bioRxiv Subject Collection: Neuroscience's Journal
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Sunday, September 22nd, 2024
| Time |
Event |
| 3:16a |
Comparing alpha-synuclein-interactomes between multiple systems atrophy and Parkinsons disease reveals unique and shared pathological features.
Introduction: Primary synucleinopathies, such as Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are neurodegenerative disorders with some shared clinical and pathological features. Aggregates of alpha-synuclein (syn) phosphorylated at serine 129 (PSER129) are the hallmark of synucleinopathies, which for PD/DLB are found predominantly in neurons (Neuronal cytoplasmic inclusions NCIs), but for MSA, aggregates are primarily found in oligodendroglia (Glial cytoplasmic inclusions GCIs). It remains unclear if the distinct pathological presentation of PD/DLB and MSA are manifestations of distinct or shared pathological processes. We hypothesize that the distinct synucleinopathies MSA and PD/DLB share common molecular features. Methods: Using the in-situ proximity labeling technique biotinylation by antibody recognition (BAR), we compare aggregated syn-interactomes (BAR-PSER129) and total syn-interactomes (BAR-MJFR1) between MSA (n=5) and PD/DLB (n=10) in forebrain and midbrain structures. Results: For BAR-PSER129 and BAR-MJFR1 captures, syn was the most significantly enriched protein in PD/DLB and MSA. In PD/DLB, BAR-PSER129 identified 194 syn-aggregate-interacting proteins, while BAR-MJFR1 identified 245 syn interacting proteins. In contrast, in the MSA brain, only 38 and 175 proteins were identified for each capture, respectively. When comparing MSA and PD/DLB, a high overlap (59.5%) was observed between BAR-MJFR1 captured proteins, whereas less overlap (14.4%) was observed for BAR-PSER129. Direct comparison between MSA and PD/DLB revealed 79 PD/DLB-associated proteins and only three MSA-associated proteins (CBR1, CRYAB, and GFAP). Pathway enrichment analysis revealed PD/DLB interactions were dominated by vesicle/SNARE-associated pathways, in contrast to MSA, which strongly enriched for metabolic/catabolic, iron, and cellular oxidant detoxification pathways. A subnetwork of cytosolic antioxidant enzymes called peroxiredoxins drove cellular detoxification pathways in MSA. A common network of 25 proteins, including neuronal-specific proteins (e.g., SNYGR3) with HSPA8 at the core, was shared between MSA and DLB/PD. Extracellular exosome pathways were universally enriched regardless of disease or BAR target protein. Conclusion: Synucleinopathies show divergent and convergent syn-aggregate interactions, indicating unique and shared pathogenic mechanisms. MSA uniquely involves oxidant detoxification processes in glial cells, while vesicular processes in neurons dominate PD/DLB. Shared interactions, specifically SNYGR3 (i.e., a neuronal protein), between MSA and PD/DLB suggest neuronal axons origin for both diseases. In conclusion, we provide syn aggregates protein interaction maps for two distinct synucleinopathies. | | 3:16a |
Vocal Call Locator Benchmark (VCL) for localizing rodent vocalizations from multi-channel audio
Understanding the behavioral and neural dynamics of social interactions is a goal of contemporary neuroscience. Many machine learning methods have emerged in recent years to make sense of complex video and neurophysiological data that result from these experiments. Less focus has been placed on understanding how animals process acoustic information, including social vocalizations. A critical step to bridge this gap is determining the senders and receivers of acoustic information in social interactions. While sound source localization (SSL) is a classic problem in signal processing, existing approaches are limited in their ability to localize animal-generated sounds in standard laboratory environments. Advances in deep learning methods for SSL are likely to help address these limitations, however there are currently no publicly available models, datasets, or benchmarks to systematically evaluate SSL algorithms in the domain of bioacoustics. Here, we present the VCL Benchmark: the first large-scale dataset for benchmarking SSL algorithms in rodents. We acquired synchronized video and multi-channel audio recordings of 767,295 sounds with annotated ground truth sources across 9 conditions. The dataset provides benchmarks which evaluate SSL performance on real data, simulated acoustic data, and a mixture of real and simulated data. We intend for this benchmark to facilitate knowledge transfer between the neuroscience and acoustic machine learning communities, which have had limited overlap. | | 3:16a |
hiPSC-derived astrocytes from individuals with schizophrenia promote alterations in phagocytosis and chemotaxis of microglial-like cells
