bioRxiv Subject Collection: Neuroscience's Journal
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Sunday, June 30th, 2024
| Time |
Event |
| 12:45a |
A large-scale optogenetic neurophysiology platform for improving accessibility in NHP behavioral experiments
Optogenetics has been a powerful scientific tool for two decades, yet its integration with non-human primate (NHP) electrophysiology has been limited due to several technical challenges. These include a lack of electrode arrays capable of supporting large-scale and long-term optical access, inaccessible viral vector delivery methods for transfection of large regions of cortex, a paucity of hardware designed for large-scale patterned cortical illumination, and inflexible designs for multi-modal experimentation. To address these gaps, we introduce a highly accessible platform integrating optogenetics and electrophysiology for behavioral and neural modulation with neurophysiological recording in NHPs. We employed this platform in two rhesus macaques and showcased its capability of optogenetically disrupting reaches, while simultaneously monitoring ongoing electrocorticography activity underlying the stimulation-induced behavioral changes. The platform exhibits long-term stability and functionality, thereby facilitating large-scale electrophysiology, optical imaging, and optogenetics over months, which is crucial for translationally relevant multi-modal studies of neurological and neuropsychiatric disorders. | | 1:16a |
Representational drift as the consequence of ongoing memory storage
Memory systems with biologically constrained synapses have been the topic of intense theoretical study for over thirty years. Perhaps the most fundamental and far-reaching finding from this work is that the storage of new memories implies the partial erasure of already-stored ones. This overwriting leads to a decorrelation of sensory-driven activity patterns over time, even if the input patterns remain similar. Representational drift (RD) should therefore be an expected and inevitable consequence of ongoing memory storage. We tested this hypothesis by fitting a network model to data from long-term chronic calcium imaging experiments in mouse hippocampus. Synaptic turnover in the model inputs, consistent with the ongoing encoding of new activity patterns, accounted for the observed statistics of RD. This mechanism also provides a parsimonious explanation for the recent finding that RD in CA1 place cells has two distinct components: one which depends only on the passage of time, and another which depends on the time spent exploring a given environment. Furthermore, in the context of ongoing learning, the drift rate of any one memory depends on its repetition rate, a mechanism which can reproduce the diverse effects of experience on drift found in experiment. Our results suggest that RD should be observed wherever neuronal circuits are involved in a process of ongoing learning or memory storage. | | 1:16a |
Stereotyped spatiotemporal dynamics of spontaneous activity in visual cortex prior to eye-opening
Over the course of development, functional sensory representations emerge in the visual cortex. Prior to eye-opening, modular patterns of spontaneous activity form long-range networks that may serve as a precursor for mature network organization. Although the spatial structure of these networks has been well studied, their temporal features, which may contribute to their continued plasticity and development, remain largely uncharacterized. To address this, we imaged hours of spontaneous network activity in the visual cortex of developing ferrets of both sexes utilizing a fast calcium indicator (GCaMP8m) and widefield imaging at high temporal resolution (50Hz), then segmented out spatiotemporal events. The spatial structure of this activity was highly modular, exhibiting spatially segregated active domains consistent with prior work. We found that the vast majority of events showed a clear dynamic component in which modules activated sequentially across the field of view, but only a minority of events were well-fit with a linear traveling wave. We found that spatiotemporal events occur in repeated and stereotyped motifs, reoccurring across hours of imaging. Finally, we found that the most frequently occurring single-frame spatial activity patterns were predictive of future activity patterns over hundreds of milliseconds. Together, our results demonstrate that spontaneous activity in the early developing cortex exhibits a rich spatiotemporal structure, suggesting a potential role in the maturation and refinement of future functional representations. | | 2:36a |
Predictions of bimanual self-touch determine the temporal tuning of somatosensory perception
