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Nature Mar 2024Astrocytes are heterogeneous glial cells of the central nervous system. However, the physiological relevance of astrocyte diversity for neural circuits and behaviour...
Astrocytes are heterogeneous glial cells of the central nervous system. However, the physiological relevance of astrocyte diversity for neural circuits and behaviour remains unclear. Here we show that a specific population of astrocytes in the central striatum expresses μ-crystallin (encoded by Crym in mice and CRYM in humans) that is associated with several human diseases, including neuropsychiatric disorders. In adult mice, reducing the levels of μ-crystallin in striatal astrocytes through CRISPR-Cas9-mediated knockout of Crym resulted in perseverative behaviours, increased fast synaptic excitation in medium spiny neurons and dysfunctional excitatory-inhibitory synaptic balance. Increased perseveration stemmed from the loss of astrocyte-gated control of neurotransmitter release from presynaptic terminals of orbitofrontal cortex-striatum projections. We found that perseveration could be remedied using presynaptic inhibitory chemogenetics, and that this treatment also corrected the synaptic deficits. Together, our findings reveal converging molecular, synaptic, circuit and behavioural mechanisms by which a molecularly defined and allocated population of striatal astrocytes gates perseveration phenotypes that accompany neuropsychiatric disorders. Our data show that Crym-positive striatal astrocytes have key biological functions within the central nervous system, and uncover astrocyte-neuron interaction mechanisms that could be targeted in treatments for perseveration.
Topics: Animals; Humans; Mice; Astrocytes; Corpus Striatum; Gene Editing; Gene Knockout Techniques; mu-Crystallins; Rumination, Cognitive; Synaptic Transmission; CRISPR-Cas Systems; Medium Spiny Neurons; Synapses; Prefrontal Cortex; Presynaptic Terminals; Neural Inhibition
PubMed: 38418885
DOI: 10.1038/s41586-024-07138-0 -
HCA Healthcare Journal of Medicine 2023Description As healthcare workers, invested in the wellbeing of our patients while also hoping to grow as individuals, we sometimes tend to view our jobs as a rigid...
Description As healthcare workers, invested in the wellbeing of our patients while also hoping to grow as individuals, we sometimes tend to view our jobs as a rigid duality-we are either "in love" with our practice and persevere flawlessly through all hardship, or we are "burnt out," coldhearted, and defeated by the heavy workload and expectations of medicine. In reality, we all sit somewhere in the middle of a blurry spectrum, balancing out physical, mental, and emotional pain with the immense honor of saving and cherishing human life, while simultaneously struggling to reconcile our altruistic goals with realistic but necessary human incentives. I want this open-ended work to acknowledge these challenging but critical "and yet" moments, and I hope anyone who is reading it can connect to the words personally and find new insight, regardless of where they are in life.
PubMed: 37753413
DOI: 10.36518/2689-0216.1507 -
Handbook of Clinical Neurology 2024New onset movement disorders are a common clinical problem in pediatric neurology and can be infectious, inflammatory, metabolic, or functional in origin. Encephalitis... (Review)
Review
New onset movement disorders are a common clinical problem in pediatric neurology and can be infectious, inflammatory, metabolic, or functional in origin. Encephalitis is one of the more important causes of new onset movement disorders, and movement disorders are a common feature (~25%) of all encephalitis. However, all encephalitides are not the same, and movement disorders are a key diagnostic feature that can help the clinician identify the etiology of the encephalitis, and therefore appropriate treatment is required. Movement disorders are a characteristic feature of autoimmune encephalitis such as anti-NMDAR encephalitis, herpes simplex virus encephalitis-induced autoimmune encephalitis, and basal ganglia encephalitis. Other rarer autoantibody-associated encephalitis syndromes with movement disorder associations include encephalitis associated with glycine receptor, DPPX, and neurexin-3 alpha autoantibodies. In addition, movement disorders can accompany acute disseminated encephalomyelitis with and without myelin oligodendrocyte glycoprotein antibodies. Extremely important infectious encephalitides that have characteristic movement disorder associations include Japanese encephalitis, dengue fever, West Nile virus, subacute sclerosing panencephalitis (SSPE), and SARS-CoV-2 (COVID-19). This chapter discusses how specific movement disorder phenomenology can aid clinician diagnostic suspicion, such as stereotypy, perseveration, and catatonia in anti-NMDAR encephalitis, dystonia-Parkinsonism in basal ganglia encephalitis, and myoclonus in SSPE. In addition, the chapter discusses how the age of the patients can influence the movement disorder phenomenology, such as in anti-NMDAR encephalitis where chorea is typical in young children, even though catatonia and akinesia is more common in adolescents and adults.
