bioRxiv Subject Collection: Neuroscience's Journal
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Tuesday, July 2nd, 2024
| Time |
Event |
| 1:46a |
PRDM16-DT is a Brain and Astrocyte-Specific lncRNA Implicated in Alzheimers Disease
Astrocytes provide crucial support for neurons, contributing to synaptogenesis, synaptic maintenance, and neurotransmitter recycling. Under pathological conditions, deregulation of astrocytes contributes to neurodegenerative diseases such as Alzheimers disease (AD), highlighting the growing interest in targeting astrocyte function to address early phases of AD pathogenesis. While most research in this field has focused on protein-coding genes, non-coding RNAs, particularly long non-coding RNAs (lncRNAs), have emerged as significant regulatory molecules. In this study, we identified the lncRNA PRDM16-DT as highly enriched in the human brain, where it is almost exclusively expressed in astrocytes. PRDM16-DT and its murine homolog, Prdm16os, are downregulated in the brains of AD patients and in AD models. In line with this, knockdown of PRDM16-DT and Prdm16os revealed its critical role in maintaining astrocyte homeostasis and supporting neuronal function by regulating genes essential for glutamate uptake, lactate release, and neuronal spine density through interactions with the RE1-Silencing Transcription factor (Rest) and Polycomb Repressive Complex 2 (PRC2). Notably, CRISPR-mediated overexpression of Prdm16os mitigated functional deficits in astrocytes induced by stimuli linked to AD pathogenesis. These findings underscore the importance of PRDM16-DT in astrocyte function and its potential as a novel therapeutic target for neurodegenerative disorders characterized by astrocyte dysfunction | | 1:46a |
Disturbance of the Sense of Agency in Obsessive-Compulsive Disorder and its Modulation by Social Context
Executing precise actions and perceiving them as one's own is a fundamental ability underlying the sense of agency (SoA). The SoA thereby heavily relies on the accuracy and reliability of forward models, capturing sensory movement consequences. Impairments thereof thus represent a promising candidate mechanism contributing to cases of SoA pathogenesis. In obsessive-compulsive disorder (OCD), for example, the feeling of control over one's actions is perturbed: Compulsive actions are often experienced as uncontrollable and performed without conscious awareness. At the same time, compulsions can be coupled with an inflated sense of illusory control for uncontrollable events. Here we studied self-action perception in virtual reality with and without veridical or rotated visual feedback about subjects' pointing movements to test whether patients' internal forward models are indeed less reliable compared to controls. Interestingly, OCD patients did not exhibit deficits in their accuracy and reliability of motor performance and self-action perception in the absence of visual feedback, suggesting intact forward models. Nonetheless, OCD patients weighted rotated visual action-feedback significantly stronger perceptually. Furthermore, they adapted their movement to this false feedback on a trial-by-trial basis. Finally, increasing the social relevance of action consequences led to stronger feedback weighting in all participants while this effect increased with the strength of OCD symptomatology under conditions with strongest social relevance. We suggest that internal forward models are equally reliable in OCD but their weight is pathologically decreased leading to patients' overreliance on explicit visual action-feedback and, more generally, to their over-attribution of unrelated events to themselves. | | 1:46a |
Metabolic mode estimated by breathing reflects long-term motor memory
Respiration is a crucial metabolic process that converts macronutrients and oxygen (O2) into energy and carbon dioxide (CO2), supporting motor actions. In addition to the energy demands for movements, the brain is a significant energy consumer for neural activity and plasticity. However, it is not known whether breathing patterns can serve as an indicator for them as they can for movement intensity. According to computational theory, motor memory updating involves fast and slow timescales, which may correspond to neural activity and plasticity. To investigate whether breathing patterns reflect these time constants, human experiments assessed short- and long-term memories while recording the O2-CO2 gas exchange. We found that the respiratory exchange ratio (RER), an indicator of metabolic mode, was not influenced by the execution and learning of the reaching movement and was stable within individuals but diverse across individuals. Interestingly, the individual differences in the RER reflect individual variation in long-term memory rather than short-term memory. Furthermore, to manipulate the RER, we provided 200 kcal of glucose immediately before the task. Surprisingly, 24-hour retention increased by 21%. Together, the RER would serve as a remarkable proxy for long-term motor memory and ingesting glucose would shift the neurophysiological idling state for learning. | | 1:46a |