We effortlessly distinguish between touching ourselves with our hands and being touched by other people or objects. Motor control theories posit that this distinction is made possible by the brain predicting the somatosensory consequences of our voluntary movements based on an efference copy, and attenuating our responses to the predicted self-touch. However, it remains unclear how these predictions impact somatosensory perception at times other than during self-touch: for example, as our hand reaches to touch our body or moves away from it. Here participants discriminated forces applied on their passive left index finger. The forces were applied during the reaching movement of their right hand towards the left hand, including the time the reaching ended by simulating self-touch between the hands, or after the reaching movement. We observed that the forces on the left hand felt progressively weaker during the reaching phase, reached their minimum perceived intensity at the time of self-touch, and quickly recovered after the end of the reaching. All effects were replicated with a new cohort of participants that further demonstrated that this gradual attenuation of the perceived magnitude of touch vanished during similar right hand reaching movements that did not produce expectations for self-touch between the two hands. Together, our results indicate a temporal tuning of somatosensory perception during movements to self-touch and underscore the role of sensorimotor context in forming predictions that attenuate the intensity of self-generated touch. | | 2:36a |
Single-nucleus multiomics reveals the disrupted regulatory programs in three brain regions of sporadic early-onset Alzheimer's disease
Sporadic early-onset Alzheimer's disease (sEOAD) represents a significant but less-studied subtype of Alzheimer's disease (AD). Here, we generated a single-nucleus multiome atlas derived from the postmortem prefrontal cortex, entorhinal cortex, and hippocampus of nine individuals with or without sEOAD. Comprehensive analyses were conducted to delineate cell type-specific transcriptomic changes and linked candidate cis-regulatory elements (cCREs) across brain regions. We prioritized seven conservative transcription factors in glial cells in multiple brain regions, including RFX4 in astrocytes and IKZF1 in microglia, which are implicated in regulating sEOAD-associated genes. Moreover, we identified the top 25 altered intercellular signaling between glial cells and neurons, highlighting their regulatory potential on gene expression in receiver cells. We reported 38 cCREs linked to sEOAD-associated genes overlapped with late-onset AD risk loci, and sEOAD cCREs enriched in neuropsychiatric disorder risk loci. This atlas helps dissect transcriptional and chromatin dynamics in sEOAD, providing a key resource for AD research. | | 3:45a |
Depletion of TDP-43 exacerbates tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-mediated endoproteolysis of tau in a mouse model of Multiple Etiology Dementia
TDP-43 proteinopathy, initially disclosed in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coexists with tauopathy in a variety of neurodegenerative disorders, termed multiple etiology dementias (MEDs), including Alzheimers Disease (AD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration and steeper cognitive decline, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. The loss of TDP-43 splicing repression that occurs in presymptomatic ALS-FTD individuals suggests that such early loss could facilitate the pathological conversion of tau to accelerate neuron loss. Here, we report that the loss of TDP-43 repression of cryptic exons in forebrain neurons (CaMKII-CreER;Tardbpf/f mice) is necessary to exacerbate tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-dependent cleavage of endogenous tau to promote tauopathy. Corroborating this finding within the human context, we demonstrate that loss of TDP-43 function in iPSC-derived cortical neurons promotes early cryptic exon inclusion and subsequent caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in CaMKII-CreER;Tardbpf/f mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed positively correlates with levels of caspase 3-cleaved tau. Importantly, we found that the vulnerability of hippocampal neurons to TDP-43 depletion is dependent on the amount of caspase 3-cleaved tau: from most vulnerable neurons in the CA2/3, followed by those in the dentate gyrus, to the least in CA1. Taken together, our findings strongly support the view that TDP-43 loss-of-function exacerbates tauopathy-dependent brain atrophy by increasing the sensitivity of vulnerable neurons to caspase 3-mediated endoproteolysis of tau, resulting in a greater degree of neurodegeneration in human disorders with co-pathologies of tau and TDP-43. Our work thus discloses novel mechanistic insights and therapeutic targets for human tauopathies harboring co-pathology of TDP-43 and provides a new MED model for testing therapeutic strategies. | | 8:31a |
Rbm24 maintains survival of cochlear outer hair cells by repressing Insm1
