bioRxiv Subject Collection: Neuroscience's Journal
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Thursday, August 15th, 2024
| Time |
Event |
| 10:48a |
Peripubertal antagonism of corticotropin-releasing factor receptor 1 results in sustained, sex-specific changes in behavioral plasticity and the transcriptomic profile of the amygdala
Peripuberty is a significant period of neurodevelopment with long-lasting effects on the brain and behavior. Blocking type 1 corticotropin-releasing factor receptors (CRFR1) in neonatal and peripubertal rats attenuates detrimental effects of early-life stress on neural plasticity, behavior, and stress hormone action, long after exposure to the drug has ended. CRFR1 antagonism can also impact neural and behavioral development in the absence of stressful stimuli, suggesting sustained alterations under baseline conditions. To investigate this further, we administered a CRFR1 antagonist (CRFR1a), R121919, to young adolescent male and female rats across 4 days. Following each treatment, rats were tested for locomotion, social behavior, mechanical allodynia, or PPI of the acoustic startle reflex. Acute CRFR1 blockade immediately reduced PPI in peripubertal males, but not females. In adulthood, each assay was repeated without CRFR1a exposure to test for long-term effects of the adolescent treatment, with males continuing to experience deficits in PPI, while females displayed altered locomotion, PPI, and social behavior. The amygdala was collected to measure long-term effects on gene expression in pathways related to neural plasticity and neurodevelopmental disorders. Relative expression of cannabinoid type 1 receptors (CB1R), which mediate sensorimotor and HPA function, was also measured. In the adult amygdala, peripubertal CRFR1a induced alterations in pathways related to neural plasticity and stress in males and lower expression of CB1R protein in females. Understanding how acute exposure to neuropharmacological agents can have sustained impacts on brain and behavior, in the absence of further exposures, has important clinical implications for adolescent psychiatric treatment protocols. | | 10:48a |
Cell type-specific dysregulation of gene expression due to Chd8 haploinsufficiency during mouse cortical development
Disruptive variants in the chromodomain helicase CHD8, which acts as a transcriptional regulator during neurodevelopment, are strongly associated with risk for autism spectrum disorder (ASD). Loss of CHD8 function is hypothesized to perturb gene regulatory networks in the developing brain, thereby contributing to ASD etiology. However, insight into the cell type-specific transcriptional effects of CHD8 loss of function remains limited. We used single-cell and single-nucleus RNA-sequencing to globally profile gene expression and identify dysregulated genes in the embryonic and juvenile wild type and Chd8+/- mouse cortex, respectively. Chd8 and other ASD risk-associated genes showed a convergent expression trajectory that was largely conserved between the mouse and human developing cortex, increasing from the progenitor zones to the cortical plate. Genes associated with risk for neurodevelopmental disorders and genes involved in neuron projection development, chromatin remodeling, signaling, and migration were dysregulated in Chd8+/- embryonic day (E) 12.5 radial glia. Genes implicated in synaptic organization and activity were dysregulated in Chd8+/- postnatal day (P) 25 deep- and upper-layer excitatory cortical neurons, suggesting a delay in synaptic maturation or impaired synaptogenesis due to CHD8 loss of function. Our findings reveal a complex pattern of transcriptional dysregulation in Chd8+/- developing cortex, potentially with distinct biological impacts on progenitors and maturing neurons in the excitatory neuronal lineage. | | 11:18a |
Hierarchical Working Memory and a New Magic Number
The extremely limited working memory span, typically around four items, contrasts sharply with our everyday experience of processing much larger streams of sensory information concurrently. This disparity suggests that working memory can organize information into compact representations such as chunks, yet the underlying neural mechanisms remain largely unknown. Here, we propose a recurrent neural network model for chunking within the framework of the synaptic theory of working memory. We showed that by selectively suppressing groups of stimuli, the network can maintain and retrieve the stimuli in chunks, hence exceeding the basic capacity. Moreover, we show that our model can dynamically construct hierarchical representations within working memory through hierarchical chunking. A consequence of this proposed mechanism is a new limit on the number of items that can be stored and subsequently retrieved from working memory, depending only on the basic working memory capacity when chunking is not invoked. Predictions from our model were confirmed by analyzing single-unit responses in epileptic patients and memory experiments with verbal material. Our work provides a novel conceptual and analytical framework for understanding the on-the-fly organization of information in the brain that is crucial for cognition. | | 4:15p |