Neuroinflammation, particularly astrocyte reactivity, are increasingly linked to schizophrenia (SCZ). Yet, the crosstalk between astrocytes and microglia in SCZ, especially under pro-inflammatory conditions, remains unclear. Here, we apply human induced pluripotent stem cells (hiPSCs) to compare the reactivity of astrocytes from individuals with SCZ and neurotypical controls, towards resolving how patient-derived astrocytes affect microglial biology. TNF-[a] stimulation of SCZ astrocytes, relative to control astrocytes, trigger an increase in expression of pro-inflammatory cytokines and CX3CL1, a chemokine involved in chemotaxis and synapse pruning. Transcriptomic analyses reveal that TNF-[a]-stimulated SCZ astrocytes promote the downregulation of biological processes associated with phagocytosis and chemotaxis in induced microglial-like cells (iMGs). Interestingly, TNF-[a]-stimulated SCZ astrocytes lead to reduced synaptoneurosomes engulfment by iMGs. Alternatively, TNF-[a]-stimulated astrocytes (control and SCZ) induce microglial migration in a CX3CR1-dependent manner. Surprisingly, TNF-[a]-stimulated SCZ astrocytes do not promote a more pronounced microglial chemotaxis, despite secreting twice as much CX3CL1 compared to stimulated control astrocytes, possibly due to lower CX3CR1 plasma membrane content after exposure to ACM from individuals with SCZ. Altogether, these findings suggest that astrocytes contribute to SCZ pathology by altering normal microglial function. | | 3:16a |
Lower limb pointing to assess intersegmental dynamics after incomplete spinal cord injury and the associated role of proprioceptive impairments.
Background: Disorders in the recovery of gait strategies in individuals with incomplete spinal cord injury (SCI) suggest difficulties in controlling lower limb intersegmental dynamics, which could relate to proprioceptive impairments. To probe discrete aspects of lower limb interjoint coordination, we present here a novel protocol to assess lower limb motor strategies and evaluate the influence of proprioceptive impairments following SCI. Methods: Twelve able-bodied controls and 16 participants with SCI performed lower limb pointing to three targets that involved combined hip and knee flexion, or hip or knee flexion only while standing, with either full or obstructed visual feedback. We quantified lower limb proprioceptive sense in individuals with SCI using a robotic gait device. We used motion analysis to determine lower limb joint angles and foot trajectory, computed inverse dynamics to quantify joint and intersegmental dynamics, and derived muscle torque as an indicator of the motor strategies produced to control the motion to each target. We used linear mixed-effects models to assess differences between the control and SCI groups on end-point performance and muscle torque, and to assess the relationship of muscle torque with end-point performance and proprioceptive sense. Results: Groups differed in motor strategies, but not end-point performance, when pointing to all three targets. Compared to controls, the SCI group had difficulty controlling knee muscle torque when performing the hip-flexion-only target (p = 0.008) or when flexing the hip and knee simultaneously (p = 0.0004). To complete the knee-flexion-only target, the SCI group had difficulties generating the required hip extensor muscle torque to maintain the thigh in neutral (p = 0.0001). These altered motor strategies in individuals with SCI were associated with proprioceptive impairments and end-point performance. Conclusion: This novel lower limb pointing task can identify disordered motor strategies in individuals with SCI, especially at the knee, and are associated with proprioceptive impairment. Variations of this paradigm can be employed to further understand differences in motor strategies between controls and individuals with SCI, and the impact of proprioceptive deficits. | | 3:16a |
Spinal neuron diversity scales exponentially with swim-to-limb transformation during frog metamorphosis
Vertebrates exhibit a wide range of motor behaviors, ranging from swimming to complex limb-based movements. Here we take advantage of frog metamorphosis, which captures a swim-to-limb-based movement transformation during the development of a single organism, to explore changes in the underlying spinal circuits. We find that the tadpole spinal cord contains small and largely homogeneous populations of motor neurons (MNs) and V1 interneurons (V1s) at early escape swimming stages. These neuronal populations only modestly increase in number and subtype heterogeneity with the emergence of free swimming. In contrast, during frog metamorphosis and the emergence of limb movement, there is a dramatic expansion of MN and V1 interneuron number and transcriptional heterogeneity, culminating in cohorts of neurons that exhibit striking molecular similarity to mammalian motor circuits. CRISPR/Cas9-mediated gene disruption of the limb MN and V1 determinants FoxP1 and Engrailed-1, respectively, results in severe but selective deficits in tail and limb function. Our work thus demonstrates that neural diversity scales exponentially with increasing behavioral complexity and illustrates striking evolutionary conservation in the molecular organization and function of motor circuits across species. | | 3:46a |
Concurrent large-scale brain dynamics during the emotional face matching task and their relation to behavior and mental health
