bioRxiv Subject Collection: Neuroscience's Journal
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Tuesday, November 12th, 2024
| Time |
Event |
| 2:47a |
A Mouse-adapted SARS-CoV-2 Model for Investigating Post-acute Sequelae of COVID infection
The coronavirus disease of 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), remains a major health issue after nearly 7 millions of death toll in the last four years. As the world is recovering with improving vaccines and antiviral treatments, the alarming rate of long-COVID, or Post-acute Sequelae of COVID-19 (PASC), calls for further investigations. Among a list of symptoms associated with multi-organ dysfunctions, the neurological complications are particularly intriguing, yet the underlying mechanisms remain elusive. With the recently developed mouse adapted SARS-CoV-2 stain, we are now able to model the mild COVID infection in C57BL/6 mice and study the chronic immune responses and subsequent damages in different organs long after the viruses are clearly naturally in the body. More specifically, we found adult C57BL/6J mice developed neurological impairments, including behavior changes related to sensorimotor coordination, depression- and anxiety-like behaviors, and inflammation in multiple organs including lung, liver and brain, which persisted over at least 4 weeks in mice even with mild infection. Therefore, this model can be used to further explopred the mechanisms of PASC, as well as potential intervention or therapeutic approaches. | | 3:17a |
Generation of morphologically distinct astrocyte subtypes from human iPSCs reveals a link between glial shape, function and reactivity
Astrocyte morphology in vivo is heterogeneous across different subtypes and dynamically changes in response to various stimuli. However, several questions on the mechanistic links between shape and function remain unanswered. Here, we developed an efficient protocol to generate pure populations of morphologically distinct human astrocytes in vitro, which we used for a systematic analysis of shape-function relationships. We performed a structural, molecular, and functional characterization of these populations and highlighted how their distinct morphologies mirror distinct functional and transcriptional patterns at the population level. We were also able to both correlate gene expression profiles of these morphologically distinct astrocyte subtypes with in vivo astrocytes in the human brain, and to validate our findings with primary isolated murine astrocytes in vitro. Moreover, we show that the observed morphological differences are correlated with changes in key cytoskeletal proteins, which offers a potential link to the observed functional differences. Finally, we demonstrated that different morphological subtypes of astrocytes have distinct reactivity responses to a common stimulus. This study offers a glimpse into the shape-function dynamics of human astrocytes, highlighting potential mechanistic links between cytoskeletal usage and astrocyte function, while also providing tools and datasets that will be useful for further studies into human glial biology in health and disease. | | 8:18a |
Hunger modulates exploration through suppression of dopamine signaling in the tail of striatum
Caloric depletion leads to behavioral changes that help an animal find food and restore its homeostatic balance. Hunger increases exploration and risk-taking behavior, allowing an animal to forage for food despite risks; however, the neural circuitry underlying this change is unknown. Here, we characterize how hunger restructures an animal's spontaneous behavior as well as its directed exploration of a novel object. We show that hunger-induced changes in exploration are accompanied by and result from modulation of dopamine signaling in the tail of the striatum (TOS). Dopamine signaling in the TOS is modulated by internal hunger state through the activity of agouti-related peptide (AgRP) neurons, putative "hunger neurons" in the arcuate nucleus of the hypothalamus. These AgRP neurons are poly-synaptically connected to TOS-projecting dopaminergic neurons through the lateral hypothalamus, the central amygdala, and the periaqueductal grey. We thus delineate a hypothalamic-midbrain circuit that coordinates changes in exploration behavior in the hungry state. | | 8:18a |
Extended amygdala corticotropin-releasing hormone neurons regulate sexually dimorphic changes in pair bond formation following social defeat in prairie voles (Microtus ochrogaster)
