Postsynaptic Receptors Research Articles

Extracellular vesicles from mesenchymal stem cells improve neuroinflammation and neurotransmission in hippocampus and cognitive impairment in rats with mild liver damage and minimal hepatic encephalopathy

BackgroundPatients with steatotic liver disease may show mild cognitive impairment. Rats with mild liver damage reproduce this cognitive impairment, which is mediated by neuroinflammation that alters glutamate neurotransmission in the hippocampus. Treatment with extracellular vesicles (EV) from mesenchymal stem cells (MSC) reduces neuroinflammation and improves cognitive impairment in different animal models of neurological diseases. TGFβ in these EVs seems to be involved in its beneficial effects. The aim of this work was to assess if MSCs-EVs may improve cognitive impairment in rats with mild liver damage and to analyze the underlying mechanisms, assessing the effects on hippocampal neuroinflammation and neurotransmission. We also aimed to analyze the role of TGFβ in the in vivo effects of MSCs-EVs.MethodsMale Wistar rats with CCl4-induced mild liver damage were treated with EVs from unmodified MSC or with EVs derived from TGFβ—silenced MSCs and its effects on cognitive function and on neuroinflammation and altered neurotransmission in the hippocampus were analysed.ResultsUnmodified MSC-EVs reversed microglia activation and TNFα content, restoring membrane expression of NR2 subunit of NMDA receptor and improved object location memory. In contrast, EVs derived from TGFβ—silenced MSCs did not induce these effects but reversed astrocyte activation, IL-1β content and altered GluA2 AMPA receptor subunit membrane expression leading to improvement of learning and working memory in the radial maze.ConclusionsEVs from MSCs with TGFβ silenced induce different effects on behavior, neuroinflammation and neurotransmitter receptors alterations than unmodified MSC-EVs, indicating that the modification of TGFβ in the MSC-EVs has a notable effect on the consequences of the treatment. This work shows that treatment with MSC-EVs improves learning and memory in a model of mild liver damage and MHE in rats, suggesting that MSC-EVs may be a good therapeutic option to reverse cognitive impairment in patients with steatotic liver disease.

Decreased neurotensin induces ovulatory dysfunction via the NTSR1/ERK/EGR1 axis in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the predominant cause of subfertility in reproductive-aged women; however, its pathophysiology remains unknown. Neurotensin (NTS) is a member of the gut-brain peptide family and is involved in ovulation; its relationship with PCOS is unclear. Here, we found that NTS expression in ovarian granulosa cells and follicular fluids was markedly decreased in patients with PCOS. In the in vitro culture of cumulus-oocyte complexes, the neurotensin receptor 1 (NTSR1) antagonist SR48692 blocked cumulus expansion and oocyte meiotic maturation by inhibiting metabolic cooperation and damaging the mitochondrial structure in oocytes and surrounding cumulus cells. Furthermore, the ERK1/2-early growth response 1 pathway was found to be a key downstream mediator of NTS/NTSR1 in the ovulatory process. Animal studies showed that in vivo injection of SR48692 in mice reduced ovulation efficiency and contributed to irregular estrus cycles and polycystic ovary morphology. By contrast, NTS partially ameliorated the ovarian abnormalities in mice with dehydroepiandrosterone-induced PCOS. Our findings highlighted the critical role of NTS reduction and consequent abnormal NTSR1 signaling in the ovulatory dysfunction of PCOS, suggesting a potential strategy for PCOS treatment.

Neuroreceptor Mapping in 2024.

Neuroreceptor mapping provides insights into neurotransmitter changes and receptor dynamics that improve the understanding of brain functions. This Viewpoint highlights the advancements in the development of novel radiotracers (imaging tools) and quantification of receptor dynamics based on presentations from the XIV International Symposium on Functional Neuroreceptor Mapping (NRM) of the Living Brain, 2024. The Viewpoint also emphasizes the applications of neuroreceptor mapping in clinical research and the latest technologies for imaging the brain with positron emission tomography (PET). The goal of the Viewpoint is to highlight an important community of researchers within the field of chemical neuroscience.