Prior investigations of emotion processing's neural underpinnings rely on a priori models of brain response, obscuring detection of task-relevant neurobiological processes with complex temporal dynamics. To overcome this limitation, we applied unsupervised machine learning to functional magnetic resonance imaging data acquired during the emotional face matching task (EFMT) in healthy young adults from the Human Connectome Project (n=413; n=416 replication). Tensorial independent component analysis showed that the EFMT engages 10 large-scale brain networks - each recruiting visual association cortex in distinct temporal fashions and in tandem with diverse non-visual regions - that collectively recruit 74% of cortex, posterior cerebellum, and amygdala. Despite prominent use of the EFMT to probe negative affect and related psychopathology, EFMT-recruited networks strongly reflected individual differences in cognition but not internalizing/negative affect. Overall, we characterize a richer-than-expected tapestry of concurrent EFMT-recruited brain processes, their diverse activation dynamics, and their relations to task performance and latent mental health phenotypes. | | 3:46a |
Increased listening effort and decreased speech discrimination at high presentation sound levels in acoustic hearing listeners and cochlear implant users
The sounds we experience in our everyday communication can vary greatly in terms of level and background noise depending on the environment. Paradoxically, increasing the sound intensity may lead to worsened speech understanding, especially in noise. This is known as the "Rollover" phenomenon. There have been limited studies on rollover and how it is experienced differentially across aging groups, for those with and without hearing loss, as well as cochlear implant (CI) users. There is also mounting evidence that listening effort plays an important role in challenging listening conditions and can be directly quantified with objective measures such as pupil dilation. We found that listening effort was modulated by sound level and that rollover occurred primarily in the presence of background noise. The effect on listening effort was exacerbated by age and hearing loss in acoustic listeners, with greatest effect in older listeners with hearing loss, while there was no effect in CI users. The age- and hearing- dependent effects of rollover highlight the potential negative impact of amplification to high sound levels and therefore has implications for effective treatment of age-related hearing loss | | 3:46a |
Human medial pulvinar is involved in face and tactile processing and dynamically adjusts its cortical connectivity based on ongoing stimulation
Optimal processing of our surrounding environment relies on our ability to detect and integrate external information through multiple sensory modalities to build a coherent representation of the world. Interactions between cortical and subcortical structures contribute to this process. In this context, there is growing evidence that the pulvinar plays a crucial role in visual and face processing. In contrast, its role in auditory, voice and tactile processing has been poorly investigated. Here, we use fMRI localizer tasks to describe pulvinar functional organization and functional connectivity with the brain during face, voice and tactile processing. We reproduce the activation of the ventral part of the medial pulvinar in face perception and we describe an increased pulvinar connectivity with face processing areas and a decreased connectivity with low level visual areas during face processing. In addition, we describe activations of the medial pulvinar during air-puff face, hands and feet tactile stimulations and changes in pulvino-cortical connectivity as a function of which body part is being stimulated. No activations are observed during either voice or non-voice stimulations. Overall, this supports a role of medial pulvinar in multisensory processing and the modulation of cortical areas as a function of the sensory context. | | 4:44a |
Differential representations for affective and informative components of reward in the striatum and hippocampus
Receipt of a reward is composed of affective and informative components, which are often intertwined in most reward-processing and decision-making tasks. Our previous work allowed us to identify regions that were more strongly engaged for the affective and informative components of reward upon receipt (Smith et al., 2016) and showed that the ventral striatum responds to both affective and informative components of reward processing. However, the limited spatial resolution and coarse analytical approaches made it hard to understand how these different components of reward were represented in the brain, wherein similar engagement may not necessitate similar representations. In our current study, we used high-resolution functional magnetic resonance imaging (voxel size: 1.75 mm3) and representational similarity analysis to investigate the representation of affective and informative components of reward receipt in the striatum and the hippocampus, another region that is sensitive to reward information. We found a differential representation of affective and informative components of reward receipt in the striatum and the hippocampus, with no difference in representation between the two structures. However, in the dorsal striatum, we found that representations were stronger for affective rather than the informative components of reward receipt. Finally, we observed that the ventral striatum was sensitive to the predictiveness of information, such that across-run pattern similarity in the ventral striatum increased with the predictiveness of information. In sum, our results provide evidence of how affective and informative components of rewards are represented in the striatum and the hippocampus, potentially indicating a differential coding schema for the dorsal and the ventral striatum. | | 4:44a |
