bioRxiv Subject Collection: Neuroscience's Journal
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Saturday, February 17th, 2024
| Time |
Event |
| 12:48a |
YY1 mutations disrupt corticogenesis and cytoarchitecture through a cell-type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs
Germline mutations of YY1 cause Gabriele-de Vries syndrome (GADEVS), a neurodevelopmental disorder featuring intellectual disability and a wide range of systemic manifestations. To dissect the cellular and molecular mechanisms underlying GADEVS, we combined large-scale imaging, single-cell multiomics and gene regulatory network reconstruction in 2D and 3D patient-derived physiopathologically relevant cell lineages. YY1 haploinsufficiency causes a pervasive alteration of cell type specific transcriptional networks, disrupting corticogenesis at the level of neural progenitors and terminally differentiated neurons, including cytoarchitectural defects reminiscent of GADEVS clinical features. Transcriptional alterations in neurons propagated to neighboring astrocytes through a major non-cell autonomous pro-inflammatory effect that grounds the rationale for modulatory interventions. Together, neurodevelopmental trajectories, synaptic formation and neuronal-astrocyte cross talk emerged as salient domains of YY1 dosage-dependent vulnerability. Mechanistically, cell-type resolved reconstruction of gene regulatory networks uncovered the regulatory interplay between YY1, NEUROG2 and ETV5 and its aberrant rewiring in GADEVS. Our findings underscore the reach of advanced in vitro models in capturing developmental antecedents of clinical features and exposing their underlying mechanisms to guide the search for targeted interventions. | | 12:48a |
Targeting a specific motor control process reveals an age-related compensation that adapts movement to gravity environment
AO_SCPLOWBSTRACTC_SCPLOWAs the global population ages, it is crucial to understand sensorimotor compensation mechanisms that allow older adults to remain in good physical health, i.e. underlying successful aging. Although age-related compensation has long been conceptualized and despite important research efforts in varied gerontological subfields, behavioral compensatory processes and their underlying neural mechanisms remain essentially chimeras. This study investigates age-related compensation at the behavioral level. It tests the basic hypothesis that age-related compensatory processes may correspond to an adaptation process that changes movement strategy. More specifically, we focused on the ability of younger (n = 20; mean age = 23.6 years) and older adults (n = 24; mean age = 72 years) to generate movements that are energetically efficient in the gravitational environment. Previous results, from separate studies, suggest that aging differently alters energy efficiency in arm movement and whole-body movement tasks. With aging, energy efficiency seems to remain highly functional in arm movements but has been shown to decrease in whole-body movements. Here, we built on recent theoretical and experimental results demonstrating a behavioral process that optimally adapts human arm movements to the gravitational environment. Analyzing phasic muscle activation patterns, previous studies provided electromyographic measurements that quantified the output of an optimal strategy using gravity effects to discount muscle effort. Using these measurements, we probed the effort-minimization process in younger and older adults during arm movement and whole-body movement tasks. The key finding demonstrates that aging differently alters motor strategies for arm movements vs whole-body movements. Older adults used gravity effects to a similar extent as younger ones when performing arm movements, but to a lesser extent when performing whole body movements. These results provide clear experimental support for an adaptation strategy that down-regulates effort minimization in older adults. | | 1:16a |
The Body Knows Better: Sensorimotor signals reveal "Suboptimal" inference of the Sense of Agency in the human mind
Sense of Agency (SoA) is the feeling of control over our actions. SoA has been suggested to arise from both implicit sensorimotor integration as well as higher-level decision processes. SoA is typically measured by collecting participants subjective judgments, conflating both implicit and explicit processing. Consequently, the interplay between implicit sensorimotor processing and explicit agency judgments is not well understood. Here, we evaluated in one exploratory and one preregistered experiment (N=60), using a machine learning approach, the relation between a well-known mechanism of implicit sensorimotor adaptation and explicit SoA judgments. Specifically, we examined whether subjective judgments of SoA and sensorimotor conflicts could be inferred from hand kinematics in a sensorimotor task using a virtual hand (VH). In both experiments participants performed a hand movement and viewed a virtual hand making a movement that could either be synchronous with their action or include a parametric temporal delay. After each movement, participants judged whether their actual movement was congruent with the movement they observed. Our results demonstrated that sensorimotor conflicts could be inferred from implicit motor kinematics on a trial by trial basis. Moreover, detection of sensorimotor conflicts from machine learning models of kinematic data provided more accurate classification of sensorimotor congruence than participants explicit judgments. These results were replicated in a second, preregistered, experiment. These findings show evidence of diverging implicit and explicit processing for SoA and suggest that the brain holds high-quality information on sensorimotor conflicts that is not fully utilized in the inference of conscious agency. | | 11:32a |