Rapid Parallel Visual Presentation Provides a New Perspective on Relative Clause Processing in Mandarin Chinese
A fundamental question in language processing research is the degree to which the acceptability and ease of interpretation of a sentence are affected by the moment-by-moment memory encoding and retrieval processes needed to process it in time, vs. the properties of the linguistic representation itself, such as syntactic complexity. This manuscript investigates relative clauses, a crucial testing ground for theories of language processing, using parallel presentation, a technique in which the key elements of the target syntactic dependency are displayed to the visual system at the same time. Compared to serial presentation, parallel presentation mitigates the extent to which complex memory operations must be deployed to process the structure word-by-word. We report on an electroencephalography (EEG) experiment in Mandarin Chinese. Participants were presented with sentences which contained either a subject- or object-modifying subject- or object-extracted relative clause. Sentence presentation was split across two separate screens, with each screen being displayed only for 166ms on average. We find a behavioral preference for subject-extracted relative clauses and distinct EEG signatures for subject- and object-extracted relative clauses. Together, these results - on account of the parallel presentation scheme applied here - provide support for the independent contribution of linguistic representation in processing difficulty and the perspective that relative clause processing involves more than the factors that word by word accounts of this phenomenon would suggest. Further, the EEG result contributes to a growing body of electrophysiology literature attempting to illuminate the processing mechanisms deployed in the context of parallel presentation. | | 5:30p |
qPRF: A system to accelerate population receptive field decoding
Patterns of BOLD response can be decoded using the population receptive field (PRF) model to reveal how visual input is represented on the cortex (Dumoulin and Wandell, 2008). The time cost of evaluating the PRF model is high, often requiring days to decode BOLD signals for a small cohort of subjects. We introduce the qPRF, an efficient method for decoding that reduced the computation time by a factor of 1436 when compared to another widely available PRF decoder (Kay,Winawer, Mezer andWandell, 2013) on a benchmark of data from the Human Connectome Project (HCP; Van Essen, Smith, Barch, Behrens, Yacoub and Ugurbil, 2013). With a specially designed data structure and an efficient search algorithm, the qPRF optimizes the five PRF model parameters according to a least-squares criterion. To verify the accuracy of the qPRF solutions, we compared them to those provided by Benson, Jamison, Arcaro, Vu, Glasser, Coalson, Van Essen, Yacoub, Ugurbil, Winawer and Kay (2018). Both hemispheres of the 181 subjects in the HCP data set (a total of 10,753,572 vertices, each with a unique BOLD time series of 1800 frames) were decoded by qPRF in 15.2 hours on an ordinary CPU. The absolute difference in 2 reported by Benson et al. and achieved by the qPRF was negligible, with a median of 0.39% (2 units being between 0% and 100%). In general, the qPRF yielded a slightly better fitting solution, achieving greater 2 on 99.7% of vertices. The qPRF may facilitate the development and computation of more elaborate models based on the PRF framework, as well as the exploration of novel clinical applications. | | 5:30p |
Age-Related Cerebral Ventriculomegaly occurs in Patients with Primary Ciliary Dyskinesia
Primary ciliary dyskinesia (PCD) is a genetic disorder causing motile ciliary dysfunction primarily affecting the respiratory and reproductive systems. However, the impact of PCD on the central nervous system, through dysfunction of motile cilia in multiciliated ependymal cells, remains poorly understood. We hypothesized that patients with PCD exhibit sub-clinical ventriculomegaly due to ependymal ciliary dysfunction, which may influence neuropsychiatric diagnoses. We demonstrated highly specific expression levels of known PCD-related genes in human brain ependymal cells (p<0.0001), supporting their potential role in regulating ependymal ciliary function. Computed tomography sinus images from patients with PCD (n=33) and age/sex-matched controls (n=64) were analysed. Patients with PCD displayed significantly larger ventricular areas (p<0.0001) and Evans index (p<0.01), indicating ventriculomegaly that was consistent across all genetic subgroups. Ventricular enlargement correlated positively with increasing age in patients with PCD compared to controls (p<0.001). Chart review demonstrated a high prevalence (39%) of neuropsychiatric/neurological disorders in adult PCD patients that did not correlate with degree of ventriculomegaly. Our findings suggest that patients with PCD may have unrecognized, mild ventriculomegaly potentially due to ependymal ciliary dysfunction which correlates with ageing. Further study is required to determine if ventricular enlargement contributes to neuropsychiatric/neurological or other morbidity in PCD. |
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