Advances in neurobiology最新文献

Microglial cells are unique tissue-resident macrophages located in the parenchyma of the central nervous system (CNS). A recent comparative transcriptional study on microglia across more than 20 species from leach across chicken and many more up to humans revealed multiple conserved features. The results indicate the imperative role of microglia over the last 500 million years (Geirsdottir et al. Cell 181:746, 2020). Improved understanding of microglial evolution provides essential insights into conserved and divergent microglial pathways and will have implications for future development of microglia-based therapies to treat CNS disorders. Not only therapeutic approaches may be rethought, but also the understanding of sex specificity of the immune system within the CNS needs to be renewed. Besides revealing the highly detailed characteristics of microglia, the former paradigm of microglia being the only CNS-resident immune cells was outdated by the identification of CNS-associated macrophages (CAMs) as CNS interface residents, who, most likely, accompanied microglia in evolution over the past million years.

Microglia, which are the resident innate immune cells of the central nervous system (CNS), have emerged as critical for maintaining health by not only ensuring proper development, activity, and plasticity of neurones and glial cells but also maintaining and restoring homeostasis when faced with various challenges across the lifespan. This chapter is dedicated to the current understanding of microglia, including their beneficial versus detrimental roles, which are highly complex, rely on various microglial states, and intimately depend on their spatiotemporal context. Microglia are first contextualized within the perspective of finding therapeutic strategies to cure diseases in the twenty-first century-the overall functions of neuroglia with relation one to another and to neurones, and their shared CNS environment. A historical framework is provided, and the main principles of glial neuropathology are enunciated. The current view of microglial nomenclature is then covered, notably by discussing the rejected concepts of microglial activation, their polarisation into M1 and M2 phenotypes, and neuroinflammation. The transformation of the microglial population through the addition, migration, and elimination of individual members, as well as their dynamic metamorphosis between a wide variety of structural and functional states, based on the experienced physiological and pathological stimuli, is subsequently discussed. Lastly, the perspective of microglia as a cell type endowed with a health status determining their outcomes on adaptive CNS plasticity as well as disease pathology is proposed for twenty-first-century approaches to disease prevention and treatment.

Microglia are the resident immune cells of the brain. As such, they rapidly detect changes in normal brain homeostasis and accurately respond by fine-tuning in a tightly regulated manner their morphology, gene expression, and functional behavior. Depending on the nature of these changes, microglia can thicken and retract their processes, proliferate and migrate, release numerous signaling factors and compounds influencing neuronal physiology (e.g., cytokines and trophic factors), in addition to secreting proteases able to transform the extracellular matrix, and phagocytosing various types of cellular debris, etc. Because microglia also transform rapidly (on a time scale of minutes) during experimental procedures, studying these very special cells requires methods that are specifically non-invasive. The development of such methods has provided unprecedented insights into the roles of microglia during normal physiological conditions. In particular, transcranial two-photon in vivo imaging revealed that presumably "resting" microglia continuously survey the brain parenchyma with their highly motile processes, in addition to modulating their structural and functional interactions with neuronal circuits along the changes in neuronal activity and behavioral experience occurring throughout the lifespan. In this chapter, we will describe how surveillant microglia interact with synaptic elements and modulate the number, maturation, function, and plasticity of synapses in the healthy developing, mature, and aging brain, with consequences on neuronal activity, learning and memory, and the behavioral outcome.

Aging is the greatest risk factor for neurodegenerative diseases. Microglia are the resident immune cells in the central nervous system (CNS), playing key roles in its normal functioning, and as mediators for age-dependent changes of the CNS, condition at which they generate a hostile environment for neurons. Transforming Growth Factor β1 (TGFβ1) is a regulatory cytokine involved in immuneregulation and neuroprotection, affecting glial cell inflammatory activation, neuronal survival, and function. TGFβ1 signaling undergoes age-dependent changes affecting the regulation of microglial cells and can contribute to the pathophysiology of neurodegenerative diseases. This chapter focuses on assessing the role of age-related changes on the regulation of microglial cells and their impact on neuroinflammation and neuronal function, for understanding age-dependent changes of the nervous system.

Amyotrophic lateral sclerosis (ALS) is a complex disease impacting motor neurons of the brain, brainstem, and spinal cord. Disease etiology is quite heterogeneous with over 40 genes causing the disease and a vast ~90% of patients having no prior family history. Astrocytes are major contributors to ALS, particularly through involvement in accelerating disease progression. Through study of genetic forms of disease including SOD1, TDP43, FUS, C9orf72, VCP, TBK1, and more recently patient-derived cells from sporadic individuals, many biological mechanisms have been identified to cause intrinsic or glial-mediated neurotoxicity to motor neurons. Overall, many of the normally supportive and beneficial roles that astrocytes contribute to neuronal health and survival instead switch to become deleterious and neurotoxic. While the exact pathways may differ based on disease-origin, altered astrocyte-neuron communication is a common feature of ALS. Within this chapter, distinct genetic forms are examined in detail, along with what is known from sporadic patient-derived cells. Overall, this chapter highlights the interplay between astrocytes and neurons in this complex disease and describes the key features underlying: astrocyte-mediated motor neuron toxicity, excitotoxicity, oxidative/nitrosative stress, protein dyshomeostasis, metabolic imbalance, inflammation, trophic factor withdrawal, blood-brain/blood-spinal cord barrier involvement, disease spreading, and the extracellular matrix/cell adhesion/TGF-β signaling pathways.