Histone deacetylase 5 in prelimbic prefrontal cortex limits context-associated cocaine seeking
Background Repeated cocaine use produces neuroadaptations that support drug craving and relapse in substance use disorders (SUDs). Powerful associations formed with drug-use environments can promote a return to active drug use in SUD patients, but the molecular mechanisms that control the formation of these prepotent drug-context associations remain unclear. Methods In the rat intravenous cocaine self-administration (SA) model, we examined the role and regulation of histone deacetylase 5 (HDAC5) in the prelimbic (PrL) and infralimbic (IL) cortices in context-associated drug seeking. To this end, we employed viral molecular tools, chemogenetics, RNA-sequencing, electrophysiology, and immunohistochemistry. Results In the PrL, reduction of endogenous HDAC5 augmented context-associated, but not cue- or drug prime-reinstated cocaine seeking, whereas overexpression of HDAC5 in PrL, but not IL, reduced context-associated cocaine seeking, but it had no effects on sucrose seeking. In contrast, PrL HDAC5 overexpression following acquisition of cocaine SA had no effects on future cocaine seeking. We found that HDAC5 and cocaine SA altered the expression of numerous PrL genes, including many synapse-associated genes. HDAC5 significantly increased inhibitory synaptic transmission onto PrL deep-layer pyramidal neurons, and it reduced the induction of FOS-positive neurons in the cocaine SA environment. Conclusions Our findings reveal an essential and selective role for PrL HDAC5 to limit associations formed in cocaine, but not sucrose, SA environments, and that it alters the PrL excitatory/inhibitory balance, possibly through epigenetic regulation of synaptic genes. These results further position HDAC5 as a key factor regulating reward-circuit neuroadaptations that underlie common relapse triggers in SUD. | | 4:44a |
A role for acetylcholine in reinforcement learning and decision making under uncertainty
The neuromodulator acetylcholine has been suggested to govern learning under uncertainty. Here, we investigated the role of muscarinic receptors in reward-guided learning and decision making under different degrees of uncertainty. We administered the muscarinic M1 antagonist biperiden (4 mg) to healthy male participants (n = 43) in a within-subjects, placebo-controlled design. Participants performed two tasks that both involved choices between options characterized by two attributes, reward probability and magnitude. In the gambling task, both attributes were explicitly provided, whereas in the learning task, reward probabilities had to be inferred from past experience. In addition, uncertainty was manipulated within the learning task by inclusion of a stable phase with fixed reward contingencies, and a volatile phase with frequent contingency reversals. We show that biperiden did not affect decision making in the gambling task, where no learning was required. However, in the learning task, biperiden reduced the sensitivity to the learnt reward probabilities. Notably, this was primarily driven by choices under higher uncertainty in the volatile phase. Using reinforcement learning models, we reveal that the change in behaviour was caused by noisier estimates of probabilities resulting from maladaptively increased learning rates under biperiden. Together, these findings suggest that muscarinic acetylcholine transmission is involved in controlling learning in highly uncertain contexts, when the demand for carefully calibrated adjustments is highest. | | 4:44a |
A large cohort study (n = 591) on the impact of the presence or absence of the interthalamic adhesion: cognitive, neuroimaging, and genetic results
Both thalami can be connected by an Interthalamic Adhesion (IA). The extent of its presence varies among individuals and remains poorly understood. This study examines the IA's prevalence, anatomical variations, genetic determinants, and cognitive associations. Data from 591 healthy subjects (25-35 years) from the Human Connectome Project were analyzed and grouped as monozygotic (MZ) twins, dizygotic (DZ) twins, non-twin siblings, and unrelated individuals. MRI was used to characterize the IA, while neuropsychological assessments and Freesurfer parcellations were used to assess cognition and anatomical differences between subjects with or without an IA. The IA was absent in 12.7% of subjects, more commonly in males (20.0%) than females (6.3%), with no significant differences in age, education, or cognition between those with and without an IA. IA absence was associated with increased cerebrospinal fluid volumes, enlarged third ventricles, and thinning in several cortical areas. Genetic analysis revealed a higher concordance of IA presence among MZ twins (96%) than in other groups, indicating a strong genetic influence. The remaining 4% discrepancy was observed in male pairs only. This study underscores the genetic basis of IA, highlighting sexual dimorphism and neuroanatomical differences associated with its absence, though it does not affect cognition in healthy individuals. | | 4:44a |
Abstinence from cocaine self-administration promotes microglia pruning of astrocytes which drives cocaine-seeking behavior