Dual roles of idling moments in past and future memories
Every day, we experience new daily episodes and store new memories. Although memories are stored in corresponding engram cells, how different sets of engram cells are selected for current and next episodes, and how they create their memories, remains unclear. We report that in mice, hippocampal CA1 neurons show an organized synchronous activity in prelearning home cage sleep that correlates with the learning ensembles only in engram cells, termed preconfigured ensembles. Moreover, after learning, a subset of nonengram cells develops population activity, which is constructed during postlearning offline periods through synaptic depression and scaling, and then emerges to represent engram cells for new learning. Together, our findings indicate that during offline periods there are two parallel processes occurring: conserving of past memories through reactivation, and preparation for upcoming ones through offline synaptic plasticity mechanisms. | | 3:02a |
Assessing the predictive value of peak alpha frequency for the sensitivity to pain
Pain perception varies considerably between and within individuals. How the brain determines these variations has yet to be fully understood. The peak frequency of alpha oscillations (PAF) has recently been shown to predict an individual's sensitivity to longer-lasting experimental and clinical pain. PAF is, thus, discussed as a potential biomarker and novel target for neuromodulatory treatments of pain. Here, we scrutinized the generalizability of the relation between PAF and pain. We applied brief painful laser stimuli to 159 healthy participants and related inter- and intra-individual variations of pain perception to PAF measured with electroencephalography. Comprehensive multiverse analyses across two sessions did not provide consistent evidence for a predictive role of PAF for brief experimental pain. This indicates that the relationship between PAF and pain does not generalize to all types of pain and calls for a systematic exploration of the relationship between PAF, pain perception, and other neuropsychiatric symptoms. | | 9:19a |
Interhemispheric Connectivity of the Human Temporal Lobes
Much is known regarding the major white matter pathways connecting the right and left temporal lobes, which project through the posterior corpus callosum, the anterior commissure, and the dorsal hippocampal commissure. However, details about the spatial location of these tracts are unclear, including their exact course and proximity to cortical and subcortical structures, the spatial relations between corpus callosum and anterior commissure projections, and the caudal extent of transcallosal connections within the splenium. We present an atlas of these tracts derived from high angular resolution diffusion tractography maps, providing improved visualization of the spatial relationships of these tracts. The data show several new details, including branching of the transcallosal pathway into medial and lateral divisions, projections of the transcallosal pathway into the external capsule and claustrum, complex patterns of overlap and interdigitation of the transcallosal and anterior commissure tracts, distinct dorsal and ventral regions of the splenium with high tract densities, and absence of temporal lobe projections in the caudal third of the splenium. Intersection of individual tract probability maps with individual cortical surfaces were used to identify likely regions with relatively higher cortical termination densities. These data should be useful for planning surgical approaches involving the temporal lobe and for developing functional-anatomical models of processes that depend on interhemispheric temporal lobe integration, including speech perception, semantic memory, and social cognition. | | 12:47p |
Glycation of alpha-synuclein enhances aggregation and neuroinflammatory responses
The risk of developing Parkinson's disease (PD) is elevated in people with type 2 diabetes, but the precise molecular pathways underlying this connection are still unclear. One hypothesis is that glycation, a non-enzymatic family of reactions between glycating agents, such as reducing sugars or reactive dicarbonyls, and specific amino acids, such as lysines and arginines, may alter proteostasis and trigger pathological alterations. Glycation of alpha-synuclein (aSyn), a central player in PD pathology, causes profound changes in the aggregation process of aSyn. Methylglyoxal (MGO), a strong glycating agent, induces the formation of pathological inclusions enriched in phosphorylated aSyn on serine 129 (pS129). In addition, we found that neuroinflammatory responses are enhanced by MGO-mediated aSyn glycation. Using novel polyclonal antibodies developed towards specific MGO-glycated aSyn residues, we confirmed the occurrence of glycated aSyn both in vitro as well as in animal and in human brain tissue. In total, our findings shed light into the interplay between glycation, PD, and type 2 diabetes, potentially paving the way for the development of novel therapeutic strategies targeting these intertwined conditions. | | 3:31p |