In the intricate landscape of neurophysiology, astrocytes have been traditionally cast as homeostatic cells; however, their mechanistic involvement in allostasis-particularly how they modulate the adaptive response to stress and its accumulative impact that disrupts cognitive functions and precipitates psychiatric disorders-is now starting to be unraveled. Here, we address the gap by positing astrocytes as crucial allostatic players whose molecular adaptations underlie cognitive flexibility in stress-related neuropsychiatric conditions. We review how astrocytes, responding to stress mediators such as glucocorticoid and epinephrine/norepinephrine, undergo morphological and functional transformations that parallel the maladaptive changes. Our synthesis of recent findings reveals that these glial changes, especially in the metabolically demanding prefrontal cortex, may underlie some of the neuropsychiatric mechanisms characterized by the disruption of energy metabolism and astrocytic networks, compromised glutamate clearance, and diminished synaptic support. We argue that astrocytes extend beyond their homeostatic role, actively participating in the brain's allostatic response, especially by modulating energy substrates critical for cognitive functions.

In this overview, intended for a multidisciplinary readership, we address the challenges in early management of children who have sustained mild, moderate, or severe traumatic brain injuries. Pediatric traumatic brain injuries (pTBIs) present unique diagnostic and management challenges as compared with adults. Proper management requires careful interpretation of data and strong clinical judgment. Children with injuries due to nonaccidental trauma present unique diagnostic and management challenges. In the pediatric intensive care unit, care is provided as part of a multidisciplinary, collaborative team, with medical and surgical interventions tailored to injury severity. Intensive care focuses on managing cerebral perfusion, temperature, mechanical ventilation, and continuous EEG monitoring to mitigate secondary brain injury. Long-term recovery emphasizes multidisciplinary rehabilitation and support to address physical, cognitive, and emotional challenges.

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder that affects multiple systems in the body and is characterized by a variety of motor and non-motor (e.g., psychiatric, autonomic) symptoms. As the fastest growing neurological disorder expected to affect over 12 million people globally by 2040 (Dorsey, Bloem JAMA Neurol 75(1):9-10. https://doi.org/10.1001/jamaneurol.2017.3299 . PMID: 29131880, 2018), PD poses an enormous individual and public health burden. Currently, there are no therapies that can slow down the disease progression in PD, and existing therapies are limited to symptomatic treatment. Importantly, people in the prodromal phase who are at high risk of developing PD can now be identified, which makes disease prevention an achievable goal. An in-depth understanding of the pathological processes in PD is crucial for prevention and treatment development. Advanced multimodal neuroimaging techniques provide unique biomarkers that can further our understanding of PD at multiple levels ranging from neurotransmitters to neural networks. These neuroimaging biomarkers also have value in clinical application, for example, in the differential diagnosis of PD. As the field continues to advance, neuroimaging biomarkers are expected to become more specific, more widely accessible, and can be readily incorporated into translational research for treatment development in PD.

Deficits in cognitive control contribute to behavioral impairments across neuropsychiatric disorders. Cognitive control is captured as a construct in the Research Domain Construct (RDoC) matrix and incorporate subdomains of goal selection, response selection, and performance monitoring. Relevant tasks for these subdomains include the "AX" version of the continuous performance task (goal selection) and the Go/NoGo and Stop-Signal reaction time tasks (response selection). Underlying mechanisms for these domains have been investigated intensively using fMRI and event-related potential (ERP) approaches, which provide candidate biomarkers for translational research. In RDoC, impulsive behaviors are provisionally assigned to the cognitive control/response selection construct, but other factors may also contribute. Impulsivity has gained increased importance over recent years due to its link to aggression and suicidality, which is mediated especially through the constructs of urgency and frustrative nonreward. These constructs, in turn, may be captured through scales such as the Urgency, (Lack of) Premeditation, (Lack of) Perseverance, and Sensation Seeking (UPPS-P) impulsivity scale and the Point Subtraction Aggression Paradigm (PSAP), respectively. At present, no validated biomarkers exist for either urgency or aggressivity. Potential directions for the development of predictive biomarkers for both targets are discussed.

The human brain's complexity is underpinned by billions of neurons and trillions of synapses, necessitating coordinated activities across diverse cell types. Conventional techniques like in situ hybridization and immunohistochemistry, while valuable, face limitations in resolution and comprehensiveness when analyzing neuron types. Advances in spatial omics technologies, especially those integrating transcriptomics and proteomics, have revolutionized our understanding of brain tissue organization. These technologies, such as FISH-based, in situ sequencing-based (ISS), and next-generation sequencing (NGS)-based methods, provide detailed spatial context, overcoming previous limitations. FISH techniques, including smFISH and its variants like seqFISH and MERFISH, offer high-resolution spatial gene expression data. ISS approaches leverage padlock probes and rolling circle amplification to yield spatial transcriptome information. NGS-based methods, such as spatial transcriptomics and spatial-epigenomics, integrate spatial barcodes with single-cell sequencing, enabling comprehensive profiling of gene expression and epigenetic states in tissues. These innovations have propelled insights into neural development and disease, identifying cellular heterogeneity and molecular alterations in conditions like Alzheimer's and major depression. Despite challenges in cost, speed, and data analysis, spatial omics technologies continue to evolve, promising deeper insights into the molecular mechanisms of the brain and neurodegenerative diseases.