Drug Treatments for Neurodevelopmental Disorders: Targeting Signaling Pathways and Homeostasis.

Preclinical and clinical evidence support the notion that neurodevelopmental disorders (NDDs) are synaptic disorders, characterized by excitatory-inhibitory imbalance. Despite this, NDD drug development programs targeting glutamate or gamma-aminobutyric acid (GABA) receptors have been largely unsuccessful. Nonetheless, recent drug trials in Rett syndrome (RTT), fragile X syndrome (FXS), and other NDDs targeting other mechanisms have met their endpoints. The purpose of this review is to identify the basis of these successful studies. Despite increasing evidence of disruption in synaptic homeostasis, most genetic variants associated with NDDs implicate proteins involved in cell regulation and not in neurotransmission. Metabolic processes, in particular mitochondrial function, appear to play a role in NDD pathophysiology. NDDs are also characterized by distinctive cell signaling abnormalities, which link cellular and synaptic homeostasis. Recent successful trials in NDDs, including those of trofinetide, the first drug specifically approved for one of these disorders (i.e., RTT), implicate the targeting of downstream processes (i.e., signaling pathways) rather than neurotransmitter receptors. Recent positive drug studies in NDDs and their underlying mechanisms, in conjunction with new knowledge on the pathophysiology of these disorders, support the concept that targeting signaling and cellular and synaptic homeostasis may be a preferred approach for ameliorating synaptic abnormalities in many NDDs.

Enhanced prefrontal nicotinic signaling as evidence of active compensation in Alzheimer’s disease models

BackgroundCognitive reserve allows for resilience to neuropathology, potentially through active compensation. Here, we examine ex vivo electrophysiological evidence for active compensation in Alzheimer’s disease (AD) focusing on the cholinergic innervation of layer 6 in prefrontal cortex. Cholinergic pathways are vulnerable to neuropathology in AD and its preclinical models, and their modulation of deep layer prefrontal cortex is essential for attention and executive function.MethodsWe functionally interrogated cholinergic modulation of prefrontal layer 6 pyramidal neurons in two preclinical models: a compound transgenic AD mouse model that permits optogenetically-triggered release of endogenous acetylcholine and a transgenic AD rat model that closely recapitulates the human trajectory of AD. We then tested the impact of therapeutic interventions to further amplify the compensated responses and preserve the typical kinetic profile of cholinergic signaling.ResultsIn two AD models, we found potentially compensatory upregulation of functional cholinergic responses above non-transgenic controls after onset of pathology. To identify the locus of this enhanced cholinergic signal, we dissected key pre- and post-synaptic components with pharmacological strategies. We identified a significant and selective increase in post-synaptic nicotinic receptor signalling on prefrontal cortical neurons. To probe the additional impact of therapeutic intervention on the adapted circuit, we tested cholinergic and nicotinic-selective pro-cognitive treatments. Inhibition of acetylcholinesterase further enhanced endogenous cholinergic responses but greatly distorted their kinetics. Positive allosteric modulation of nicotinic receptors, by contrast, enhanced endogenous cholinergic responses and retained their rapid kinetics.ConclusionsWe demonstrate that functional nicotinic upregulation occurs within the prefrontal cortex in two AD models. Promisingly, this nicotinic signal can be further enhanced while preserving its rapid kinetic signature. Taken together, our work suggests that compensatory mechanisms are active within the prefrontal cortex that can be harnessed by nicotinic receptor positive allosteric modulation, highlighting a new direction for cognitive treatment in AD neuropathology.

How antipsychotics work in schizophrenia: a primer on mechanisms.

