Alzheimer's disease risk gene CD2AP is a dose-sensitive determinant of synaptic structure and plasticity.

CD2-Associated protein (CD2AP) is a candidate susceptibility gene for Alzheimer's disease, but its role in the mammalian central nervous system remains largely unknown. We show that CD2AP protein is broadly expressed in the adult mouse brain, including within cortical and hippocampal neurons, where it is detected at pre-synaptic terminals. Deletion of Cd2ap altered dendritic branching and spine density, and impaired ubiquitin-proteasome system activity. Moreover, in mice harboring either one or two copies of a germline Cd2ap null allele, we noted increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release. Whereas conditional Cd2ap knockout in the brain revealed no gross behavioral deficits in either 3.5- or 12-month-old mice, Cd2ap heterozygous mice demonstrated subtle impairments in discrimination learning using a touchscreen task. Based on unbiased proteomics, partial or complete loss of Cd2ap triggered perturbation of proteins with roles in protein folding, lipid metabolism, proteostasis, and synaptic function. Overall, our results reveal conserved, dose-sensitive requirements for CD2AP in the maintenance of neuronal structure and function, including synaptic homeostasis and plasticity, and inform our understanding of possible cell-type specific mechanisms in Alzheimer's Disease.

WITHDRAWN: Exploring The Diverse Therapeutic Potentials of Synthetic Analogues of Keto-terpenoids (+) Carvone: A Future Scaffold

The article has been withdrawn at the request of the authors of the journal "Central Nervous System Agents in Medicinal Chemistry" as a conflict has arisen among the authors in adding another author at the later stage of publicationBentham Science apologizes to the readers of the journal for any inconvenience this may have caused.The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Integrated electrophysiological and genomic profiles of single cells reveal spiking tumor cells in human glioma.

Prior studies have described the complex interplay that exists between glioma cells and neurons, however, the electrophysiological properties endogenous to tumor cells remain obscure. To address this, we employed Patch-sequencing on human glioma specimens and found that one third of patched cells in IDH mutant (IDH mut ) tumors demonstrate properties of both neurons and glia by firing single, short action potentials. To define these hybrid cells (HCs) and discern if they are tumor in origin, we developed a computational tool, Single Cell Rule Association Mining (SCRAM), to annotate each cell individually. SCRAM revealed that HCs represent tumor and non-tumor cells that feature GABAergic neuron and oligodendrocyte precursor cell signatures. These studies are the first to characterize the combined electrophysiological and molecular properties of human glioma cells and describe a new cell type in human glioma with unique electrophysiological and transcriptomic properties that are likely also present in the non-tumor mammalian brain.

Integrated electrophysiological and genomic profiles of single cells reveal spiking tumor cells in human glioma.

Prior studies have described the complex interplay that exists between glioma cells and neurons; however, the electrophysiological properties endogenous to glioma cells remain obscure. To address this, we employed Patch-sequencing (Patch-seq) on human glioma specimens and found that one-third of patched cells in IDH mutant (IDHmut) tumors demonstrate properties of both neurons and glia. To define these hybrid cells (HCs), which fire single, short action potentials, and discern if they are of tumoral origin, we developed the single cell rule association mining (SCRAM) computational tool to annotate each cell individually. SCRAM revealed that HCs possess select features of GABAergic neurons and oligodendrocyte precursor cells, and include both tumor and non-tumor cells. These studies characterize the combined electrophysiological and molecular properties of human glioma cells and describe a cell type in human glioma with unique electrophysiological and transcriptomic properties that may also exist in the non-tumor brain.

Cholinergic Basal Forebrain Connectivity to the Basolateral Amygdala Modulates Food Intake.