Cortical beta oscillations map to shared brain networks modulated by dopamine
Brain rhythms can facilitate neural communication for the maintenance of brain function. Beta rhythms (13-35 Hz) have been proposed to serve multiple domains of human ability, including motor control, cognition, memory and emotion, but the overarching organisational principles remain unknown. To uncover the circuit architecture of beta oscillations, we leverage normative brain data, analysing over 30 hours of invasive brain signals from 1772 cortical areas in epilepsy patients, to demonstrate that beta is the most distributed cortical brain rhythm. Next, we identify a shared brain network from beta dominant areas with deeper brain structures, like the basal ganglia, by mapping parametrised oscillatory peaks to whole-brain functional and structural MRI connectomes. Finally, we show that these networks share significant overlap with dopamine uptake as indicated by positron emission tomography. Our study suggests that beta oscillations emerge in cortico-subcortical brain networks that are modulated by dopamine. It provides the foundation for a unifying circuit-based conceptualisation of the functional role of beta activity beyond the motor domain and may inspire an extended investigation of beta activity as a feedback signal for closed-loop neurotherapies for dopaminergic disorders. | | 11:32a |
Investigating altered limbic reward system in Huntington's Disease: Implications for apathy
Huntingtons disease (HD) is an inherited neurodegenerative condition characterized by motor, cognitive, and behavioral impairments. Apathy, marked by reduced motivation and goal-directed behavior, is the most prevalent psychiatric symptom in HD, impacting both patients and caregivers. Traditionally linked to executive dysfunction within the dorsolateral prefrontal cortex (dlPFC)-dorsal striatum loop in HD, the role of limbic regions in the basal ganglia and their impact on reward processing deficits remains poorly understood. This study sought to dissociate the functional correlates that are altered in reward valuation and may underlie apathy in HD. We aimed to tease apart whether apathy is associated with insensitivity to processing rewards, hypersensitivity to losses, or both, leading to the observed lack of motivation in apathetic individuals. Thirty-nine HD gene-expansion carriers (HDGEC) and 26 non-apathetic control participants underwent functional magnetic resonance imaging during a gambling task. The goal was to identify disrupted reward-related regions in HDGEC and their association with apathetic symptoms. Whole-brain analysis of gains and losses separately showed a significant reduction in activity, when HD group was compered to controls, within the left ventral striatum (VS), including the nucleus accumbens. The effect observed in the VS remained when clinically apathetic HDGEC were compared with controls. Conversely, non-apathetic HDGEC did not show any significant differences from controls. Interestingly, these group differences appeared exclusively during the processing of the reward. Additionally, higher levels of apathy were associated with especially decreased activity related with the processing of gains in this region. Our findings highlight the vulnerability of the left VS in HD and its association with the altered processing of gains, particularly in apathetic individuals, while preserving the valuation of losses. This suggests that reward insensitivity associated with VS dysfunction may be an important component of apathy in HD. Understanding the underlying mechanisms of reward processing and apathy in HD may help elucidate the implications of limbic regions as opposed to frontal executive dysfunction in apathy. | | 11:32a |
Anterior thalamus functional connectivity with cortical regions underpinning prospective memory: a 7-Tesla fMRI seed-based study
IntroductionProspective memory (PM), or memory for future intentions, engages particular cortical regions. Lesion studies also implicate the thalamus, with PM deterioration following thalamic stroke. Neuroimaging, anatomical, and lesion studies suggest the anterior nuclei of the thalamus (ANT) in particular are involved in episodic memory processing, with electrophysiological studies providing evidence for an active role in selection of neural assemblies underlying particular memory traces. Here we hypothesized that the ANT are also engaged in realizing prospectively-encoded intentions.