Antipsychotics effective for schizophrenia approved prior to 2024 shared the common mechanism of postsynaptic dopamine D2 receptor antagonism or partial agonism. Positive psychosis symptoms correlate with excessive presynaptic dopamine turnover and release, yet this postsynaptic mechanism improved positive symptoms only in some patients, and with concomitant risk for off-target motor and endocrine adverse effects; moreover, these agents showed no benefit for negative symptoms and cognitive dysfunction. The sole exception was data supporting cariprazine's superiority to risperidone for negative symptoms. The muscarinic M1/M4 agonist xanomeline was approved in September 2024 and represents the first of a new antipsychotic class. This novel mechanism improves positive symptoms by reducing presynaptic dopamine release. Xanomeline also lacks any D2 receptor affinity and is not associated with motor or endocrine side effects. Of importance, xanomeline treated patients with higher baseline levels of cognitive dysfunction in clinical trials data saw cognitive improvement, a finding likely related to stimulation of muscarinic M1 receptors. Treatment resistance is seen in one-third of schizophrenia patients. These individuals do not have dopamine dysfunction underlying their positive symptoms, and therefore show limited response to antipsychotics that target dopamine neurotransmission. Clozapine remains the only medication with proven efficacy for resistant schizophrenia, and with unique benefits for persistent impulsive aggression and suicidality. New molecules are being studied to address the array of positive, negative and cognitive symptoms of schizophrenia; however, until their approval, clinicians must be familiar with currently available agents and be adept at prescribing clozapine.

A Single-Center Pilot Study of Therapeutic Apheresis in Patients with Severe Post-COVID Syndrome.

After the COVID-19 pandemic, many patients have reported chronic fatigue and severe post-exertional malaise, with symptoms similar to those of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The accumulation of agonistic receptor autoantibodies targeting beta-adrenergic (β1 and β2) and muscarinic (M3 and M4) neurotransmitter receptors may play a crucial role in the pathomechanism of both ME/CFS and post-COVID conditions. Therapeutic apheresis has been suggested as an effective treatment option for alleviating and mitigating symptoms in this desperate group of patients. In this single-center pilot study, we analyzed autoantibodies in a cohort of 20 post-COVID patients before and after therapeutic apheresis. Apheresis resulted in a decline of β1 or β2 adrenergic receptor antibodies in all patients. Additionally, the majority of patients experienced a concurrent reduction in symptoms such as fatigue, physical activity restrictions, myalgia, post-exertional malaise, and concentration disorders. This study clearly demonstrates an association between autoantibodies and the clinical improvement of post-COVID patients. Even if future sham-controlled trials do not show a positive outcome, extracorporeal apheresis may still be valuable for this patient group by temporarily improving microperfusion and symptoms. Success in restoring patients to work and normal life, as observed in many individuals after therapeutic apheresis, should be recognized. Therefore, we believe that extracorporeal therapeutic apheresis, as part of a multimodal treatment, should be considered an early intervention for postinfectious syndromes in selected patients.

Medical Treatment of Hypercortisolism with Relacorilant: Final Results of the Phase 3 GRACE Study

Diabetic cardiomyopathy (DCM) is a cardiometabolic syndrome, manifested by ventricular diastolic or systolic dysfunction which occurs in approximately 12% of diabetic patients. Diabetes perpetuates the development of microvascular complications that can exacerbate cardiovascular pathologies. Understanding the common molecular targets underlying these two conditions is important for designing effective interventions that can address diabetes and related complications simultaneously. Herein, we aim to investigate the underlying network of key modules associated with diabetic cardiomyopathy. In current study, microarray gene expression profiles of diabetic and cardiomyopathy patients possessing accession number (GSE30122 and GSE20966) and (GSE89714, GSE3586, and GSE1145) were retrieved from Gene Expression Omnibus (GEO) database to explore key modulators. The differentially expressed genes (DEGs) were analyzed via GEO2R tool, based on the cut off criteria (p ≤ 0.05) and log2(FC)>|±1|. 37 overlapped DEGs were identified which then subjected to miRNA target prediction, protein-protein interaction (PPI) network construction and module screening via TargetScan, ShinyGO, STRING, and Cytoscape respectively, to screen hub genes as potential targets. Functional gene enrichment analysis identified enrichment of DEGs in heart contraction, apoptosis, cytokines signaling, beta adrenergic signaling and GPCR neurotransmitter receptor activity. The miRNA-mRNA regulatory network identified 9 hub genes, including ADRB1, TGFB2, RAP2A, CALD1, WIPF1, ATP10a, AKAP1, NR4A3, EXT1 and 4 hub miRNAs including miR-199-5, miR-200a, mir141-3, and miR-19-3p based on their degree of connectivity and centrality within the network. Conclusively, our analysis unveiled hub genes and miRNAs associated with diabetes-linked cardiomyopathy that might considered as biomarkers and offer a reliable tool for developing effective therapeutic strategies in future.