Obesity results from excessive caloric input associated with overeating and presents a major public health challenge. The hypothalamus has received significant attention for its role in governing feeding behavior and body weight homeostasis. However, extrahypothalamic brain circuits also regulate appetite and consumption by altering sensory perception, motivation, and reward. We recently discovered a population of basal forebrain cholinergic (BFc) neurons that regulate appetite suppression. Through viral tracing methods in the mouse model, we found that BFc neurons densely innervate the basolateral amygdala (BLA), a limbic structure involved in motivated behaviors. Using channelrhodopsin-assisted circuit mapping, we identified cholinergic responses in BLA neurons following BFc circuit manipulations. Furthermore, in vivo acetylcholine sensor and genetically encoded calcium indicator imaging within the BLA (using GACh3 and GCaMP, respectively) revealed selective response patterns of activity during feeding. Finally, through optogenetic manipulations in vivo, we found that increased cholinergic signaling from the BFc to the BLA suppresses appetite and food intake. Together, these data support a model in which cholinergic signaling from the BFc to the BLA directly influences appetite and feeding behavior.

Neural landscape is associated with functional outcomes in irradiated patients with oropharyngeal squamous cell carcinoma.

The incidence of human papilloma virus-mediated oropharyngeal squamous cell carcinoma (OPSCC) has increased over the past 40 years, particularly among young individuals with a favorable prognosis; however, current therapy often leads to unfortunate side effects, such as dysphagia. Despite the emphasis on dysphagia in previous studies, there is an important research gap in understanding the correlation between neuronal changes and patient-reported and functional outcomes in patients with OPSCC. To address this issue, we examined pathologic tissue samples from patients with OPSCC using multiplex immunofluorescence staining and machine learning to correlate tumor-associated neuronal changes with prospectively collected patient-reported and functional outcomes. We found that tumor enrichment of adrenergic (TH+) and CGRP+ sensory-afferent nerves correlated with poorer swallowing outcomes. Functional electromyography recordings showed correlations between growing (GAP43+) and immature cholinergic (ChAT+DCX+) nerves and denervation patterns in survivors of OPSCC. A murine model of radiation-induced dysphagia further confirmed that immature cholinergic and CGRP+ nerves were correlated with impaired swallowing. Preclinical interventional studies also supported the independent contributions of CGRP+ and cholinergic (ChAT+) nerves to dysphagia in treated mouse models of OPSCC. Our results suggest that CGRP+ and ChAT+ neuronal signaling play distinct roles in tumor- and radiation-induced dysphagia in OPSCC and offer a comprehensive dataset on the neural landscape of OPSCC. These insights may guide early interventions for swallow preservation and the repurposing of neurology-related drugs, such as CGRP blockers, in clinical oncology and survivorship.

Advancement in Epilepsy Pharmacotherapy: An Insight into the Pharmacophoric Approaches of Recent Drugs.

Epilepsy is the most general, extensive, and severe neurological disorder, affecting more than 50 million individuals globally. Initially, conventional medicines and simple salts like potassium bromide were employed as antiepileptic medication candidates. Nowadays, many anticonvulsant drugs have been discovered as first-generation and second-generation and newer drugs and are still in development phases. The pharmacophore-based drug design process includes pharmacophore modeling and validation, pharmacophore-based virtual screening, virtual hits profiling, and lead identification with special reference. This comprehensive article reviews recently developed anticonvulsant derivatives on the basis of pharmacophoric approaches. A literature survey was performed using various search engines like Google Scholar, Scopus, Sci Finder, ScienceDirect, Science gate, Scilit, PubMed, NINDS database of NIH, Bentham Sciences, and other online and print journals and scientific databases. The presented review discusses such kinds of newer drugs that are in the market as well as in clinical trial phases. Detailed outcomes of pharmacophoric modeling have been discussed for newly derived derivatives like targets involved in Epilepsy, lead molecules etc., for the treatment of epilepsy. This exhaustive review will assist the researchers in the further development of potential antiepileptic agents.

Advancements in the Quest to Map, Monitor, and Manipulate Neural Circuitry.

