bioRxiv Subject Collection: Neuroscience's Journal
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Sunday, October 20th, 2024
| Time |
Event |
| 10:45a |
Frontoparietal theta synchronization causally links working memory with impulsive decision making
Delaying gratification in value-based decision making is canonically related to activation in the dorsolateral prefrontal cortex (dlPFC), but past research neglected that the dlPFC is part of a larger frontoparietal network. It is therefore unknown whether the dlPFC causally implements delay of gratification in concert with posterior parts of the frontoparietal network rather than in isolation. Here, we addressed this gap by testing the effects of frontoparietal theta synchronization and desynchronization on impulsive decision making using transcranial alternating current stimulation (tACS). Healthy participants performed an intertemporal choice task and a 3-back working memory task while left frontal and parietal cortices were stimulated with a 5 Hz theta frequency at in-phase (synchronization), anti-phase (desynchronization), or sham tACS. We found frontoparietal theta coupling to improve working memory performance, while in the decision task desynchronization was associated with more impulsive choices and stronger hyperbolic discounting of future rewards. Overall, our findings overcome the past focus of the dlPFC in isolation and show that patient decision making causally relies on synchronous activation in a frontoparietal network related to working memory. | | 10:45a |
Hippocampal place cell sequences are impaired in a rat model of Fragile X Syndrome
Fragile X Syndrome (FXS) is a neurodevelopmental disorder that can cause impairments in spatial cognition and memory. The hippocampus is thought to support spatial cognition through the activity of place cells, neurons with spatial receptive fields. Coordinated firing of place cell populations is organized by different oscillatory patterns in the hippocampus during specific behavioral states. Theta rhythms organize place cell populations during awake exploration. Sharp wave-ripples organize place cell population reactivation during waking rest. Here, we examined the coordination of CA1 place cell populations during active behavior and subsequent rest in a rat model of FXS (Fmr1 knockout rats). While the organization of individual place cells by the theta rhythm was normal, the coordinated activation of sequences of place cells during individual theta cycles was impaired in Fmr1 knockout rats. Further, the subsequent replay of place cell sequences was impaired during waking rest following active exploration. Together, these results expand our understanding of how genetic modifications that model those observed in FXS affect hippocampal physiology and suggest a potential mechanism underlying impaired spatial cognition in FXS. | | 10:45a |
Chronic circadian disruption in adolescent mice impairs hippocampal memory disrupting gene expression oscillations
Chronodisruption, the misalignment of internal biological systems with external environmental changes, leads to adverse health effects. Particularly, Social Jet Lag (SJL) is defined as the discrepancy between social and biological time and it exemplifies this misalignment, affecting a large part of the young population and impacting cognitive function. Despite its prevalence, our understanding of how developmental chronodisruption ultimately translates into morbidity is limited. To address this, we implemented a chronic chronodisruption protocol in adolescent mice consisting of light/dark cycle manipulation. We employed a comprehensive battery of established behavioral tests alongside an in-depth analysis of the oscillatory expression of the molecular clock and other genes involved in relevant physiological function. Our results show that chronic circadian disruption during adolescence induces impairments in short-term, social, and spatial memory without prompting anxiety-like behavior. Additionally, we report altered gene expression patterns of circadian clock genes per1, per2, cry2 and npas2 in the hypothalamus and the hippocampus. Lastly, we observed a disruption of hippocampal gene expression oscillations which may underlie the hippocampal memory impairments. Overall, this work underscores the critical role of adolescent circadian rhythms in maintaining cognitive function, the relevance of circadian control of hippocampal homeostasis, and the importance of further research into the mechanisms of chronodisruption, particularly during adolescence, to better understand its long-term implications for cognitive function and overall health. | | 11:18a |
Template-driven dynamic functional network connectivity predicts medication response for major depression and bipolar disorders
The process of finding reliable treatment for major depression and bipolar disorder can be arduous. The myriad behavioral symptoms presented by patients and resistance to treatment from particular medication classes complicate standard diagnostic and prescription methodologies, often requiring multiple attempted treatments during which symptoms may still be present. Physiological information such as neuroimaging scans may help to alleviate some of the uncertainty surrounding diagnosis and treatment when incorporated into a clinical setting. Changes in functional magnetic resonance imaging show particular promise, as the incorporation of dynamical information may provide insights into physiological changes prior to static, structural changes. In this work, we present a novel method for generating robust and replicable dynamic functional network connectivity (dFNC) features from neuroimaging data using a template of dynamic states derived from a large, non-affected data set. We demonstrate that this template-driven dFNC approach expands on standard dFNC approaches by allowing for the derivation of a continuous state-contribution time series. We demonstrate that the derived biomarkers can support high predictive performance for the identification of medication class and non-responders while also expanding the set of biomarkers available for studying differences in mood disorder medication response. | | 11:18a |