Comparative genomics analyses reveal selection on neuronal and cuticular hydrocarbon genes is associated with aggression in ants (Hymenoptera: Formicidae)

Abstract Aggression is an essential component of survival and fitness, although the expression of aggression behaviors can also carry fitness costs. As a result, aggressive behaviors vary significantly across animals and are likely acted on by natural selection to produce this variation. Aggression, and associated traits like nestmate discrimination, both complex traits, have well studied genetic components, with links to genes involved in processes like neuronal function, metabolism, and hormone and cuticular hydrocarbon (CHC) production and reception. However, whether and how natural selection acts on these genes to produce variation across species is not fully understood. Using a comparative genomics approach, we analyzed natural selection in ants (Hymenoptera: Formicidae) with candidate genes previously linked to these traits. We find that aggression is associated with shifts in selection intensity, including positive selection on neurotransmitter receptors, and that ants with low levels of nestmate discrimination experience positive or relaxed selection on several CHC genes. Interestingly, we find that most candidate genes analyzed experience positive selection across ants, regardless of aggression level or discrimination ability. Our results shed new light on the means by which natural selection may act to produce variation in aggression across the ants.

Autism-Linked Mutations in α2δ-1 and α2δ-3 Reduce Protein Membrane Expression but Affect Neither Calcium Channels nor Trans-Synaptic Signaling

Background: α2δ proteins regulate membrane trafficking and biophysical properties of voltage-gated calcium channels. Moreover, they modulate axonal wiring, synapse formation, and trans-synaptic signaling. Several rare missense variants in CACNA2D1 (coding for α2δ-1) and CACNA2D3 (coding for α2δ-3) genes were identified in patients with autism spectrum disorder (ASD). However, the pathogenicity of these variants is not known, and the molecular mechanism by which α2δ proteins may contribute to the pathophysiology of autism is, as of today, not understood. Therefore, in this study we functionally characterized two heterozygous missense variants in α2δ-1 (p.R351T) and α2δ-3 (p.A275T), previously identified in patients with ASD. Methods: Electrophysiological recordings in transfected tsA201 cells were used to study specific channel-dependent functions of mutated α2δ proteins. Membrane expression, presynaptic targeting, and trans-synaptic signaling of mutated α2δ proteins were studied upon expression in murine cultured hippocampal neurons. Results: Homologous expression of both mutated α2δ proteins revealed a strongly reduced membrane expression and synaptic localization compared to the corresponding wild type α2δ proteins. Moreover, the A275T mutation in α2δ-3 resulted in an altered glycosylation pattern upon heterologous expression. However, neither of the mutations compromised the biophysical properties of postsynaptic L-type (CaV1.2 and CaV1.3) and presynaptic P/Q-type (CaV2.1) channels when co-expressed in tsA201 cells. Furthermore, presynaptic expression of p.R351T in the α2δ-1 splice variant lacking exon 23 did not affect trans-synaptic signaling to postsynaptic GABAA receptors. Conclusions: Our data provide evidence that the pathophysiological mechanisms of ASD-causing mutations of α2δ proteins may not involve their classical channel-dependent and trans-synaptic functions. Alternatively, these mutations may induce subtle changes in synapse formation or neuronal network function, highlighting the need for future α2δ protein-linked disease models.