Pathogenic variants associated with speech/cognitive delay and seizures affect genes with expression biases in excitatory neurons and microglia in developing human cortex
Background & Objective: Congenital brain malformations and neurodevelopmental disorders (NDDs) are common pediatric neurological disorders and result in chronic disability. With the expansion of genetic testing, new etiologies for NDDs are continually uncovered, with as many as one third attributable to single-gene pathogenic variants. While our ability to identify pathogenic variants has continually improved, we have little understanding of the underlying cellular pathophysiology in the nervous system that results from these variants. We therefore integrated phenotypic information from subjects with monogenic diagnoses with two large, single-nucleus RNA-sequencing (snRNAseq) datasets from human cortex across developmental stages in order to investigate cell-specific biases in gene expression associated with distinct neurodevelopmental phenotypes. Methods: Phenotypic data was gathered from 1) a single-institution cohort of 84 neonates with pathogenic single-gene variants referred to Duke Pediatric Genetics, and 2) a cohort of 4,238 patients with neurodevelopmental disorders and pathogenic single-gene variants enrolled in the Deciphering Developmental Disorders (DDD) study. Pathogenic variants were grouped into genesets by neurodevelopmental phenotype and geneset expression across cortical cell subtypes was compared within snRNAseq datasets from 86 human cortex samples spanning the 2nd trimester of gestation to adulthood. Results: We find that pathogenic variants associated with speech/cognitive delay or seizures involve genes that are more highly expressed in cortical excitatory neurons than variants in genes not associated with these phenotypes (Speech/cognitive: p=2.25x10^-7; Seizures: p=7.97x10^-12). A separate set of primarily rare variants associated with speech/cognitive delay or seizures, distinct from those with excitatory neuron expression biases, demonstrated expression biases in microglia. We also found that variants associated with speech/cognitive delay and an excitatory neuron expression bias could be further parsed by the presence or absence of comorbid seizures. Variants associated with speech/cognitive delay without seizures tended to involve calcium regulatory pathways and showed greater expression in extratelencephalic neurons, while those associated with speech/cognitive delay with seizures tended to involve synaptic regulatory machinery and an intratelencephalic neuron expression bias (ANOVA by geneset p<2x10^-16). Conclusions: By combining extensive phenotype datasets from subjects with neurodevelopmental disorders with massive human cortical snRNAseq datasets across developmental stages, we identified cell-specific expression biases for genes in which pathogenic variants are associated with speech/cognitive delay and seizures. The involvement of genes with enriched expression in excitatory neurons or microglia highlights the unique role both cell types play in proper sculpting of the developing brain. Moreover, this information begins to shed light on distinct cortical cell types that are more likely to be impacted by pathogenic variants and that may mediate the symptomatology of resulting neurodevelopmental disorders. | | 7:45p |
A central steering circuit in Drosophila
Locomotion steering control enables animals to pursue targets, evade threats, avoid obstacles, and explore their environment. Steering commands are generated in the brain and communicated via descending neurons to leg or wing motor circuits. The diversity of ways in which turns are triggered and executed has led to the view that steering might rely on distributed neural processing across multiple control circuits. Here, however, we present evidence for a central steering circuit in Drosophila that is used for both goal-directed and exploratory turns and is capable of eliciting turns ranging from subtle course corrections to rapid saccades. The circuit is organized in a hierarchy, the top layer of which comprises the reciprocally connected DNa03 and LAL013 neurons. Our data suggest that turns are initiated by DNa03 neurons and reinforced and stabilized through a winner-take-all mechanism involving LAL013. The descending DNa11 neurons form an intermediate layer. They receive input from both DNa03 and LAL013 and target leg motor circuits directly as well as indirectly through subordinate descending neurons. DNa11 activation coordinately changes the stepping directions of all six legs to generate rapid saccadic turns. Together, these data define a central steering control circuit in Drosophila that is flexibly used to generate turns as the fly exploits or explores its environment. | | 8:16p |
