bioRxiv Subject Collection: Neuroscience's Journal
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Thursday, January 11th, 2024
| Time |
Event |
| 3:32a |
Neuropsychiatric sequelae in an experimental model of post-COVID syndrome in mice
The global impact of the COVID-19 pandemic has been unprecedented, and presently, the world is facing a new challenge known as Post-COVID syndrome (PCS). Current estimates suggest that more than 65 million people are grappling with PCS, encompassing several manifestations, including pulmonary, musculoskeletal, metabolic, and neuropsychiatric sequelae (cognitive and behavioral). The mechanisms underlying PCS remain unclear. The present study aimed to: (i) comprehensively characterize the acute effects of pulmonary inoculation of the betacoronavirus MHV-A59 in immunocompetent mice at clinical, cellular, and molecular levels; (ii) examine potential acute and long-term pulmonary, musculoskeletal, and neuropsychiatric sequelae induced by the betacoronavirus MHV-A59; and to (iii) assess sex-specific differences. Male and female C57Bl/6 mice were initially inoculated with varying viral titers (3x103 to 3x105 PFU/30 L) of the betacoronavirus MHV-A59 via the intranasal route to define the highest inoculum capable of inducing disease without causing mortality. Further experiments were conducted with the 3x104 PFU inoculum. Mice exhibited an altered neutrophil/lymphocyte ratio in the blood in the 2nd and 5th day post-infection (dpi). Marked lung lesions were characterized by hyperplasia of the alveolar walls, infiltration of polymorphonuclear leukocytes (PMN) and mononuclear leukocytes, hemorrhage, increased concentrations of CCL2, CCL3, CCL5, and CXCL1 chemokines, as well as high viral titers until the 5th dpi. While these lung inflammatory signs resolved, other manifestations were observed up to the 60 dpi, including mild brain lesions with gliosis and hyperemic blood vessels, neuromuscular dysfunctions, anhedonic-like behavior, deficits in spatial working memory, and short-term aversive memory. These musculoskeletal and neuropsychiatric complications were exclusive to female mice and were prevented after ovariectomy. In summary, our study describes for the first time a novel sex-dependent model of PCS focused on neuropsychiatric and musculoskeletal disorders. This model provides a unique platform for future investigations regarding the effects of acute therapeutic interventions on the long-term sequelae unleashed by betacoronavirus infection. | | 7:46p |
ER-detect: a pipeline for robust detection of early evoked responses in BIDS-iEEG electrical stimulation data
Human brain connectivity can be measured in different ways. Intracranial EEG (iEEG) measurements during single pulse electrical stimulation provide a unique way to assess the spread of electrical information with millisecond precision. To provide a robust workflow to process these cortico-cortical evoked potential (CCEP) data and detect early evoked responses in a fully automated and reproducible fashion, we developed Early Response (ER)-detect. ER-detect is an open-source Python package and Docker application to preprocess BIDS structured iEEG data and detect early evoked CCEP responses. ER-detect can use three response detection methods, which were validated against 14 manually annotated CCEP datasets from two different sites by four independent raters. Results showed that ER-detect's automated detection performed on par with the inter-rater reliability (Cohen's Kappa of ~0.6). Moreover, ER-detect was optimized for processing large CCEP datasets, to be used in conjunction with other connectomic investigations. ER-detect provides a highly efficient standardized workflow such that iEEG-BIDS data can be processed in a consistent manner and enhance the reproducibility of CCEP based connectivity results. | | 7:46p |
Integrity of arousal-regulating brain circuitry predicts human cognitive abilities
Arousal state is regulated by the brainstem nucleus locus coeruleus, which sends wide-reaching projections to cortex. How this powerful neuromodulatory system is recruited to aid cognition is largely underexplored. Here, we hypothesized that select cortical regions may activate the arousal system, which in turn modulates large-scale brain activity, creating a circuit whose integrity predicts cognitive ability. We utilized the Human Connectome Project 7T functional magnetic resonance imaging dataset (N=149), acquired at rest with simultaneous eye tracking, along with extensive cognitive assessment for each subject. First, we discovered select frontoparietal cortical regions that likely drive large-scale spontaneous brain activity specifically via engaging the arousal system. Second, we show that the integrity of the arousal circuit driven by bilateral posterior cingulate cortex (associated with the default mode network) predicts subjects' cognitive abilities. This suggests that a cortical region that is typically associated with self-referential processing supports cognition by regulating the arousal system. | | 7:46p |