Topics: Adolescent; Child; Child, Preschool; Humans; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Autoantibodies; Catatonia; Chorea; Movement Disorders; Subacute Sclerosing Panencephalitis
PubMed: 38494280
DOI: 10.1016/B978-0-12-823912-4.00018-9 -
North American Spine Society Journal Dec 2023Spinal tuberculosis (TB) is the most common extrapulmonary form of tuberculosis. In both developing and developed countries, TB has been on the rising trend due to...
BACKGROUND
Spinal tuberculosis (TB) is the most common extrapulmonary form of tuberculosis. In both developing and developed countries, TB has been on the rising trend due to factors such as increasing HIV coinfection, multidrug resistance of the organism, and global migration. Spinal TB, which most often affects the lower thoracic and thoracolumbar area, accounts for 50% of all musculoskeletal tuberculosis.
METHODS
Using the Cochrane Database of Systematic Reviews, EMBASE, and PubMed, a systematic computerized literature search was performed. Analyses of studies published within the past 10 years were conducted. The searches were performed using Medical Subject Headings terms, with "spinal tuberculosis," "diagnosis," "epidemiology," and "etiology","management," "surgery," and "therapy" as subheadings.
RESULTS
Progressive collapse, kyphosis, and neurological deficiency are hallmarks of the disease because of its destructive effect on the intervertebral disc and adjacent vertebral bodies. The condition may be identified using laboratory testing and distinctive imaging features, but the gold standard for diagnosis is tissue diagnosis using cultures, histology, and polymerase chain reaction. Uncomplicated spinal TB is today a medical condition that can be adequately treated by multidrug ambulatory chemotherapy. Surgery is reserved for individuals who have instability, neurological impairment, and deformity correction. Debridement, deformity correction, and stable fusion are the cornerstones of surgical treatment.
CONCLUSIONS
Clinical results for the treatment of spinal TB are generally satisfactory when the disease is identified and treated early. However, the major health issue and the biggest obstacle in achieving the goals of the "End TB strategy" is the recent rise in the emergence of drug resistance. Hence strict vigilance and patient perseverance in the completion of the treatment is the main need of the hour.
PubMed: 37736557
DOI: 10.1016/j.xnsj.2023.100267 -
Memory & Cognition Apr 2024To acquire and process information, performers can frequently rely on both internal and extended cognitive strategies. However, after becoming acquainted with two...
To acquire and process information, performers can frequently rely on both internal and extended cognitive strategies. However, after becoming acquainted with two strategies, performers in previous studies exhibited a pronounced behavioral preference for just one strategy, which we refer to as perseveration. What is the origin of such perseveration? Previous research suggests that a prime reason for cognitive strategy choice is performance: Perseveration could reflect the preference for a superior strategy as determined by accurately monitoring each strategy's performance. However, following our preregistered hypotheses, we conjectured that perseveration persisted even if the available strategies featured similar performances. Such persisting perseveration could be reasonable if costs related to decision making, performance monitoring, and strategy switching would be additionally taken into account on top of isolated strategy performances. Here, we used a calibration procedure to equalize performances of strategies as far as possible and tested whether perseveration persisted. In Experiment 1, performance adjustment of strategies succeeded in equating accuracy but not speed. Many participants perseverated on the faster strategy. In Experiment 2, calibration succeeded regarding both accuracy and speed. No substantial perseveration was detected, and residual perseveration was conceivably related to metacognitive performance evaluations. We conclude that perseveration on cognitive strategies is frequently rooted in performance: Performers willingly use multiple strategies for the same task if performance differences appear sufficiently small. Surprisingly, other possible reasons for perseveration like effort or switch cost avoidance, mental challenge seeking, satisficing, or episodic retrieval of previous stimulus-strategy-bindings, were less relevant in the present study.
Topics: Humans; Cognition
PubMed: 37874485
DOI: 10.3758/s13421-023-01475-7 -
Telemedicine Journal and E-health : the... Mar 2024
PubMed: 38457685
DOI: 10.1089/tmj.2024.29108.editorial -
Viruses Oct 2023Despite remarkable progress, a cure for HIV-1 infection remains elusive. Rebound competent latent and transcriptionally active reservoir cells persevere despite...