The neurobiological mechanisms underlying the connection between anxiety brought on by social stressors and the negative impact on relationship formation have remained elusive. In order to address this question, we used the social defeat model in the socially monogamous prairie vole to investigate the impact of this stress on pair bond formation. Social defeat experience inhibited partner preference formation in males but promoted preference in females. Furthermore, pair bonding increased corticotropin-releasing hormone (CRH) expression in the bed nucleus of the stria terminalis (BNST) in male prairie voles, while defeat experience increased BNST CRH expression in females. Chemogenetic excitation of BNST CRH neurons during a short cohabitation with a new partner promoted a partner preference in stress-naive prairie voles. Interestingly, chemogenetic inhibition of BNST CRH neurons during cohabitation with a new partner blocked partner preference in stress-naive males but promoted preference in defeated males. Inhibition of BNST CRH neurons also blocked partner preference in stress-naive females but did not alter preference behavior in defeated females. This study revealed sexual dimorphism in not only the impact of social defeat on pair bond formation, but also in the role BNST CRHergic neurons play in regulating changes in pair bonding following social conflict. | | 8:18a |
Asymmetric neuromodulation in the respiratory network contributes to rhythm and pattern generation
Like other brain circuits, the brainstem respiratory network is continually modulated by neurotransmitters that activate slow metabotropic receptors. In many cases, activation of these receptors only subtly modulates the respiratory motor pattern. However, activation of some receptor types evokes the arrest of the respiratory motor pattern as can occur following the activation of mu-opioid receptors. We propose that the varied effects of neuromodulation on the respiratory motor pattern depend on the pattern of neuromodulator receptor expression and their influence on the excitability of their post-synaptic targets. Because a comprehensive characterization of these cellular properties across the respiratory network remains challenging, we test our hypothesis by combining computational modelling with ensemble electrophysiologic recording in the pre-Botzinger complex (pre-BotC) using high-density multi-electrode arrays (MEA). Our computational model encapsulates the hypothesis that neuromodulatory transmission is organized asymmetrically across the respiratory network to promote rhythm and pattern generation. To test this hypothesis, we increased the strength of neuromodulatory connections in the model and used selective agonists in situ while monitoring pre-BotC ensemble activities. The model predictions of increasing slow inhibition were consistent with experiments examining the effect of systemic administration of the 5HT1aR agonist 8-OH-DPAT. Similarly, the predicted effects of increasing slow excitation in the model were experimentally confirmed in pre-BotC ensemble activities before and after systemic administration of the mu-opioid receptor agonist fentanyl. We conclude that asymmetric neuromodulation can contribute to respiratory rhythm and pattern generation and accounts for its varied effects on breathing. | | 8:18a |
Excitatory Cortical Neurons from CDKL5 Deficiency Disorder Patient-Derived Organoids Show Early Hyperexcitability Not Identified in Neurogenin2 Induced Neurons
CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy resulting from variants in cyclin-dependent kinase-like 5 (CDKL5) that lead to impaired kinase activity or loss of function. CDD is one of the most common genetic etiologies identified in epilepsy cohorts. To study how CDKL5 variants impact human neuronal activity, gene expression and morphology, CDD patient-derived induced pluripotent stem cells and their isogenic controls were differentiated into excitatory neurons using either an NGN2 induction protocol or a guided cortical organoid differentiation. Patient-derived neurons from both differentiation paradigms had decreased phosphorylated EB2, a known molecular target of CDKL5. Induced neurons showed no detectable differences between cases and isogenic controls in network activity using a multielectrode array, or in MAP2+ neurite length, and only two genes were differentially expressed. However, patient-derived neurons from the organoid differentiation showed increased synchrony and weighted mean firing rate on the multielectrode array within the first month of network maturation. CDD patient-derived cortical neurons had lower expression of CDKL5 and HS3ST1, which may change the extracellular matrix around the synapse and contribute to hyperexcitability. Similar to the induced neurons, there were no differences in neurite length across or within patient-control cell lines. Induced neurons have poor cortical specification while the organoid derived neurons expressed cortical markers, suggesting that the changes in neuronal excitability and gene expression are specific to cortical excitatory neurons. Examining molecular mechanisms of early hyperexcitability in cortical neurons is a promising avenue for identification of CDD therapeutics. | | 7:16p |
A systematic and meta-analytic review of non-verbal auditory memory in the brain
