bioRxiv Subject Collection: Neuroscience's Journal
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Wednesday, December 25th, 2024
| Time |
Event |
| 6:21a |
Alternating hemiplegia of childhood associated mutations in Atp1a3 reveal diverse neurological alterations in mice.
Pathogenic variants in the neuronal Na+/K+ ATPase transmembrane ion transporter (ATP1A3) cause a spectrum of neurological disorders including alternating hemiplegia of childhood (AHC). The most common de novo pathogenic variants in AHC are p.D801N (~40% of patients) and p.E815K (~25% of patients), which lead to early mortality by spontaneous death in mice. Nevertheless, knowledge of the development of clinically relevant neurological phenotypes without the obstacle of premature death, is critical for the identification of pathophysiological mechanisms and ultimately, for the testing of therapeutic strategies in disease models. Here, we used hybrid vigor attempting to mitigate the fragility of AHC mice and then, performed behavioral, electrophysiological, biochemical, and molecular testing to comparatively analyze mice that carry either of two most common AHC patient observed variants in the Atp1a3 gene. Collectively, our data reveal the presence but also the differential impact of the p.D801N and p.E815 variants on disease relevant alterations such as spontaneous and stress-induced paroxysmal episodes, motor function, behavioral and neurophysiological activity, and neuroinflammation. Our alternate AHC mouse models with their phenotypic deficits open novel avenues for the investigation of disease biology and therapeutic testing for ATP1A3 research. | | 2:15p |
WWOX deficiency impairs neurogenesis and neuronal function in human organoids
WOREE and SCAR12 syndromes are rare neurodevelopmental disorders caused by WWOX mutations, severely impairing brain development. The pleiotropic nature of WWOX complicates identifying specific mechanisms. Using neural organoids and single-cell transcriptomics, we identified radial glial cells (RGs) as preferentially affected, with disrupted cell cycle dynamics leading to an accumulation of cells in the G2/M and S phases, overexpression of the proto-oncogene MYC, and concomitant reduction in neuronal generation. Patient-derived organoids exhibited milder phenotypes compared to knockout organoids, showing functional neuronal impairments like hyperexcitability and delayed differentiation rather than RG dysfunction. Remarkably, gene therapy restored neuronal function, normalizing hyperexcitability and promoting maturation, without disturbing RG populations. We propose a model in which WWOX mutations impair neurogenesis via RG through cell-type specific dysregulation of the MYC and Wnt signaling pathways. These insights highlight potential therapeutic strategies for WWOX-related disorders and open avenues for interventions targeting these key molecular pathways. | | 2:15p |
Anatomy-to-Tract Mapping: Inferring White Matter Pathways Without Diffusion Streamline Propagation
Diffusion tractography, a cornerstone of white matter mapping, relies on point-to-point streamline propagation---a process often compromised by errors stemming from inadequate signal-to-noise ratio and limited spatial-angular resolution in diffusion MRI (dMRI) data. Here, we present Anatomy-to-Tract Mapping (ATM), a novel deep learning framework that, for the first time, generates complete, bundle-specific streamlines directly from anatomical MRI, entirely bypassing the limitations of streamline propagation. ATM leverages the superior quality and minimal distortion of anatomical MRI, learning from multi-subject datasets to deliver robust, subject-specific streamline bundles while accurately preserving structural connectivity. This paradigm-shifting approach overcomes challenges associated with complex configurations, such as crossing, kissing, bending, and bottlenecks, providing anatomically precise reconstructions. Beyond individual-level mapping, ATM facilitates the creation of population-level streamline bundles aligned to average anatomical templates derived from diverse datasets. By offering global connectivity insights less affected by local uncertainties, ATM complements diffusion tractography, advancing white matter pathway reconstruction with a more reliable, anatomy-driven perspective. | | 2:46p |
Afadin-deficient retinas exhibit severe neuronal lamination defects but preserve visual functions
