Neuroscientist最新文献

Fatally injured neurons may necrose and rupture immediately, or they may initiate a programmed cell death pathway and then wait for microglial phagocytosis. Biochemical and histopathologic assays of neuronal death assess the numbers of neurons awaiting phagocytosis at a particular time point after injury. This number varies with the fraction of neurons that have necrosed vs initiated programmed cell death, the time elapsed since injury, the rate of phagocytosis, and the assay's ability to detect neurons at different stages of programmed cell death. Many of these variables can be altered by putatively neurotoxic and neuroprotective interventions independent of the effects on neuronal death. This complicates analyses of neurotoxicity and neuroprotection and has likely contributed to difficulties with clinical translation of neuroprotective strategies after brain injury. Time-resolved assays of neuronal health, such as ongoing expression of transgenic fluorescent proteins, are a useful means of avoiding these problems.

Down syndrome (DS), a prevalent cognitive disorder resulting from trisomy of human chromosome 21 (Hsa21), poses a significant global health concern. Affecting approximately 1 in 800 live births worldwide, DS is the leading genetic cause of intellectual disability and a major predisposing factor for early-onset Alzheimer's dementia. The estimated global population of individuals with DS is 6 million, with increasing prevalence due to advances in DS health care. Global efforts are dedicated to unraveling the mechanisms behind the varied clinical outcomes in DS. Recent studies on DS mouse models reveal disrupted neuronal circuits, providing insights into DS pathologies. Yet, translating these findings to humans faces challenges due to limited systematic electrophysiological analyses directly comparing human and mouse. Additionally, disparities in experimental procedures between the two species pose hurdles to successful translation. This review provides a concise overview of neuronal oscillations in human and rodent cognition. Focusing on recent DS mouse model studies, we highlight disruptions in associated brain function. We discuss various electrophysiological paradigms and suggest avenues for exploring molecular dysfunctions contributing to DS-related cognitive impairments. Deciphering neuronal oscillation intricacies holds promise for targeted therapies to alleviate cognitive disabilities in DS individuals.

Deficits in learning and memory are some of the most commonly reported symptoms following a traumatic brain injury (TBI). We will examine whether the neural basis of these deficits stems from alterations to bidirectional synaptic plasticity within the hippocampus. Although the CA1 subregion of the hippocampus has been a focus of TBI research, the dentate gyrus should also be given attention as it exhibits a unique ability for adult neurogenesis, a process highly susceptible to TBI-induced damage. This review examines our current understanding of how TBI results in deficits in synaptic plasticity, as well as how TBI-induced changes in endocannabinoid (eCB) systems may drive these changes. Through the synthesis and amalgamation of existing data, we propose a possible mechanism for eCB-mediated recovery in synaptic plasticity deficits. This hypothesis is based on the plausible roles of CB1 receptors in regulating inhibitory tone, influencing astrocytes and microglia, and modulating glutamate release. Dysregulation of the eCBs may be responsible for deficits in synaptic plasticity and learning following TBI. Taken together, the existing evidence indicates eCBs may contribute to TBI manifestation, pathogenesis, and recovery, but it also suggests there may be a therapeutic role for the eCB system in TBI.

Complex mechanisms govern the transport and action of oxytocin (Oxt), a neuropeptide and hormone that mediates diverse physiologic processes. While Oxt exerts site-specific and rapid effects in the brain via axonal and somatodendritic release, volume transmission via CSF and the neurovascular interface can act as an additional mechanism to distribute Oxt signals across distant brain regions on a slower timescale. This review focuses on modes of Oxt transport and action in the CNS, with particular emphasis on the roles of perivascular spaces, the blood-brain barrier (BBB), and circumventricular organs in coordinating the triadic interaction among circulating blood, CSF, and parenchyma. Perivascular spaces, critical conduits for CSF flow, play a pivotal role in Oxt diffusion and distribution within the CNS and reciprocally undergo Oxt-mediated structural and functional reconstruction. While the BBB modulates the movement of Oxt between systemic and cerebral circulation in a majority of brain regions, circumventricular organs without a functional BBB can allow for diffusion, monitoring, and feedback regulation of bloodborne peripheral signals such as Oxt. Recognition of these additional transport mechanisms provides enhanced insight into the systemic propagation and regulation of Oxt activity.

Axons are an essential component of the nervous system, and axon degeneration is an early feature of many neurodegenerative disorders. The NAD⁺ metabolome plays an essential role in regulating axonal integrity. Axonal levels of NAD⁺ and its precursor NMN are controlled in large part by the NAD⁺ synthesizing survival factor NMNAT2 and the pro-neurodegenerative NADase SARM1, whose activation triggers axon destruction. SARM1 has emerged as a promising axon-specific target for therapeutic intervention, and its function, regulation, structure, and role in neurodegenerative diseases have been extensively characterized in recent years. In this review, we first introduce the key molecular players involved in the SARM1-dependent axon degeneration program. Next, we summarize recent major advances in our understanding of how SARM1 is kept inactive in healthy neurons and how it becomes activated in injured or diseased neurons, which has involved important insights from structural biology. Finally, we discuss the role of SARM1 in neurodegenerative disorders and environmental neurotoxicity and its potential as a therapeutic target.