Microglia regulate GABAergic neurogenesis in prenatal human brain through IGF1
GABAergic neurons are an essential cellular component of neural circuits. Their abundance and diversity have enlarged significantly in the human brain, contributing to the expanded cognitive capacity of humans. However, the developmental mechanism of the extended production of GABAergic neurons in the human brain remains elusive. Here, we use single-cell transcriptomics, bioinformatics, and histological analyses to uncover microglial regulation of the sustained proliferation of GABAergic progenitors and neuroblasts in the human medial ganglionic eminence (hMGE). We show that insulin-like growth factor 1 (IGF1) and its receptor IGR1R as the top ligand-receptor pair underlying microglia-progenitor communication in the prenatal human brain. Using our newly developed neuroimmune hMGE organoids, which mimics hMGE cytoarchitecture and developmental trajectory, we demonstrate that microglia-derived IGF1 promotes progenitor proliferation and the production of GABAergic neurons. Conversely, IGF1-neutralizing antibodies and IGF1 knockout human embryonic stem cells (hESC)-induced microglia (iMG) completely abolished iMG-mediated progenitor proliferation. Together, these findings reveal a previously unappreciated role of microglia-derived IGF1 in promoting proliferation of neural progenitors and the development of GABAergic neurons. | | 12:30p |
A network based study of the dynamics of Aβ and {tau} proteins in Alzheimer's disease
Due to the extreme complexity of Alzheimer's disease (AD), the aetiology of which is not yet known, nor are there any known effective treatments, mathematical modelling can be very useful. Indeed, mathematical models, if deemed reliable, can be used to test medical hypotheses that could be difficult to verify directly. In this context, it is important to understand how A{beta} and {tau} proteins, which in abnormal aggregate conformations are hallmarks of the disease, interact and spread. We are particularly interested in this paper in studying the spreading of misfolded {tau}. To this end, we present four different mathematical models, all on networks on which the protein evolves. The models differ in both the choice of network and diffusion operator. Through comparison with clinical data on {tau} concentration, that we carefully obtained with multimodal analysis techniques, we show that some models are more adequate than others to simulate the dynamics of the protein. This type of study may suggest that, when it comes to modelling certain pathologies, the choice of the mathematical setting must be made with great care if comparison with clinical data is considered decisive. | | 12:30p |
Altered Proteasome Composition in Aging Brains, Genetic Proteasome Augmentation Mitigates Age-Related Cognitive Declines, and Acute Proteasome Agonist Treatment Rescues Age-Related Cognitive Deficits in Mice
The aging brain experiences a significant decline in proteasome function, The proteasome is critical for many key neuronal functions including neuronal plasticity, and memory formation/retention. Treatment with proteasome inhibitors impairs these processes. Our study reveals a marked reduction in 20S and 26S proteasome activities in aged mice brains driven by reduced functionality of aged proteasome. This is matched by a decline in 20S proteasome but an increase in 26S proteasome. Our data suggests this may be a compensatory response to reduced functionality. By overexpressing the proteasome subunit PSMB5 in the neurons of mice, enhancing proteasome function, we slowed age-related declines in spatial learning and memory as well neuromuscular declines. We then showed acute treatment with a proteasome activator to rescue spatial learning and memory deficits in aged mice. These findings highlight the potential of proteasome augmentation as a therapeutic strategy to mitigate age-related cognitive declines. | | 12:30p |
Androgen receptor modulation of vocal circuitry in Alston's singing mouse
Animal courtship and aggressive displays are dramatic, often sexually dimorphic behaviors that require the coordinated modulation of diverse motivational and motor circuits. In Alstons singing mice (Scotinomys teguina), a novel and elaborate advertisement vocalization is sexually dimorphic and steroid sensitive. Males sing more often than females, and on average male songs have more notes. Song is influenced by circulating androgens, but how such hormonal differences influence the diverse brain regions involved in vocal display is not understood. To characterize androgen-sensitive sites in the vocal motor pathway, we used two isoforms of pseudorabies virus (PRV) to double-label circuits ending in laryngeal and jaw muscles involved in vocalization, and co-labeled these neurons for androgen receptor (AR). Next we manipulated circulating androgens and observed the effects on AR distribution and male song. We find androgens drive coordinated changes in AR abundance across motor and motivational circuits, and both individual and group differences in song are associated with AR abundance. The results reveal how circulating androgens and the auto-regulation of androgen receptors can influence the diverse circuits necessary for elaborate advertisement displays. |
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