Neural lamination is a common feature of the central nervous system (CNS), with several subcellular structures, such as adherens junctions (AJs), playing a role in this process. The retina is also heavily laminated, but it remains unclear how laminar formation impacts retinal cell morphology, synapse integrity, and overall retinal function. In this study, we demonstrate that the loss of afadin, a key component of AJs, leads to significant pathological changes. These include the disruption of outer retinal lamination and a notable decrease as well as mislocalization of photoreceptors, their outer segments, and photoreceptor synapses. Interestingly, despite these severe impairments, we recorded small local field potentials, including the a- and b-waves. We also classified ganglion cells into ON, ON-OFF, and OFF types based on their firing patterns in response to light stimuli. Additionally, we successfully characterized the receptive fields of certain retinal ganglion cells. Overall, these findings provide the first evidence that retinal circuit function can be partially preserved even when there are significant disruptions in retinal lamination and photoreceptor synapses. Our results indicate that retinas with severely altered morphology still retain some capacity to process light stimuli. | | 2:46p |
Distinct cortical populations drive multisensory modulation of segregated auditory sources
Auditory perception can be modulated by other sensory stimuli. However, we do not fully understand the neural mechanisms that support multisensory behavior. Here, we recorded spiking activity from the primary auditory cortex (A1) in non-human primates, while they detected a target vocalization that was embedded in a background chorus of vocalizations. We found that a congruent video of a monkey eliciting a vocalization improved the monkeys behavior, relative to their performance when we only presented a static image of the monkey. As a proxy for the functional organization of A1, we compared the contribution of neurons with significant spectrotemporal response fields (STRFs) with those that had non-significant STRFs (nSTRFs). Based on spike-waveform shape and functional connectivity, STRF and nSTRF neurons appeared to belong to distinct neural populations. Consistent with this, we found that although STRF neurons encoded stimulus information through synchronized activity, the population of nSTRF neurons encoded task-related information in the primate A1 more as a structured dynamic process. Together, these findings demonstrate a functional distinction between the behavioral contributions of nSTRF and STRF neurons. | | 2:46p |
Afadin Sorts Different Retinal Neuron Types into Accurate Cellular Layers
Neurons use cell-adhesion molecules (CAMs) to interact with other neurons and the extracellular environment: the combination of CAMs specifies migration patterns, neuronal morphologies, and synaptic connections across diverse neuron types. Yet little is known regarding the intracellular signaling cascade mediating the CAM recognitions at the cell surface across different neuron types. In this study, we investigated the neural developmental role of Afadin1-4, a cytosolic adapter protein that connects multiple CAM families to intracellular F-actin. We introduced the conditional Afadin mutant5 to an embryonic retinal Cre, Six3-Cre6-8. We reported that the mutants lead to the scrambled retinal neuron distribution, including Bipolar Cells (BCs), Amacrine Cells (ACs), and retinal ganglion cells (RGCs), across three cellular layers of the retina. This scrambled pattern was first reported here at neuron-type resolution. Importantly, the mutants do not display deficits for BCs, ACs, or RGCs in terms of neural fate specifications or survival. Additionally, the displayed RGC types still maintain synaptic partners with putative AC types, indicating that other molecular determinants instruct synaptic choices independent of Afadin. Lastly, there is a significant decline in visual function and mis-targeting of RGC axons to incorrect zones of the superior colliculus, one of the major retinorecipient areas. Collectively, our study uncovers a unique cellular role of Afadin in sorting retinal neuron types into proper cellular layers as the structural basis for orderly visual processing. | | 2:46p |
Comprehensive profiling of small RNAs and their changes and linkages to mRNAs in schizophrenia and bipolar disorder