The tau protein is a key contributor to multiple neurodegenerative diseases. The pathology of tau is thought to be related to tau's propensity to form self-templating fibrillar structures that allow tau fibers to propagate in the brain by prion-like mechanisms. Unresolved issues with respect to tau pathology are how the normal function of tau and its misregulation contribute to disease, how cofactors and cellular organelles influence the initiation and propagation of tau fibers, and determining the mechanism of tau toxicity. Herein, we review the connection between tau and degenerative diseases, the basis for tau fibrilization, and how that process interacts with cellular molecules and organelles. One emerging theme is that tau interacts with RNA and RNA-binding proteins, normally and in pathologic aggregates, which may provide insight into alterations in RNA regulation observed in disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), could affect brain structure and function. SARS-CoV-2 can enter the brain through different routes, including the olfactory, trigeminal, and vagus nerves, and through blood and immunocytes. SARS-CoV-2 may also enter the brain from the peripheral blood through a disrupted blood-brain barrier (BBB). The neurovascular unit in the brain, composed of neurons, astrocytes, endothelial cells, and pericytes, protects brain parenchyma by regulating the entry of substances from the blood. The endothelial cells, pericytes, and astrocytes highly express angiotensin converting enzyme 2 (ACE2), indicating that the BBB can be disturbed by SARS-CoV-2 and lead to derangements of tight junction and adherens junction proteins. This leads to increased BBB permeability, leakage of blood components, and movement of immune cells into the brain parenchyma. SARS-CoV-2 may also cross microvascular endothelial cells through an ACE2 receptor-associated pathway. The exact mechanism of BBB dysregulation in COVID-19/neuro-COVID is not clearly known, nor is the development of long COVID. Various blood biomarkers could indicate disease severity and neurologic complications in COVID-19 and help objectively diagnose those developing long COVID. This review highlights the importance of neurovascular and BBB disruption, as well as some potentially useful biomarkers in COVID-19, and long COVID/neuro-COVID.

Historical evidence from stimulation and lesion studies in animals and humans demonstrated a close association between the hypothalamus and typical and atypical socioemotional behavior. A central hypothalamic contribution to regulation of socioemotional responses was also provided indirectly by studies on oxytocin and arginine vasopressin. However, a limited number of studies have so far directly investigated the contribution of the hypothalamus in human socioemotional behavior. To reconsider the functional role of the evolutionarily conserved hypothalamic region in regulating human social behavior, here I provide a synthesis of neuroimaging investigations showing that the hypothalamus is involved in multiple and diverse facets of human socioemotional behavior through widespread functional interactions with other cortical and subcortical regions. These neuroimaging findings are then integrated with recent optogenetics studies in animals demonstrating that the hypothalamus plays a more active role in eliciting socioemotional responses and is not simply a downstream effector of higher-level brain systems. Building on the aforementioned evidence, the hypothalamus is argued to substantially contribute to a continuum of human socioemotional behaviors promoting survival and preservation of the species that extends from exploratory and approaching responses facilitating social bonding to aggressive and avoidance responses aimed to protect and defend formed relationships.

Several studies have provided interesting evidence about the role of the bidirectional communication between the gut and brain in the onset and development of several pathologic conditions, including inflammatory bowel diseases (IBDs), neurodegenerative diseases, and related comorbidities. Indeed, patients with IBD can experience neurologic disorders, including depression and cognitive impairment, besides typical intestinal symptoms. In parallel, patients with neurodegenerative disease, such as Parkinson disease and Alzheimer disease, are often characterized by the occurrence of functional gastrointestinal disorders. In this context, enteric glial cells and brain astrocytes are emerging as pivotal players in the initiation/maintenance of neuroinflammatory responses, which appear to contribute to the alterations of intestinal and neurologic functions observed in patients with IBD and neurodegenerative disorders. The present review was conceived to provide a comprehensive and critical overview of the available knowledge on the morphologic, molecular, and functional changes occurring in the enteric glia and brain astroglia in IBDs and neurologic disorders. In addition, our intent is to identify whether such alterations could represent a common denominator involved in the onset of comorbidities associated with the aforementioned disorders. This might help to identify putative targets useful to develop novel pharmacologic approaches for the therapeutic management of such disturbances.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid β and phosphorylated τ protein aggregates in the brain, which leads to the loss of neurons. Under the microscope, the function of mitochondria is uniquely primed to play a pivotal role in neuronal cell survival, energy metabolism, and cell death. Research studies indicate that mitochondrial dysfunction, excessive oxidative damage, and defective mitophagy in neurons are early indicators of AD. This review article summarizes the latest development of mitochondria in AD: 1) disease mechanism pathways, 2) the importance of mitochondria in neuronal functions, 3) metabolic pathways and functions, 4) the link between mitochondrial dysfunction and mitophagy mechanisms in AD, and 5) the development of potential mitochondrial-targeted therapeutics and interventions to treat patients with AD.