The inactivation of Rbm24, an RNA-binding protein, results in the degeneration of cochlear outer hair cells (OHCs) during the postnatal period. However, the specific molecular mechanisms underlying this OHC death remain elusive. To address this, we conducted a comprehensive analysis comparing the gene profiles of wild-type OHCs to those lacking Rbm24 (Rbm24-/-) at postnatal day 7 (P7). Our results revealed that the overall differentiation program of OHCs is delayed in the absence of Rbm24. Furthermore, the expression of Insm1, a crucial factor for OHC development that is normally switched off by P2, remains prolonged in Rbm24-/- OHCs. Interestingly, when Insm1 is overexpressed, it also leads to OHC death. Significantly, the OHC degeneration is much less severe when both Rbm24 and Insm1 are simultaneously inactivated. These findings shed light on the important role of Rbm24 in repressing Insm1 and its impact on OHC differentiation and survival. Our study provides valuable insights into the complex genetic signaling pathways involved in OHC development. | | 9:48a |
PKA Activity-Driven Modulation of Bidirectional Long-Distance transport of Lysosomal vesicles During Synapse Maintenance
The bidirectional long-distance transport of organelles is crucial for cell body-synapse communication. However, the mechanisms by which this transport is modulated for synapse formation, maintenance, and plasticity are not fully understood. Here, we demonstrate through quantitative analyses that maintaining sensory neuron-motor neuron synapses in the Aplysia gill-siphon withdrawal reflex is linked to a sustained reduction in the retrograde transport of lysosomal vesicles in sensory neurons. Interestingly, while mitochondrial transport in the anterograde direction increases within 12 hours of synapse formation, the reduction in lysosomal vesicle retrograde transport appears three days after synapse formation. Moreover, we find that formation of new synapses during learning induced by neuromodulatory neurotransmitter serotonin further reduces lysosomal vesicle transport within 24 hours, whereas mitochondrial transport increases in the anterograde direction within one hour of exposure. Pharmacological inhibition of several signaling pathways pinpoints PKA as a key regulator of retrograde transport of lysosomal vesicles during synapse maintenance. These results demonstrate that synapse formation leads to organelle-specific and direction specific enduring changes in long-distance transport, offering insights into the mechanisms underlying synapse maintenance and plasticity. | | 9:48a |
Cell-specific inhibitory modulation of sound processing in the auditory thalamus.
Inhibition along the auditory pathway is crucial for processing of acoustic information. Within the auditory thalamus, a key region in the central auditory pathway, inhibition is provided by the thalamic reticular nucleus (TRN), comprised of two large classes of inhibitory neurons, parvalbumin (PVTRN) and somatostatin (SSTTRN) positive. In the auditory cortex, PV and SST neurons differentially shape auditory processing. We found that the ventral MGB, the thalamic region in the direct ascending auditory pathway, receives inputs predominantly from PVTRN neurons, whereas SSTTRN neurons project to the dorso-medial regions of MGB. Consistently, inactivating PVTRN neurons increased sound-evoked activity in over a third of neurons in the vMGB, with another large fraction of neurons being suppressed. By contrast, inactivating SSTTRN neuronal activity largely reduced tone-evoked activity in vMGB neurons. Cell type-specific computational models revealed candidate circuit mechanisms for generating the bi-directional effects of TRN inactivation on MGB sound responses. These differential inhibitory pathways within the auditory thalamus suggest a cell-specific role for thalamic inhibition in auditory computation and behavior. | | 9:48a |
Human-specific paralogs of SRGAP2 induce neotenic features of microglia structural and functional maturation
Microglia play key roles in shaping synaptic connectivity during neural circuits development. Whether microglia display human-specific features of structural and functional maturation is currently unknown. We show that the ancestral gene SRGAP2A and its human-specific (HS) paralogs SRGAP2B/C are not only expressed in cortical neurons but are the only HS gene duplications expressed in human microglia. Here, using combination of xenotransplantation of human induced pluripotent stem cell (hiPSC)-derived microglia and mouse genetic models, we demonstrate that (1) HS SRGAP2B/C are necessary and sufficient to induce neotenic features of microglia structural and functional maturation in a cell-autonomous manner, and (2) induction of SRGAP2-dependent neotenic features of microglia maturation non-cell autonomously impacts synaptic development in cortical pyramidal neurons. Our results reveal that, during human brain evolution, human-specific genes SRGAP2B/C coordinated the emergence of neotenic features of synaptic development by acting as genetic modifiers of both neurons and microglia. |
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