A novel anxiety-associated SNP identified in LYNX2 (LYPD1) is associated with decreased protein binding to nicotinic acetylcholine receptorsAnderson, Cao, Lee
et alFront Behav Neurosci (2024) 18, 1347543
Abstract: Anxiety disorders are among the most common mental illnesses in the US. An estimated 31.1% of U.S. adults experience any anxiety disorder at some time in their lives. Understanding some of the molecular underpinnings of anxiety could lead to improved treatments over current strategies focusing on symptom relief rather than root causes. One significant neurotransmitter system exerting control over anxiety is the nicotinic receptor subdivision of the cholinergic system. The murine Lynx2 gene, encoding a protein modulator of nicotinic acetylcholine receptors, is expressed in anxiety-related neural circuitry in rodents and has been functionally associated with anxiety-like behavior.We examined variations in the human LYNX2 (LYPD1) gene and their potential effects on anxiety levels in a cohort of 624 participants. Participants completed validated anxiety questionnaires (e.g., STICSA and STAI), which assessed both their current anxiety and their general tendency to experience anxiety. Possible functional alterations due to one such mutation was assessed through atomic force microscopy (AFM) and computational modeling.We identified a previously unreported single nucleotide polymorphism (SNP) in the mature protein-coding region of LYNX2 that was associated with significantly higher than normal anxiety scores. These elevated scores resembled those seen in patients clinically diagnosed with generalized anxiety disorder and panic disorder, although this genetically defined subpopulation did not typically report such diagnoses. Through computational modeling of the homopentameric α7 nicotinic receptor subtype and in vitro atomic force microscopy (AFM), we discovered that a specific LYNX2 SNP is linked to a reduced binding affinity between the LYNX2 protein and nAChRs, offering a potential functional explanation for the role that this mutation may play in anxiety.A polymorphism in LYNX2, which codes for an inhibitory modulator of nicotinic acetylcholine receptors, has the potential to lead to sensitized nicotinic receptor activity in anxiety-related circuits. The LYNX2 protein has been shown to bind to multiple nicotinic acetylcholine receptor subtypes, including α4β2, α7, and α3β4 subtypes, each of which have been shown to be involved in affective behaviors. This work suggests that a subpopulation of individuals harboring a deleterious mutation in LYNX2 may predispose them to anxiety through abnormal nicotinic receptor control. In the future, this work may lead to the development of a biomarker for anxiety or a diagnostic tool for the early detection of individuals with susceptibility to anxiety.Copyright © 2024 Anderson, Cao, Lee, Crenshaw, Palumbo, Fisher-Perez, DeGraaf, Rogu, Beatty, Gracias, Pisapati, Hoffman, McLaughlin, Hupbach, Im, Zhang and Miwa.
Convergence of Type 1 Spiral Ganglion Neuron Subtypes onto Principal Neurons of the Anteroventral Cochlear NucleusWong, Brongo, Forero
et alJ Neurosci (2025) 45 (6)
Abstract: The mammalian auditory system encodes sounds with subtypes of spiral ganglion neurons (SGNs) that differ in sound level sensitivity, permitting discrimination across a wide range of levels. Recent work suggests the physiologically defined SGN subtypes correspond to at least three molecular subtypes. It is not known how information from the different subtypes converges within the cochlear nucleus. We examined this issue using transgenic mice of both sexes that express Cre recombinase in SGNs that are positive for markers of two subtypes: CALB2 (calretinin) in type 1a SGNs and LYPD1 in type 1c SGNs, which correspond to high- and low-sensitivity subtypes, respectively. We crossed these with mice expressing floxed channelrhodopsin, which allowed specific activation of axons from type 1a or 1c SGNs using optogenetics. We made voltage-clamp recordings from bushy cells in the anteroventral cochlear nucleus (AVCN) and found that the synapses formed by CALB2- and LYPD1-positive SGNs had similar EPSC amplitudes and short-term plasticity. Immunohistochemistry revealed that individual bushy cells receive a mix of 1a, 1b, and 1c synapses with VGluT1-positive puncta of similar sizes. We used optogenetic stimulation during in vivo recordings to classify chopper and primary-like units as receiving versus nonreceiving 1a- or 1c-type inputs. These groups showed no significant difference in threshold or spontaneous rate, suggesting the subtypes do not segregate into distinct processing streams in the AVCN. Our results indicate that principal cells in the AVCN integrate information from all SGN subtypes with extensive convergence, which could optimize sound encoding across a large dynamic range.Copyright © 2024 the authors.