Despite remarkable progress, a cure for HIV-1 infection remains elusive. Rebound competent latent and transcriptionally active reservoir cells persevere despite antiretroviral therapy and rekindle infection due to inefficient proviral silencing. We propose a novel "block-lock-stop" approach, entailing long term durable silencing of viral expression towards an irreversible transcriptionally inactive latent provirus to achieve long term antiretroviral free control of the virus. A graded transformation of remnant HIV-1 in PLWH from persistent into silent to permanently defective proviruses is proposed, emulating and accelerating the natural path that human endogenous retroviruses (HERVs) take over millions of years. This hypothesis was based on research into delineating the mechanisms of HIV-1 latency, lessons from latency reversing agents and advances of Tat inhibitors, as well as expertise in the biology of HERVs. Insights from elite controllers and the availability of advanced genome engineering technologies for the direct excision of remnant virus set the stage for a rapid path to an HIV-1 cure.
Topics: Humans; HIV-1; Virus Latency; Proviruses; Endogenous Retroviruses; HIV Infections; HIV Seropositivity; CD4-Positive T-Lymphocytes
PubMed: 38005849
DOI: 10.3390/v15112171 -
Nature Nov 2023Resource-seeking behaviours are ordinarily constrained by physiological needs and threats of danger, and the loss of these controls is associated with pathological...
Resource-seeking behaviours are ordinarily constrained by physiological needs and threats of danger, and the loss of these controls is associated with pathological reward seeking. Although dysfunction of the dopaminergic valuation system of the brain is known to contribute towards unconstrained reward seeking, the underlying reasons for this behaviour are unclear. Here we describe dopaminergic neural mechanisms that produce reward seeking despite adverse consequences in Drosophila melanogaster. Odours paired with optogenetic activation of a defined subset of reward-encoding dopaminergic neurons become cues that starved flies seek while neglecting food and enduring electric shock punishment. Unconstrained seeking of reward is not observed after learning with sugar or synthetic engagement of other dopaminergic neuron populations. Antagonism between reward-encoding and punishment-encoding dopaminergic neurons accounts for the perseverance of reward seeking despite punishment, whereas synthetic engagement of the reward-encoding dopaminergic neurons also impairs the ordinary need-dependent dopaminergic valuation of available food. Connectome analyses reveal that the population of reward-encoding dopaminergic neurons receives highly heterogeneous input, consistent with parallel representation of diverse rewards, and recordings demonstrate state-specific gating and satiety-related signals. We propose that a similar dopaminergic valuation system dysfunction is likely to contribute to maladaptive seeking of rewards by mammals.
Topics: Animals; Dopamine; Dopaminergic Neurons; Drosophila melanogaster; Electroshock; Learning; Odorants; Optogenetics; Punishment; Reward; Starvation; Models, Animal
PubMed: 37880370
DOI: 10.1038/s41586-023-06671-8 -
Nature Reviews. Neuroscience May 2024Compulsive behaviour, an apparently irrational perseveration in often maladaptive acts, is a potential transdiagnostic symptom of several neuropsychiatric disorders,... (Review)
Review
Compulsive behaviour, an apparently irrational perseveration in often maladaptive acts, is a potential transdiagnostic symptom of several neuropsychiatric disorders, including obsessive-compulsive disorder and addiction, and may reflect the severe manifestation of a dimensional trait termed compulsivity. In this Review, we examine the psychological basis of compulsions and compulsivity and their underlying neural circuitry using evidence from human neuroimaging and animal models. Several main elements of this circuitry are identified, focused on fronto-striatal systems implicated in goal-directed behaviour and habits. These systems include the orbitofrontal, prefrontal, anterior cingulate and insular cortices and their connections with the basal ganglia as well as sensoriomotor and parietal cortices and cerebellum. We also consider the implications for future classification of impulsive-compulsive disorders and their treatment.
Topics: Humans; Compulsive Behavior; Animals; Brain; Obsessive-Compulsive Disorder; Neural Pathways
PubMed: 38594324
DOI: 10.1038/s41583-024-00807-z -
Therapeutic Advances in Musculoskeletal... 2023High Energy Musculoskeletal Traumas (HEMTs) represent a relevant problem for healthcare systems, considering the high social costs, and both the high morbidity and... (Review)
Review
High Energy Musculoskeletal Traumas (HEMTs) represent a relevant problem for healthcare systems, considering the high social costs, and both the high morbidity and mortality. The poor outcomes associated with HEMT are related to the high incidence of complications, including bone infection, fracture malunion and non-union. The treatment of each of these complications could be extremely difficult. Limb reconstruction often needs multiple procedures, rising some questions on the opportunity in perseverate to try to save the affected limb. In fact, theoretically, amputation may guarantee better function and lower complications. However, amputation is not free of complication, and a high long-term social cost has been reported. A comprehensive literature review was performed to suggest possible ways to optimize the limb preservation surgeries of HEMT's complications in order to ameliorate their management.
PubMed: 37529331
DOI: 10.1177/1759720X231189008