Changes in hippocampal volume, 5-HT4 receptor binding, and verbal memory over the course of antidepressant treatment in major depressive disorder

Serotonin reuptake inhibitors have been reported to increase hippocampal volume and improve memory function in patients with Major depressive disorder (MDD). The postsynaptic 5-HT4 receptor (5-HT4R) is involved in hippocampal development, familial risk for depression and depressive pathology. In an open-label trial with 91 patients (72% female, mean 27.2 years) with MDD, we investigated the relation between changes in hippocampal volume, 5-HT4R, and verbal memory during 12 weeks treatment with 10–20 mg escitalopram. Depression severity, verbal memory, MRI-determined hippocampus volume and PET-determined 5-HT4R were measured pretreatment. Forty-three patients were rescanned at week 8. HAMD17 was reassessed at week 8 and together with verbal memory at week 12. We used mixed-effects models and linear regressions. We estimated a 27 mm3 (p = 0.086) reduction in mean hippocampus volume over the course of eight weeks. In patients clinically responding to treatment, we estimated a 45 mm3 reduction (p = 0.019), 8 mm3 increase in non-responders (p = 0.78), and a 52 mm3 group difference (p = 0.12). Hippocampal 5-HT4 receptor binding before treatment and at week eight was negatively associated with hippocampal volume in females, regardless of treatment response (p-values≤0.006). However, no clear evidence for an association in males or sex interaction could be established (p-values≥0.16). Although the hippocampus volume did not increase with treatment, we found a decrease in clinically responsive patients. Our findings suggest an association between 5-HT4R signalling and changes in hippocampal volume in females with MDD during antidepressant treatment, highlighting the need for further investigation into the role of serotonergic mechanisms in hippocampal plasticity.

The Neural Palette of Heme: Altered Heme Homeostasis Underlies Defective Neurotransmission, Increased Oxidative Stress, and Disease Pathogenesis

Heme, a complex iron-containing molecule, is traditionally recognized for its pivotal role in oxygen transport and cellular respiration. However, emerging research has illuminated its multifaceted functions in the nervous system, extending beyond its canonical roles. This review delves into the diverse roles of heme in the nervous system, highlighting its involvement in neural development, neurotransmission, and neuroprotection. We discuss the molecular mechanisms by which heme modulates neuronal activity and synaptic plasticity, emphasizing its influence on ion channels and neurotransmitter receptors. Additionally, the review explores the potential neuroprotective properties of heme, examining its role in mitigating oxidative stress, including mitochondrial oxidative stress, and its implications in neurodegenerative diseases. Furthermore, we address the pathological consequences of heme dysregulation, linking it to conditions such as Alzheimer’s disease, Parkinson’s disease, and traumatic brain injuries. By providing a comprehensive overview of heme’s multifunctional roles in the nervous system, this review underscores its significance as a potential therapeutic target and diagnostic biomarker for various neurological disorders.

Reduced striatal M4-cholinergic signaling following dopamine loss contributes to parkinsonian and l-DOPA-induced dyskinetic behaviors.

A dynamic equilibrium between dopamine and acetylcholine (ACh) is essential for striatal circuitry and motor function, as imbalances are associated with Parkinson's disease (PD) and levodopa-induced dyskinesia (LID). Conventional theories posit that cholinergic signaling is pathologically elevated in PD as a result of increased ACh release, which contributes to motor deficits. However, using approaches to measure receptor-mediated signaling, we found that, rather than the predicted enhancement, the strength of cholinergic transmission at muscarinic M4 receptor synapses on direct pathway medium spiny neurons was decreased in dopamine-depleted mice. This adaptation was due to a reduced postsynaptic M4 receptor function, resulting from down-regulated receptors and downstream signaling. Restoring M4 transmission unexpectedly led to a partial alleviation of motor deficits and LID dyskinetic behavior, revealing an unexpected prokinetic effect in addition to the canonical antikinetic role of M4 receptors. These findings indicate that decreased M4 function differentially contributes to parkinsonian and LID pathophysiology, representing a promising target for therapeutic intervention.