Cellular and Molecular Changes During Aging in MEC: Unveiling the Role of Bglap3 Neurons in Cognitive Aging
Aging-correlated cognitive declines, including deficiencies in spatial orientation and memory, may reflect dysfunction in the hippocampus and medial entorhinal cortex (MEC). However, aging-related changes in MEC at the cellular and molecular levels remain unclear. In this study, we found fewer grid cells with reduced spatial stability in old mice. We compared gene expression profiles between young and old mice using 10x Genomics Visium technology. Among 1664 differentially expressed genes, we discovered Bglap3, a marker gene for subpopulation in MEC Layer III with decreased cell number with age. Silencing of Bglap3+ neurons in young mice impaired the spatial tuning of neurons in MEC and the spatial learning of a new platform location in water maze. These findings help us to understand the cellular and molecular changes in the MEC in healthy aging animals and the changes of Bglap3+ cells in old mice indicating a possible cause of aging-related MEC deficiency. | | 11:01p |
An applicable and efficient retrograde monosynaptic circuit mapping tool for larval zebrafish
The larval zebrafish is a vertebrate model for in vivo monitoring and manipulation of whole-brain neuronal activities. Tracing its neural circuits still remains challenging. Here we report an applicable methodology tailored for larval zebrafish to achieve efficient retrograde trans-monosynaptic tracing from genetically defined neurons via EnvA-pseudotyped glycoprotein-deleted rabies viruses. By combinatorially optimizing multiple factors involved, we identified the CVS strain trans-complemented with advanced expression of N2cG at 36 degrees C as the optimal combination. It yielded a tracing efficiency of up to 20 inputs per starter cell. Its low cytotoxicity enabled the viable labeling and calcium imaging of infected neurons 10 days post-infection, spanning larval ages commonly used for functional examination. Cre-dependent labeling was further developed to enable input cell-type-specific tracing and circuit reconstruction. We mapped cerebellar circuits and uncovered the ipsilateral preference and subtype specificity of granule cell-to-Purkinje cell connections. Our method offers an efficient way for tracing neural circuits in larval zebrafish | | 11:01p |
Uncertainty gates redundancy in reward integration in prefrontal-cortical and ventral-hippocampal nucleus accumbens inputs to tune engagement
Circuit neuroscience commonly seeks to assign specific functions to specific circuits. Yet, redundancy can be highly adaptive and is therefore a critical motif in circuit organization. The NAc, a highly integrative brain region controlling motivated behavior, is thought to receive distinct information from its various glutamatergic inputs yet strong evidence of functional specialization of inputs is lacking. Using dual-site fiber photometry in an operant reward task, we simultaneously recorded from two NAc glutamatergic afferents to assess circuit specialization. We identify a common neural motif that integrates reward history in medial prefrontal cortex (mPFC) and ventral hippocampus (vHip) inputs to NAc. Then, by systematically dissociating reward from choice and action, we identify key circuit-specificity in the behavioral conditions that recruit encoding. While mPFC-NAc invariantly encodes reward, vHip-NAc encoding requires goal-directed action and uncertainty. Ultimately, using optogenetic stimulation we demonstrate that both inputs co-operatively modulate task engagement. Taken together, we illustrate how similar encoding, with differential gating by behavioral state, supports outcome encoding to tune engagement to recent history of reward. | | 11:01p |
Peripheral glia and neurons jointly regulate activity-induced synaptic remodeling at the Drosophila neuromuscular junction
In the nervous system, reliable communication depends on the ability of neurons to adaptively remodel their synaptic structure and function in response to changes in neuronal activity. While neurons are the main drivers of synaptic plasticity, glial cells are increasingly recognized for their roles as active modulators. However, the underlying molecular mechanisms remain unclear. Here, using Drosophila neuromuscular junction as a model system for a tripartite synapse, we show that peripheral glial cells collaborate with neurons at the NMJ to regulate activity-induced synaptic remodeling, in part through a protein called shriveled (Shv). Shv is an activator of integrin signaling previously shown to be released by neurons during intense stimulation at the fly NMJ to regulate activity-induced synaptic remodeling. We demonstrate that Shv is also present in peripheral glia, and glial Shv is both necessary and sufficient for synaptic remodeling. However, unlike neuronal Shv, glial Shv does not activate integrin signaling at the NMJ. Instead, it regulates synaptic plasticity in two ways: 1) maintaining the extracellular balance of neuronal Shv proteins to regulate integrin signaling, and 2) controlling ambient extracellular glutamate concentration to regulate postsynaptic glutamate receptor abundance. Loss of glial cells showed the same phenotype as loss of Shv in glia. Together, these results reveal that neurons and glial cells homeostatically regulate extracellular Shv protein levels to control activity-induced synaptic remodeling. Additionally, peripheral glia maintains postsynaptic glutamate receptor abundance and contribute to activity-induced synaptic remodeling by regulating ambient glutamate concentration at the fly NMJ. | | 11:01p |