Topographic variation in neurotransmitter receptor densities explains differences in intracranial EEG spectra
Neurotransmitter receptor expression and neuronal population dynamics show regional variability across the human cortex. However, currently there is an explanatory gap regarding how cortical microarchitecture and mesoscopic electrophysiological signals are mechanistically related, limiting our ability to exploit these measures of brain (dys)function for improved treatments of brain disorder; e.g., epilepsy. To bridge this gap, we leveraged dynamic causal modelling (DCM) and fitted biophysically informed neural mass models to a normative set of intracranial EEG data. Subsequently, using a hierarchical Bayesian modelling approach, we evaluated whether model evidence improved when information about regional neurotransmitter receptor densities is provided. We then tested whether the inferred constraints - furnished by receptor density - generalise across different electrophysiological recording modalities. The neural mass models explained regionally specific intracranial EEG spectra accurately, when fitted independently. Incorporating prior information on receptor distributions, further improved model evidence, indicating that variability in receptor density explains some variance in cortical population dynamics. The output of this modelling provides a cortical atlas of neurobiologically informed intracortical synaptic connectivity parameters that can be used as empirical priors in future - e.g., patient specific - modelling, as demonstrated in a worked example (a single-subject mismatch negativity study). In summary, we show that molecular cortical characteristics (i.e., receptor densities) can be incorporated to improve generative, biophysically plausible models of coupled neuronal populations. This work can help to explain regional variations in human electrophysiology, may provide a methodological foundation to integrate multi-modal data, and might serve as a normative resource for future DCM studies of electrophysiology. | | 7:46p |
The glucocorticoid response element near the sphingosine-1-phopshate receptor 3 gene mitigates inflammatory processes and maladaptive behavior in females and stressed males
It is well established that glucocorticoid receptors (GRs) bind DNA, regulate gene expression, reduce inflammatory processes, and modulate behavior. However, the precise loci bound by GRs that are necessary for these effects are not fully understood. Here, we deleted the GR binding site near the sphingosine-1-phospate receptor 3 gene using a CRISPR/Cas9 approach (S1PR3GR-/GR- rats). Defeated S1PR3GR-/GR- males displayed increased inflammatory markers and social anxiety-like behavior. Similar effects were observed in non-stressed females, indicating a greater dependence for GR-induced S1PR3 in females. Coherent neural activity between the locus coeruleus (LC) and medial prefrontal cortex (mPFC) was increased in S1PR3GR-/GR- males following 7 defeats. Chemogenetically inhibiting mPFC-projecting LC neurons during defeat increased subsequent social interaction in wild-type and S1PR3GR-/GR- males. Together, these findings demonstrate that GR-induced S1PR3 promotes resilience by mitigating stress-induced inflammatory processes and LC-mPFC coherence. | | 11:16p |
SARS-CoV-2 papain-like protease activates nociceptors to drive sneeze and pain
SARS-CoV-2, the virus responsible for COVID-19, triggers symptoms such as sneezing, aches and pain. These symptoms are mediated by a subset of sensory neurons, known as nociceptors, that detect noxious stimuli, densely innervate the airway epithelium, and interact with airway resident epithelial and immune cells. However, the mechanisms by which viral infection activates these neurons to trigger pain and airway reflexes are unknown. Here, we show that the coronavirus papain-like protease (PLpro) directly activates airway-innervating trigeminal and vagal nociceptors in mice and human iPSC-derived nociceptors. PLpro elicits sneezing and acute pain in mice and triggers the release of neuropeptide calcitonin gene-related peptide (CGRP) from airway afferents. We find that PLpro-induced sneeze and pain requires the host TRPA1 ion channel that has been previously demonstrated to mediate pain, cough, and airway inflammation. Our findings are the first demonstration of a viral product that directly activates sensory neurons to trigger pain and airway reflexes and highlight a new role for PLpro and nociceptors in COVID-19. |
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