The Mechanism of Propofol in Treating Depression-like Behaviors Based on Network Pharmacology and Experimental Validation

Objective: To explore the potential mechanism of propofol in improving antidepressant-like behavior through network pharmacology and animal experimental validation, providing theoretical and experimental support for the development of novel antidepressant drugs based on propofol. Methods: 1. The targets of propofol and the disease targets of depression were screened through Swiss Target prediction, Super-pred, SEA, Drugbank, CTD, GeneCards, OMIM, and TTD databases. A protein-protein interaction (PPI) network was constructed, and the core targets were screened and visualized using CytoScape 3.10.2 software. Additionally, GO and KEGG enrichment analyses of the intersection targets were performed using the Metascape database. 2. Thirty male C57BL/6 mice were randomly divided into the CON group, LH model group, and PRO treatment group, with 10 mice in each group. The sucrose preference test, forced swim test, and tail suspension test were conducted to determine whether the depression model was successfully established and to assess the improvement effect of propofol on antidepressant-like behavior. 3. The pathological morphological changes of hippocampal neurons in the three groups of mice were observed through HE staining experiments. The expression of mGluR5 protein in the hippocampus was analyzed by Western blot. Results: 1. Network pharmacology analysis indicated that propofol may exert antidepressant effects by acting on core genes such as ALB, ESR1, NFKB1, HSP90AB1, and EGFR. These core target genes were mainly enriched in biological processes such as synaptic transmission and membrane potential regulation; they involved cellular components such as GABA receptor complexes and synaptic membranes; and they included molecular functions such as neurotransmitter receptor activity. Additionally, propofol may exert antidepressant effects through signaling pathways such as neuroactive ligand-receptor interaction, morphine addiction, and GABAergic synapse. 2. Compared with the CON group, the sucrose preference rate of mice in the LH model group significantly decreased, while the immobility time in the forced swim test and tail suspension test significantly increased. Compared with the LH model group, the sucrose preference rate of mice in the PRO treatment group significantly increased, and the immobility time significantly decreased. 3. The HE results showed that compared with the CON group, the number of neurons in the LH group decreased, with loose arrangement, pycnotic and deeply stained nuclei with blurred boundaries. However, the number of necrotic neurons in the PRO group significantly decreased. The Western blot results showed that compared with the CON group, the expression level of mGluR5 protein in the LH model group significantly increased, while it significantly decreased in the PRO treatment group compared with the LH model group. Conclusion: Propofol may exert antidepressant effects by regulating the expression of mGluR5, improving antidepressant-like behavior, and reducing hippocampal neuronal necrosis.

Model of the HVC neural network as a song motor in zebra finch.

The nucleus HVC within the avian song system produces crystalized instructions which lead to precise, learned vocalization in zebra finches (Taeniopygia guttata). This paper proposes a model of the HVC neural network based on the physiological properties of individual HVC neurons, their synaptic interactions calibrated by experimental measurements, as well as the synaptic signal into this region which triggers song production. This neural network model comprises of two major neural populations in this area: neurons projecting to the nucleus RA and interneurons. Each single neuron model of HVCRA is constructed with conductance-based ion currents of fast Na+ and K+ and a leak channel, while the interneuron model includes extra transient Ca2+ current and hyperpolarization-activated inward current. The synaptic dynamics is formed with simulated delivered neurotransmitter pulses from presynaptic cells and neurotransmitter receptor opening rates of postsynaptic neurons. We show that this network model qualitatively exhibits observed electrophysiological behaviors of neurons independent or in the network, as well as the importance of bidirectional interactions between the HVCRA neuron and the HVCI neuron. We also simulate the pulse input from A11 neuron group to HVC. This signal successfully suppresses the interneuron, which leads to sequential firing of projection neurons that matches measured burst onset, duration, and spike quantities during the zebra finch motif. The result provides a biophysically based model characterizing the dynamics and functions of the HVC neural network as a song motor, and offers a reference for synaptic coupling strength in the avian brain.

