bioRxiv Subject Collection: Neuroscience's Journal
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Wednesday, May 29th, 2024
| Time |
Event |
| 12:18p |
Autism gene variants disrupt enteric neuron migration and cause gastrointestinal dysmotility
The comorbidity of autism spectrum disorders and severe gastrointestinal symptoms is well- established, yet the molecular underpinnings remain unknown. The identification of high-confidence large-effect autism risk genes offers the opportunity to identify convergent, underlying biology by studying these genes in the context of the gastrointestinal system. Here we show that the expression of these genes is enriched in human prenatal gut neurons as well as their migratory progenitors, suggesting that the development and/or function of these neurons may be disrupted by autism-associated pathogenic variants, leading to gastrointestinal dysfunction. Here we document the prevalence of gastrointestinal issues in patients with large-effect variants in sixteen of these genes, highlighting dysmotility, consistent with potential enteric neuron dysfunction. Using the high- throughput diploid frog Xenopus tropicalis, we individually target five of these genes (SYNGAP1, CHD8, SCN2A, CHD2, and DYRK1A) and observe disrupted enteric neuronal progenitor migration for each. More extensive analysis of DYRK1A reveals that perturbation causes gut dysmotility in vivo, which can be ameliorated by treatment with a selective serotonin reuptake inhibitor (escitalopram) or a serotonin receptor 6 agonist, identified by in vivo drug screening. This work suggests that atypical development of enteric neurons contributes to the gastrointestinal distress commonly seen in individuals with autism and that increasing serotonin signaling may be a productive therapeutic avenue. | | 12:18p |
Developmental maturation of millimeter-scale functional networks across brain areas
Interacting with the environment to process sensory information, generate perceptions, and shape behavior engages neural networks in brain areas with highly varied representations, ranging from unimodal sensory cortices to higher-order association areas. Recent work suggests a much greater degree of commonality across areas, with distributed and modular networks present in both sensory and non-sensory areas during early development. However, it is currently unknown whether this initially common modular structure undergoes an equally common developmental trajectory, or whether such a modular functional organization persists in some areas -- such as primary visual cortex -- but not others. Here we examine the development of network organization across diverse cortical regions in ferrets of both sexes using in vivo widefield calcium imaging of spontaneous activity. We find that all regions examined, including both primary sensory cortices (visual, auditory, and somatosensory -- V1, A1, and S1, respectively) and higher order association areas (prefrontal and posterior parietal cortices) exhibit a largely similar pattern of changes over an approximately 3 week developmental period spanning eye opening and the transition to predominantly externally-driven sensory activity. We find that both a modular functional organization and millimeter-scale correlated networks remain present across all cortical areas examined. These networks weakened over development in most cortical areas, but strengthened in V1. Overall, the conserved maintenance of modular organization across different cortical areas suggests a common pathway of network refinement, and suggests that a modular organization -- known to encode functional representations in visual areas -- may be similarly engaged in highly diverse brain areas. | | 12:18p |
Progressive neural engagement within the IFG-pMTG circuit as gesture and speech entropy and MI advances
Semantic representation emerges from distributed multisensory modalities, yet a comprehensive understanding of the functional changing pattern within convergence zones or hubs integrating multisensory semantic information remains elusive. In this study, employing information-theoretic metrics, we quantified gesture and speech information, alongside their interaction, utilizing entropy and mutual information (MI). Neural activities were assessed via interruption effects induced by High-Definition transcranial direct current stimulation (HD-tDCS). Additionally, chronometric double-pulse transcranial magnetic stimulation (TMS) and high-temporal event-related potentials were utilized to decipher dynamic neural changes resulting from various information contributors. Results showed gradual inhibition of both inferior frontal gyrus (IFG) and posterior middle temporal gyrus (pMTG) as degree of gesture-speech integration, indexed by MI, increased. Moreover, a time-sensitive and staged progression of neural engagement was observed, evidenced by distinct correlations between neural activity patterns and entropy measures of speech and gesture, as well as MI, across early sensory and lexico-semantic processing stages. These findings illuminate the gradual nature of neural activity during multisensory gesture-speech semantic processing, shaped by dynamic gesture constraints and speech encoding, thereby offering insights into the neural mechanisms underlying multisensory language processing. | | 12:18p |
Deficiency of the histone lysine demethylase KDM5B causes autism-like phenotypes via increased NMDAR signalling
Loss-of-function mutations in genes encoding lysine methyltransferases (KMTs) and demethylases (KDMs) responsible for regulating the trimethylation of histone 3 on lysine 4 (H3K4me3) are associated with neurodevelopmental conditions, including autism spectrum disorder and intellectual disability. To study the specific role of H3K4me3 demethylation, we investigated neurodevelopmental phenotypes in mice without KDM5B demethylase activity. These mice exhibited autism-like behaviours and increased brain size. H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developing Kdm5b mutant neocortex. These included elevated expression of Grin2d. The Grin2d gene product NMDAR2D was increased in synaptosomes isolated from the Kdm5b-deficient neocortex and treating mice with the NMDAR antagonist memantine rescued deficits in ultrasonic vocalisations and reduced repetitive digging behaviours. These findings suggest that increased H3K4me3 levels and associated Grin2d gene upregulation disrupt brain development and function, leading to socio-communication deficits and repetitive behaviours, and identify a potential therapeutic target for neurodevelopmental disorders associated with KDM5B deficiency. | | 12:18p |
Decoding Salience: A Functional Magnetic Resonance Imaging Investigation of Reward and Contextual Unexpectedness in Memory Encoding and Retrieval
The present study investigated the neuromodulatory substrates of salience processing and its impact on memory encoding and behaviour, with a specific focus on two distinct types of salience: reward and contextual unexpectedness. 46 participants performed a novel task paradigm modulating these two aspects independently and allowing for investigating their distinct and interactive effects on memory encoding while undergoing high resolution fMRI. By using advanced image processing techniques tailored to examine midbrain and brainstem nuclei with high precision, our study additionally aimed to elucidate differential activation patterns in subcortical nuclei in response to reward-associated and contextually unexpected stimuli, including distinct pathways involving in particular dopaminergic modulation. We observed a differential involvement of the ventral striatum, substantia nigra and caudate nucleus, as well as a functional specialisation within the subregions of the cingulate cortex for the two salience types. Moreover, distinct subregions within the substantia nigra in processing salience could be identified. Dorsal areas preferentially processed salience related to stimulus processing (of both reward and contextual unexpectedness) versus ventral areas were involved in salience-related memory encoding (for contextual unexpectedness only). These functional specialisations within SN are in line with different projection patterns of dorsal and ventral SN to brain areas supporting attention and memory, respectively. By disentangling stimulus processing and memory encoding related to two salience types, we hope to further consolidate our understanding of neuromodulatory structures differential as well as interactive roles in modulating behavioural responses to salient events. | | 12:18p |
Temporal rules of fear memory cooperation and competition
Memory consolidation is highly influenced by ongoing experiences. We explore the temporal rules that determine whether events are cooperatively associated or competitively separated. We show that neutral events are associated with fearful events if they occur within less than 30 minutes. In some individuals, memory association can lead to a competitive suppression of the fearful response by the neutral event. Activation of the thalamic MGm inputs to the lateral amygdala, led to an increase in memory association, whereas manipulation of the cortical inputs had no effect. Introducing a third event leads to competition depending on the temporal relationship between the initial association and the competitive event. Our results show a critical temporal rule of memory association, modulated by thalamic activity that shapes fear memory consolidation. |
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