MethodsParticipants (N = 14) performed an n-back working memory task as the ongoing task (OGT) with two cognitive loads, each with and without a PM component, during 7-Tesla functional magnetic resonance imaging. Seed-to-voxel whole brain functional connectivity analyses were performed to establish whether including a PM component in an OGT results in greater connectivity between ANT and cortical regions known to be engaged in PM. Repeated measures ANOVAs were applied to behavioral and connectivity measures, with the factors Task Type (with PM or not) and N-Back (2-back or 3-back).
ResultsResponse accuracy was greater and reaction times faster without the PM component, and accuracy was higher in the 2-than 3-back condition. We observed a main effect of Task Type on connectivity with an ANT seed, with greater connectivity between the ANT and dorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) when a PM component was included. Post hoc testing based on a significant interaction showed greater ANT-DLPFC connectivity when PM was included with the low and ANT-STG connectivity with the high cognitive load OGT. There was no main effect of N-Back at these locations. Connectivity based on a dorsomedial nucleus of the thalamus seed did not differ according to Task Type at these locations.
ConclusionsEnhanced connectivity between the ANT and the DLPFC, a brain region with an established role in strategic monitoring for PM cues, arose with a low cognitive load OGT that enabled monitoring. This pattern was absent on directly increasing the cognitive load of the OGT without PM, suggesting specificity for PM. Greater ANT-STG connectivity on PM inclusion in the higher cognitive load OGT condition fits with reports of STG activation on PM through spontaneous retrieval. Differing connectivity based on a dorsomedial nucleus of the thalamus seed suggests ANT specificity. The findings fit with a coordinating role for the ANT in prospective remembering.
Three key points- The anterior nuclei of the thalamus are part of the brain network underpinning prospective memory.
- Greater functional connectivity arose between the anterior nuclei of the thalamus and the dorsolateral prefrontal cortex during prospective remembering through strategic monitoring.
- Increasing the cognitive load of an ongoing working-memory task, encouraging prospective memory to be achieved through spontaneous retrieval, was associated with greater functional connectivity between the anterior nuclei of the thalamus and the superior temporal gyrus. | | 12:45p |
Inverted encoding of neural responses to audiovisual stimuli reveals super-additive multisensory enhancement
A central challenge for the brain is how to combine separate sources of information from different sensory modalities to optimally represent objects and events in the external world, such as combining someones speech and lip movements to better understand them in a noisy environment. At the level of individual neurons, audiovisual stimuli often elicit super-additive interactions, where the neural response is greater than the sum of auditory and visual responses. However, investigations using electroencephalography (EEG) to record brain activity have revealed inconsistent interactions, with studies reporting a mix of super-and sub-additive effects. A possible explanation for this inconsistency is that standard univariate analyses obscure multisensory interactions present in EEG responses by overlooking multivariate changes in activity across the scalp. To address this shortcoming, we investigated EEG responses to audiovisual stimuli using inverted encoding, a population tuning approach that uses multivariate information to characterise feature-specific neural activity. Participants (n=41) completed a spatial localisation task for both unisensory stimuli (auditory clicks, visual flashes) and combined audiovisual stimuli (spatiotemporally congruent clicks and flashes). To assess multivariate changes in EEG activity, we used inverted encoding to recover stimulus location information from event-related potentials (ERPs). Participants localised audiovisual stimuli more accurately than unisensory stimuli alone. For univariate ERP analyses we found an additive multisensory interaction. By contrast, multivariate analyses revealed a super-additive interaction [~]180 ms following stimulus onset, such that the location of audiovisual stimuli was decoded more accurately than that predicted by maximum likelihood estimation. Our results suggest that super-additive integration of audiovisual information is reflected within multivariate patterns of activity rather than univariate evoked responses. |
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