Glial voltage-gated K+ channels modulate the neural abiotic stress tolerance of Drosophila melanogaster
Severe abiotic stress causes insects to lose nervous function and enter a state of paralytic coma. Central to this loss of function is a spreading depolarization (SD), where a characteristic collapse of ion gradients depolarizes neuronal and glial membranes and rapidly shuts down the CNS. Despite representing a critical limit to CNS function, the stress threshold that elicits SD can be altered by the process of acclimation, though the mechanisms underlying this response remain largely unknown. Here, we made electrophysiological measurements of SD and investigated the role of K+ channels in acclimation of the CNS stress response of Drosophila melanogaster. First, we demonstrate that improved cold tolerance in the CNS elicited by cold acclimation was abolished by pharmacological blockade of K+ channels with voltage-gated K+ channels representing most of this effect. Next, we used the UAS/Gal4 model system to screen for candidate genes encoding glial voltage-gated K+ channels and found that knockdown of sei- and Shaw-encoded channels mimicked the effect of K+ blockade in cold-acclimated flies. Furthermore we show that the knockdown of glial sei-encoded channels also impair tolerance to anoxia and heat stress. These findings suggest that voltage-gated K+ channels, especially those encoded by sei, are integral to the CNS stress- and acclimation-response and we posit that this is elicited through mechanisms involving glial spatial buffering and barrier function. Establishing such causal links between tissue-specific expression of candidate genes and SD mechanisms will inevitably aid our understanding of insect ecophysiology and SD-related neuropathologies. | | 11:31p |
Fast 3D imaging in the auditory cortex of awake mice reveals that astrocytes control neurovascular coupling responses locally at arteriole-capillary junctions.
During neuronal activity, cerebral blood flow increases to ensure adequate glucose and oxygen supply, a crucial mechanism known as the neurovascular coupling response. Blood is drawn from the brain surface through penetrating arterioles (PA) and locally redistributed via branching capillaries in the cerebral cortex. All blood vessels, regardless of cortical layer or size, are covered by astrocytic end-feet, suggesting a potential regulatory role. Though the regulatory machinery is known to be present in astrocyte end-feet, its role in this blood recruitment is still controversial. A likely explanation for the controversy is that studies so far have been done without considering the structural basis for blood flow regulation and the heterogeneity in blood vessel dilation patterns. We performed our experiments in awake mice, using a 3D+t two-photon imaging approach by which we could image regions at the branching point between PA and capillary bed at high speed. This led us to detect rapid, localized astrocytic Ca2+ signals in the end-feet surrounding the sphincter connecting the two vascular compartments. Mice often moved during experiments, and we noticed that in these cases, most of the natural vessel dilations in our imaged region were multicompartmental, extending from the PA to the 1st order capillary across the pre-capillary sphincter or vice versa. In contrast, when the mouse was at rest, dilations were more spatially restricted, with at least half of them remaining confined to one of the two compartments. The local Ca2+ rises in the end-feet encircling the pre-capillary sphincters preceded dilations spread and were notably correlated with multicompartment dilations. These Ca2+ signals were attenuated in IP3R2KO mice, lacking a major source of astrocyte Ca2+ rises, and the number of dilations crossing the sphincter was significantly reduced or slowed down compared to wild-type mice. When we induced dilations by auditory stimulation, we found that they had patterns and dependency on local astrocyte Ca2+ activity analogous to those of naturally occurring dilations. In conclusion, we discovered that pre-capillary sphincters play a pivotal role in the bidirectional dilation spread between vascular compartments and that local astrocyte Ca2+ signaling controls this function. This mechanism, described here for the first time, allows astrocytes to control the dilation transition across the sphincters and contribute to laminar blood flow regulation during neurovascular coupling responses. |
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