological behaviour of the target organs. These events convert the normal cells into pathologically active cells. The interaction of antibodies with heart beta adrenergic and cholinergic receptors triggers physiologic, morphologic, enzymatic and molecular alterations, leading to tissue damage. The analysis of the prevalence and distribution of these antibodies reveals a strong association with cardiac and esophageal autonomic dysfunction in seropositive patients in comparison with those without alteration of the heart and esophagus autonomic disorders: therefore, the presence of these antibodies may partially explain the cardiomyoneurophathy and achalasia of Chagas disease, in which the sympathetic and parasympathetic systems are affected. The deposit of autoantibodies behaving like an agonist on neurotransmitter receptors, induceds desensitization and/or down regulation of the receptors. This is turn, could lead to a progressive blockade of neurotransmitter receptors, with sympathetic and parasympathetic dennervation, a phenomenon that has been described during the course of Chagas cardioneuropathy and achalasia. The clinical relevance of these findings is the demonstration, using biomolecules, of a strong association between the existence of circulating autoantibodies against peptides corresponding to the second extracellular loop of the human heart beta, adrenoceptor and M2 cholinoceptor in chagasic patients, and the presence of dysautonomic symptoms, making these autoantibodies a proper early marker of heart and digestive autonomic dysfunction.

Overview of molecular mechanisms in chagasic cardioneuromyopathy and achalasia

Evidence accumulated by our investigations over the years give adequate proof for the existence of circulating antibodies in Chagas disease which bind to beta adrenergic and muscarinc cholinergic receptor of myocardium. The interaction of agonist-like antibodies with neurotransmitter receptors, triggers in the cells intracellular signal transductions that alter the physiological behaviour of the target organs. These events convert the normal cells into pathologically active cells. The interaction of antibodies with heart beta adrenergic and cholinergic receptors triggers physiologic, morphologic, enzymatic and molecular alterations, leading to tissue damage. The analysis of the prevalence and distribution of these antibodies reveals a strong association with cardiac and esophageal autonomic dysfunction in seropositive patients in comparison with those without alteration of the heart and esophagus autonomic disorders: therefore, the presence of these antibodies may partially explain the cardiomyoneurophathy and achalasia of Chagas disease, in which the sympathetic and parasympathetic systems are affected. The deposit of autoantibodies behaving like an agonist on neurotransmitter receptors, induceds desensitization and/or down regulation of the receptors. This is turn, could lead to a progressive blockade of neurotransmitter receptors, with sympathetic and parasympathetic dennervation, a phenomenon that has been described during the course of Chagas cardioneuropathy and achalasia. The clinical relevance of these findings is the demonstration, using biomolecules, of a strong association between the existence of circulating autoantibodies against peptides corresponding to the second extracellular loop of the human heart beta, adrenoceptor and M2 cholinoceptor in chagasic patients, and the presence of dysautonomic symptoms, making these autoantibodies a proper early marker of heart and digestive autonomic dysfunction. (AU)

Characterization of the receptors responsible for the diphasic effect of bradykinin in rat duodenum

The response of the rat duodenum to bradykinin (BK) consists of relaxant and contractile components, which have been atributed to different receptor types. To characterize the receptor responsible for this diphasic response we studied the effects of BK analogues known to act on B1 or B2 receptors in other systems. DesArg**9-Leu**8-BK and Thi**5,**8DPhe**7-BK presented only relaxant and only contractile effects, respectively, whereas DArgOHyp883Thi**5,**8DPhe**7-BK was a potent antagonist of the relaxation (but not of the contraction) induced by BK. Our results show that the relaxant and contractile components of the rat duodenum's response to BK are due to B2 and B1 receptor subtypes, respectively

Teorias aminérgicas da depressäo

Revisa-se os conceitos mais recentes em relaçäo às teorias aminérgicas da depressäo. Verifica-se que as teorias propostas no início da década de 60 sofreram certas modificaçöes contextuais. Em primeiro lugar, deixou de se dar ênfase a uma alteraçäo isolada como causa dos sintomas depressivos, pela constataçäo de que, in vivo, a variaç äo na disponibilidade de um neurotransmissor também influi na disstribuiçäo e metabolismo dos demais. Em segundo, passou-se a valorizar a contribuiçäo dos receptores pré e pós-sinápticos das aminas cerebrais, responsabilizando-os pelo prazo de latência necessários aos efeitos terapêuticos dos antidepressores em geral. As alteraç öes na sensibilidade e número desses receptores têm sido amplamente estudadas, porém resultados controversos näo permitiram correlaç äo clínica até o presente

The role of sulfhydryl and disulfide groups of membrane proteins in electrical conduction and chemical transmission

Se discuten en este trabajo las reacciones químicas de los grupos sulfidrilo y bisulfuro y se revisa el uso de reactivos específicos para estos grupos como una herramienta en electrofisiología. Los cambios drásticos y específicos que se observan cuandos e aplican estos reactivos demuestran el papel crítico que juegan los grupos sulfidrilo y bisulfuro en los procesos de excitabilidad eléctrica, transmisión sináptica y, particularmente, en la función de los receptores post-sinápticos. Se ha demostrado que lso grupos sulfidrilo intervienen en el proceso de inactivación lenta de los canales de sodio dependientes de voltaje, en la activación de canales de calcio dependientes de voltaje y determinan la conductancia de los canales de sodio. Tanto los grupos sulfidrilo como los bisulfuro juegan un papel en la función de los receptores colinergicos nicotínicos de la sinapsis neuromuscular de los vertebrados y en la de los receptores glutaminérgicos de los invertebrados. La secreción de neurotransmisor por las terminaciones nerviosas presinápticas en estas uniones neuromusculares es también afectada por la modificación química de los grupos sulfidrilo y bisulfuro. Aunque en la mayoría de los casos no se ha esclarecido aun el sitio de acción de estos reactivos, los resultados de su utilización permiten una visión mas clara de las relaciones entre la estructura y la función de los canales y receptores existentes en las membranas excitables