Rodent drug self-administration leads to compromised ability of astrocytes to maintain glutamate homeostasis within the brains reward circuitry, as well as reductions in surface area, volume, and synaptic colocalization of astrocyte membranes. However, the mechanisms driving astrocyte responses to cocaine are unknown. Here, we report that long-access cocaine self-administration followed by prolonged home cage abstinence results in decreased branching complexity of nucleus accumbens astrocytes, characterized by the loss of peripheral processes. Using a combination of confocal fluorescence microcopy and immuno-gold electron microscopy, we show that alterations in astrocyte structural features are driven by microglia phagocytosis, as labeled astrocyte membranes are found within microglia phagolysosomes. Inhibition of complement C3-mediated phagocytosis using the neutrophil inhibitory peptide (NIF) rescued astrocyte structure and decreased cocaine seeking behavior following cocaine self-administration and abstinence. Collectively, these results provide evidence for microglia pruning of accumbens astrocytes across cocaine abstinence which mediates cocaine craving. | | 4:44a |
Stimulation of otolith irregular fibers produces a rostro-caudal gradient in activity in the vestibular nuclear complex (VNC), but not the vestibulocerebellum (VeCb)
The vestibular system is important for posture, balance, motor control, and spatial orientation. Each of the vestibular end organs have specialized neuroepithelia with both regular and irregular afferents. In otolith organs, the utricle and saccule, afferents most responsive to linear jerk (jerk - derivative of acceleration) are located in the striola and project centrally to the vestibular nuclear complex (VNC) as well as the uvula and nodulus of the vestibulocerebellum (VeCb). The pattern of central neuronal activation attributed to otolith irregular afferents is relatively unknown. To address this gap, c-Fos was used as a marker of neuronal activity to map the distribution of active neurons throughout the rostro-caudal extent of the VNC and VeCb. Immunohistochemistry for c-Fos was performed to assess activation of VNC and VeCb neurons in response to a linear jerk stimulus delivered in the naso-occipital plane. Activated neurons were distributed throughout the VNC, including the lateral vestibular nucleus (LVe), magnocellular medial vestibular nucleus (MVeMC), parvocellular medial vestibular nucleus (MVePC), spinal vestibular nucleus (SpVe), and superior vestibular nucleus (SuVe). Notably, after stimulation, the MVePC exhibited the greatest number of c-Fos labeled nuclei. Significant increases in c-Fos labeling were found in mid-rostrocaudal and caudal regions of the VNC in the LVe, MVe, and SpVe. Additionally, c-Fos labeling was observed across all regions of the VeCb after jerk stimulation. Significant increases in the number of labeled nuclei were found throughout the rostro-caudal extent of the nodulus and uvula. However, jerk stimulated increases in activity for the paraflocculus were restricted to the caudal VeCb. The distribution of neuronal activity suggests that regions receiving the greatest direct otolith input exhibit the most substantial changes in response to otolith derived, irregular fiber stimulation. | | 7:49a |
Microglia determine an immune-challenged environment and facilitate ibuprofen action in human retinal organoids.
Prenatal immune challenges pose significant risks to human embryonic brain and eye development. However, we still lack knowledge about the safe usage of anti-inflammatory drugs during pregnancy. While human induced pluripotent stem cells (hIPSC)-derived brain organoid models have started to explore functional consequences upon viral stimulation, these models commonly lack microglia. Yet, microglia are susceptible to and promote inflammation and will influence the effects. Here, we generate hIPSC-derived microglia precursor cells and assemble them into retinal organoids to dissect their interplay with the developing nervous system and expose them to the immunostimulant poly(I:C). We first identified successful hIPSC-derived microglia (iMG) integration into the retinal organoid at the time when the outer plexiform layer forms. To improve ganglion cell surveillance, we adapted the retinal organoid model and found that the ganglion cell number significantly decreased only with iMG presence. While poly(I:C) exposure alters the iMG phenotype, it does not hinder their interaction with ganglion cells. Furthermore, iMG significantly enhances the supernatant's inflammatory secretome and increases retinal cell proliferation. Simultaneous exposure with the non-steroidal anti-inflammatory drug (NSAID) ibuprofen dampens the poly(I:C)-mediated changes of the iMG phenotype and ameliorates cell proliferation. Remarkably, while poly(I:C) disrupts neuronal calcium dynamics independent of iMG, ibuprofen rescues this effect only if iMG are present. This effect depends on cyclooxygenase 1 in microglia and cyclooxygenase 2, common NSAID targets. These findings underscore the importance of microglia in the context of prenatal immune challenges and provide insight into the mechanisms by which ibuprofen exerts its protective effects during embryonic development. |
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