Genoarchitectural Definition of the Adult Mouse Mesocortical Ring: A Contribution to Cortical Ring TheoryPuelles, Alonso, García-Calero
J Comp Neurol (2024) 532 (7), e25647
Abstract: Data mining was performed at the databases of the Allen Institute for Brain Science (RRID:SCR_017001) searching for genes expressed selectively throughout the adult mouse mesocortex (transitional cortex ring predicted within the concentric ring theory of mammalian cortical structure, in contrast with central isocortex [ICx] and peripheral allocortex). We aimed to explore a shared molecular profile selective of all or most mesocortex areas. This approach checks and corroborates the precision of other previous definitory criteria, such as poor myelination and high kainate receptor level. Another aim was to examine which cortical areas properly belong to mesocortex. A total of 34 positive adult selective marker genes of mesocortex were identified, jointly with 12 negative selective markers, making a total of 46 markers. All of them identify the same set of cortical areas surrounding the molecularly different ICx as well as excluding adjacent allocortex. Four representative mesocortex markers-Crym, Lypd1, Cdh13, and Smoc2-are amply illustrated, jointly with complementary material including myelin basic protein, to check myelination, and Rorb, to check layer 4 presence. The retrosplenial (ReSp) area, long held to be mesocortical, does not share any of the 46 markers of mesocortex and instead expresses Nr4a2 and Tshz2, selective parahippocampal allocortex markers. Moreover, it is not hypomyelinic and lacks a Rorb-positive layer 4, aspects generally present in mesocortex. Exclusion of the ReSp area from the mesocortex ring reveals the latter to be closed at this locus instead by two adjacent areas previously thought to be associative visual ICx (reidentified here molecularly as postsplenial and parasplenial mesocortex areas). The concepts of ICx, mesocortex, and parahippocampal allocortex are thus subtly modified by substantial molecular evidence.© 2024 The Author(s). The Journal of Comparative Neurology published by Wiley Periodicals LLC.
Genome-wide comparative analyses highlight selection signatures underlying saline adaptation in Chilika buffaloSurati, Niranjan, Pundir
et alPhysiol Genomics (2024) 56 (9), 609-620
Abstract: Chilika, a native buffalo breed of the Eastern coast of India, is mainly distributed around the Chilika brackish water lake connected with the Bay of Bengal Sea. This breed possesses a unique ability to delve deep into the salty water of the lake and stay there to feed on local vegetation of saline nature. Adaptation to salinity is a genetic phenomenon; however, the genetic basis underlying salinity tolerance is still limited in animals, specifically in livestock. The present study explores the genetic evolution that unveils the Chilika buffalo's adaptation to the harsh saline habitat, including both water and food systems. For this study, whole genome resequencing data on 18 Chilika buffalo and for comparison 10 Murrah buffalo of normal habitat were generated. For identification of selection sweeps, intrapopulation and interpopulation statistics were used. A total of 709, 309, 468, and 354 genes were detected to possess selection sweeps in Chilika buffalo using the nucleotide diversity (θπ), Tajima's D, nucleotide diversity ratio (θπ-ratio), and FST methods, respectively. Further analysis revealed a total of 23 genes including EXOC6B, VPS8, LYPD1, VPS35, CAMKMT, NCKAP5, COMMD1, myosin light chain kinase 3 (MYLK3), and B3GNT2 were found to be common by all the methods. Furthermore, functional annotation study of identified genes provided pathways such as MAPK signaling, renin secretion, endocytosis, oxytocin signaling pathway, etc. Gene network analysis enlists that hub genes provide insights into their interactions with each other. In conclusion, this study has highlighted the genetic basis underlying the local adaptive function of Chilika buffalo under saline environment.NEW & NOTEWORTHY Indian Chilika buffaloes are being maintained on extensive grazing system and have a unique ability to convert local salty vegetation into valuable human food. However, adaptability to saline habitat of Chilika buffalo has not been explored to date. Here, we identified genes and biological pathways involved, such as MAPK signaling, renin secretion, endocytosis, and oxytocin signaling pathway, underlying adaptability of Chilika buffalo to saline environment. This investigation shed light on the mechanisms underlying the buffalo's resilience in its native surroundings.
膜杰作
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