We investigated small non-coding RNAs (sncRNAs) from the prefrontal cortex of 93 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) and 77 controls. We uncovered recurring complex sncRNA profiles, with 98% of all sncRNAs being accounted for by miRNA isoforms (60.6%), tRNA-derived fragments (17.8%), rRNA-derived fragments (11.4%), and Y RNA-derived fragments (8.3%). In SCZ, 15% of all sncRNAs exhibit statistically significant changes in their abundance. In BD, the fold changes (FCs) are highly correlated with those in SCZ but less acute. Non-templated nucleotide additions to the 3'-ends of many miRNA isoforms determine their FC independently of miRNA identity or genomic locus of origin. In both SCZ and BD, disease- and age-associated sncRNAs and mRNAs reveal accelerated aging. Co-expression modules between sncRNAs and mRNAs align with the polarities of SCZ changes and implicate sncRNAs in critical processes, including synaptic signaling, neurogenesis, memory, behavior, and cognition. | | 3:18p |
Transient dopamine response on medium spiny neuron subtypes in switching approach-avoidance outcomes against action bias - A framework for exploration in action selection
An ensemble of direct and indirect pathway medium spiny neurons (dMSN and iMSN), compete via their neural activity to drive the decision to approach or avoid an object, respectively. Dopamine acting as a reward prediction error (RPE) signal causes experience-dependent synaptic changes in dMSN and iMSN, thereby shifting the dominance of neural activity to approach or avoidance signaling. These changes create bias in the striatal neuronal ensemble and restrict the choice to approach or avoidance in further iterations. However, organisms often exhibit behaviour where they choose undesirable actions in anticipation of future reward or avoid desirable actions in anticipation of future risk. These against-bias decisions or exploratory decisions are not accounted for by the existing neuronal framework. To bridge this gap, we postulate that transient motivational dopamine released from dopaminergic axons locally at sub-second timescales can cause temporary switch in dominance of neural activity between dMSN and iMSN leading to such adaptive decisions. By accounting for bias towards approach or avoidance or neither through synaptic weightages and accounting for differential affinity of DA to D1R and D2R, changes in dMSN and iMSN excitability at different levels of motivational dopamine was analyzed. Furthermore, the spiking activity of striatal neuronal ensemble comprising of dMSN projecting directly and iMSN projecting indirectly onto the output nuclei of basal ganglia i.e. SNr neurons was simulated. This led to promising findings that demonstrate how SNr neuronal activity can generate outcomes that work against the synaptic bias towards approach or avoidance.
Graphical Abstract
O_FIG O_LINKSMALLFIG WIDTH=180 HEIGHT=200 SRC="FIGDIR/small/630270v1_ufig1.gif" ALT="Figure 1">
View larger version (32K):
org.highwire.dtl.DTLVardef@7ab014org.highwire.dtl.DTLVardef@be01b4org.highwire.dtl.DTLVardef@61fce9org.highwire.dtl.DTLVardef@1235046_HPS_FORMAT_FIGEXP M_FIG C_FIG | | 5:16p |
Activity-Dependent Localization and Heterogeneous Dynamics of STIM1 and STIM2 at ER-PM contacts in Hippocampal Neurons.
Stromal interaction molecules (STIMs) are calcium sensors integral to store-operated calcium entry (SOCE), a process critical for non-excitable cells and contributing to homeostatic functions in neurons. Upon depletion of Ca2+ from the endoplasmic reticulum (ER), STIMs translocate to ER-plasma membrane (PM) junctions to contact the inner leaflet of the plasma membrane. Using single-particle tracking (SPT), we characterized the dynamic properties of neuronal STIM1 and STIM2 in hippocampal neurons.Our data reveal that STIMs exhibit heterogenous dynamics in dendrites and axons, while only transiently visiting synaptic compartments. A substantial fraction of STIM2 proteins define ER-PM contacts under resting conditions, whereas STIM1 proteins are recruited to ER-PM junctions during strong activation of glutamatergic synapses. Junctions organized by KV2.1 channels are not particularly enriched with STIM proteins. Activity-dependent confinement of STIM proteins is not influenced by L-type calcium channel (CaV1.2) activity. We propose that STIM proteins predominantly regulate the contact area and frequency of contacts between ER and PM. |
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