Neural circuits and the cells that comprise them represent the functional units of the brain. Circuits relay and process sensory information, maintain homeostasis, drive behaviors, and facilitate cognitive functions such as learning and memory. Creating a functionally-precise map of the mammalian brain requires anatomically tracing neural circuits, monitoring their activity patterns, and manipulating their activity to infer function. Advancements in cell-type-specific genetic tools allow interrogation of neural circuits with increased precision. This review provides a broad overview of recombination-based and activity-driven genetic targeting approaches, contemporary viral tracing strategies, electrophysiological recording methods, newly developed calcium, and voltage indicators, and neurotransmitter/neuropeptide biosensors currently being used to investigate circuit architecture and function. Finally, it discusses methods for acute or chronic manipulation of neural activity, including genetically-targeted cellular ablation, optogenetics, chemogenetics, and over-expression of ion channels. With this ever-evolving genetic toolbox, scientists are continuing to probe neural circuits with increasing resolution, elucidating the structure and function of the incredibly complex mammalian brain.

Activation of basal forebrain-to-lateral habenula circuitry drives reflexive aversion and suppresses feeding behavior.

Environmental cues and internal states such as mood, reward, or aversion directly influence feeding behaviors beyond homeostatic necessity. The hypothalamus has been extensively investigated for its role in homeostatic feeding. However, many of the neural circuits that drive more complex, non-homeostatic feeding that integrate valence and sensory cues (such as taste and smell) remain unknown. Here, we describe a basal forebrain (BF)-to-lateral habenula (LHb) circuit that directly modulates non-homeostatic feeding behavior. Using viral-mediated circuit mapping, we identified a population of glutamatergic neurons within the BF that project to the LHb, which responds to diverse sensory cues, including aversive and food-related odors. Optogenetic activation of BF-to-LHb circuitry drives robust, reflexive-like aversion. Furthermore, activation of this circuitry suppresses the drive to eat in a fasted state. Together, these data reveal a role of basal forebrain glutamatergic neurons in modulating LHb-associated aversion and feeding behaviors by sensing environmental cues.

Confirmation of Induced Tolerance to Alternaria Blight Disease in Indian Mustard (Brassica juncea L.).

Indian mustard (Brassica juncea L.) is an important edible oilseed crop in India. Low productivity is the major concern which is adversely affected by biotic stresses. Alternaria blight (Alternaria brassicae) is one among major diseases that has no resistant cultivar until now. Keeping in view, an experiment was conducted for isolation of Alternaria blight-tolerant mutants in Indian mustard using gamma radiation and EMS mutagens during four consecutive years in Rabi (winter season). Furthermore, the morphologically and economically superior mutants of Brassica juncea were screened artificially at cotyledonary and adult stage against Alternaria blight. Tolerance to Alternaria blight is observed in DRMR-M-163 (11.7%), DRMR-M-158 (13.1%), DRMR-M-174 (13.8%) and DRMR-M-177 (18.6%) with minimum conidia in infected cotyledons. Mutant DRMR-M-178 (19.8%) had the highest radical scavenging activity, while DRMR-M-162 (104.9 mg/g AAE), DRMR-M-169 (96.9) and DRMR-M-161 (96.9) had higher antioxidant capacity that appears to act as defence to pathogen. DRMR-M-168 (8.4%), DRMR-M-173 (8.3), DRMR-M-171 (7.9), DRMR-M-165 (7.4), DRMR-M-175 (7.2) and DRMR-M-172 (6.9) had higher phenol content which may be responsive for resistance, although DRMR-M-161 (192.7 mg/g), DRMR-M-163 (187.7 mg/g), DRMR-M-164 (132.7 mg/g), DRMR-M-167 (149.3 mg/g), DRMR-M-173 (196.0 mg/g) and DRMR-M-178 (192.7 mg/g) mutants are found to contain low levels of total soluble sugar compared with susceptible Rohini (379.3). Based on biochemical parameter's similarity, mutants are grouped in 4 major clusters. Cluster 4 contained significantly different mutant DRMR-M-172. Relative expression of mitogen-activated protein kinase 3 (MAPK3) gene was found highest in DRMR-M-177, DRMR-M-174, DRMR-M-175, DRMR-M-178, DRMR-M-170, DRMR-M-176, DRMR-M-172 and DRMR-M-173 which resulted the better response to AB stress. Based on biochemical analysis, realtime PCR and cluster analysis, DRMR-M-172 mutant appears more tolerant to Alternaria. DRMR-M-178, DRMR-M-167 and DRMR-M-177 mutants seem tolerant and could be utilized for further breeding programme.