Regional homogeneity patterns reveal the genetic and neurobiological basis of State-Trait Anxiety

ObjectiveState anxiety and trait anxiety are differentially mapped in brain function. However, the genetic and neurobiological basis of anxiety-related functional changes remain largely unknown.MethodsParticipants aged 18–30 from the community underwent resting-state fMRI and were assessed with the State-Trait Anxiety Inventory. Using a general linear regression model, we analyzed the effects of state and trait anxiety, as well as their sum and difference (delta), on regional homogeneity (ReHo) in cortical areas. ReHo patterns denote the spatial distribution of ReHo associated with anxiety scores. We further explored the spatial correlations between ReHo patterns and neuromaps, including gene expression, neurotransmitter receptor density, myelination, and functional connectivity gradients, to elucidate the genetic and molecular substrates of these ReHo patterns.ResultsOur findings demonstrated robust spatial correlations between whole-brain ReHo patterns for state and trait anxiety, with trait anxiety and the delta value exhibiting stronger network correlations, notably in the dorsal attention, salience, visual, and sensorimotor networks. Genes highly correlated with ReHo patterns exhibited unique spatiotemporal expression patterns, involvement in oxidative stress, metabolism, and response to stimuli, and were expressed in specific cell types. Furthermore, ReHo patterns significantly correlated with neuromaps of neurotransmitter receptor density, myelination, and functional connectivity gradients.ConclusionsThe ReHo patterns associated with anxiety may be driven by genetic and neurobiological traits. Our findings contribute to a deeper understanding of the pathogenesis of anxiety from a genetic and molecular perspective.

Sex differences of negative emotions in adults and infants along the prefrontal-amygdaloid brain pathway

The neural basis of sex-related differences in processing negative emotions remains poorly understood. The amygdala-related fiber pathways serve as the neuroanatomical foundation for emotion processing. However, the precise sex-related variations within these pathways remain largely elusive. Using diffusion magnetic resonance imaging data from 418 healthy individuals, we identified sex differences in white-matter microstructures of the striato-amygdaloid-prefrontal tracts, particularly the amygdala (Amy)-medial prefrontal cortex (mPFC) pathway. These differences were associated with various neurobiological factors, including pain-related negative emotions, pain sensitivity, neurotransmitter receptors, and gene expressions in the human brain. Our findings suggested that the Amy-mPFC pathway may serve as a neuroanatomical foundation for sex-specific negative emotion processing, driven by specific genetic and neurotransmitter profiles. Notably, we also found similar sex differences in this pathway in an infant imaging dataset, hinting at its developmental significance as a precursor to sex differences in adulthood. These findings underscore the importance of the striato-amygdaloid-prefrontal tracts in sex-related differences in processing negative emotions. This may enhance our understanding of sex-specific emotion regulation and potentially inform future research on strategies for preventing and diagnosing emotional regulation disorders across sexes.

Proteomic profiling of gliomas unveils immune and metabolism-driven subtypes with implications for anti-nucleotide metabolism therapy

Gliomas exhibit high heterogeneity and poor prognosis. Despite substantial progress has been made at the genomic and transcriptomic levels, comprehensive proteomic characterization and its implications remain largely unexplored. In this study, we perform proteomic profiling of gliomas using 343 formalin-fixed and paraffin-embedded tumor samples and 53 normal-appearing brain samples from 188 patients, integrating these data with genomic panel information and clinical outcomes. The proteomic analysis uncovers two distinct subgroups: Subgroup 1, the metabolic neural subgroup, enriched in metabolic enzymes and neurotransmitter receptor proteins, and Subgroup 2, the immune subgroup, marked by upregulation of immune and inflammatory proteins. These proteomic subgroups show significant differences in prognosis, tumorigenesis, microenvironment dysregulation, and potential therapeutics, highlighting the critical roles of metabolic and immune processes in glioma biology and patient outcomes. Through a detailed investigation of metabolic pathways guided by our proteomic findings, dihydropyrimidine dehydrogenase (DPYD) and thymidine phosphorylase (TYMP) emerge as potential prognostic biomarkers linked to the reprogramming of nucleotide metabolism. Functional validation in patient-derived glioma stem cells and animal models highlights nucleotide metabolism as a promising therapy target for gliomas. This integrated multi-omics analysis introduces a proteomic classification for gliomas and identifies DPYD and TYMP as key metabolic biomarkers, offering insights into glioma pathogenesis and potential treatment strategies.