While sounds are essential for human development, existing research primarily emphasizes visual and spatial memory and speech in relation to auditory processes, with a lack of a cohesive understanding of memory mechanisms for non-verbal sounds. This systematic review and coordinate-based meta-analysis of neuroimaging findings aims to comprehensively organize the literature for identifying the key brain mechanisms involved in short-term memory, working memory, and long-term memory for non-verbal auditory information. Additionally, we aimed to identify whether and how individual differences in neural memory processes related to auditory expertise (musicianship), aging or auditory impairments such as amusia are explored in the literature. Our review included ninety studies meeting the selection criteria, with only thirteen studies containing brain coordinates could be included in the meta-analysis. The coordinate-based meta-analysis identified a frontal hub for non-verbal auditory memory encompassing the medial frontal gyrus, cingulate gyrus and superior frontal gyrus. | | 7:16p |
Relationships between migraine and interoception: normal accuracy but altered sensibility and behaviour
Background: Migraine is typically precipitated by unaccustomed changes in one's internal state and/or external environment. Migraine symptoms largely involve increased, noxious, awareness of bodily changes and external stimuli. Links have been proposed between migraine and interoception (sensing and interpreting internal states), but direct evidence is limited. Methods: Unmedicated, otherwise healthy, age-matched female participants were grouped by migraine tendency: control (no unprovoked headaches, n=19); low-frequency (<=3 migraines/month, n=20); high-frequency (>=4 migraines/month, n=19). Interoception was assessed, interictally, with standardised questionnaires such as MAIA-2 and a widely used heartbeat counting task. Results: The notable significant questionnaire-based difference was in the 'noticing', 'not distracting' domain of the MAIA-2; controls were least likely to continue activities despite experiencing physical discomfort, and high-frequency migraineurs most likely. Follow-up questioning clarified that this behaviour related predominantly to migraine-related symptoms. The heartbeat task found no differences in accuracy, but lower confidence in the low-frequency migraine group than the control and high-frequency groups. Conclusions: We suggest that low interoceptive confidence is a risk factor for migraine, whilst amplification of interoceptive signals caused by migraine restores this confidence, but at the price of migraine's disabling symptoms. Self-reported tendency to deliberately ignore physical discomfort, including that caused by migraine, may result in more migraine attacks. | | 9:18p |
Hippocampal OLM interneurons regulate CA1 place cell plasticity and remapping
OLM interneurons selectively target inhibition to the distal dendrites of CA1 pyramidal cells in the hippocampus but the role of this unique morphology in controlling place cell physiology remains a mystery. Here we show that OLM activity prevents associative synaptic plasticity at Schaffer collateral synapses on CA1 pyramidal cells by inhibiting dendritic Ca2+ signalling initiated by entorhinal synaptic inputs. Furthermore, we find that OLM activity is reduced in novel environments suggesting that reducing OLM activity and thereby enhancing excitatory synaptic plasticity is important for the formation of new place cell representations. Supporting this, we show that selectively increasing OLM activity in novel environments enhances place cell stability and reduces remapping of newly formed place cells whilst increasing OLM activity in familiar environments led only to a transient silencing of place cells. Our results therefore demonstrate a critical role for distal dendrite targeting interneurons in regulating plasticity of neuronal representations. | | 11:16p |
Spectrum of gamma-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes
Autosomal Dominant Alzheimer's Disease (ADAD), caused by mutations in Presenilins (PSEN1/2) and Amyloid Precursor Protein (APP) genes, typically manifests before age 65. Age at symptom onset (AAO) is relatively consistent among carriers of the same PSEN1 mutation, but more variable for PSEN2 and APP variants, with these mutations associated with later AAOs than PSEN1. Understanding this clinical variability is crucial for developing predictive models and tailored interventions in ADAD. Biochemical in vitro assessment of gamma-secretase function is valuable in evaluating PSEN1 variant pathogenicity, disease onset and progression. Here, we examined Abeta profiles' relationships to AAO across causal genes. Our analysis showed linear correlations between mutation-induced shifts in Abeta profiles and AAO for PSEN2 and APP mutations. Integration with PSEN1 data revealed parallel but shifted correlations, indicating a common pathogenic mechanism with gene-specific onset timing shifts. Our data support a unified model of ADAD pathogenesis wherein gamma-secretase dysfunction and shifts in Abeta profiles define disease onset. This biochemical analysis of ADAD causality and established quantitative relationships deepen our understanding of ADAD pathogenesis, offering potential for predictive AAO modelling with implications for clinical practice, genetic research and development of therapeutic strategies modulating gamma-secretase across ADAD forms and potentially more broadly in AD. |
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