Maintenance of a central high frequency synapse in the absence of synaptic activity.

Activity has long been considered essential for circuit formation and maintenance. This view has recently been challenged by proper synaptogenesis and only mildly affected synapse maintenance in the absence of synaptic activity in forebrain neurons. Here, we investigated whether synaptic activity is necessary for the development and maintenance of the calyx of Held synapse. This giant synapse located in the auditory brainstem is highly specialized to maintain high frequency, high-fidelity synaptic transmission for prolonged times and thus shows particularly high synaptic activity. We expressed the protease tetanus toxin light chain (TeNT) exclusively in bushy cells of the ventral cochlear nucleus (VCN) of juvenile mice. Since globular bushy cells give rise to the calyx of Held, expression of TeNT in these cells specifically abolished synaptic transmission at the calyx without impairing general functionality of the central auditory system. Calyces lacked synaptic activity after two weeks of TeNT expression. However, this did not lead to major changes in presynaptic morphology, the number of active zones (AZs) or the composition of postsynaptic AMPA-type glutamate receptors (GluAs). Moreover, the fenestration of the calyx of Held, a hallmark of structural maturation, occurred normally. We thus show that the maintenance of a specialized high frequency synapse in the auditory brainstem occurs in a hardwired, probably genetically encoded, manner with little dependence on synaptic activity.

A novel androgen-independent radiotracer with dual targeting of NTSR1 and PSMA for PET/CT imaging of prostate cancer

A substantial proportion of patients with prostate cancer (PCa) develop treatment resistance or mortality after androgen deprivation therapy (ADT). Current methods for identifying and locating recurrent lesions using prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET) imaging, which relies on androgen levels, often result in diagnostic delays. Therefore, the development of an androgen-independent radiotracer is critical for the early identification of recurrent lesions. The neurotensin receptor 1 (NTSR1) is highly expressed in androgen-independent PCa lesions. Here, we synthesized a bispecific ligand targeting PSMA and NTSR1 by solid-phase peptide synthesis and formulated a68Ga-labeled bispecific radiotracer, ([68Ga]Ga-NT-PSMA). This radiotracer exhibited a high radiochemical yield (71.27 % ± 1.58 %) and demonstrated an affinity for NTSR1 (39.32 ± 2.98 nM) and PSMA (63.47 ± 5.14 nM) in vitro. Small animal PET imaging showed comparable uptake of [68Ga]Ga-NT-PSMA and the monomeric radiotracer [68Ga]Ga-DOTA-NT20.3 in mice bearing androgen-independent PC3 (3.64 ± 0.49 %ID/g vs. 5.60 ± 1.42 %ID/g, nonsignificant [ns]) and DU145 tumors (2.49 ± 0.20 %ID/g vs. 2.34 ± 0.18 %ID/g, ns) at 90 min post-injection. In androgen-dependent 22Rv1 xenografts, [68Ga]Ga-NT-PSMA uptake was lower (1.94 ± 0.29 %ID/g) than [68Ga]Ga-PSMA-11 (3.94 ± 0.26 %ID/g, P < 0.001). Nevertheless, [68Ga]Ga-NT-PSMA effectively imaged all three xenograft types with high contrast, an achievement not possible with monomeric radiotracers alone. These results indicate that imaging with [68Ga]Ga-NT-PSMA is independent of the androgen dependence of the model, highlighting its potential as a promising nuclear medicine diagnostic tool for the early identification and localization of castration-resistant PCa lesions.