Advances in neurobiology最新文献

Neuropathic pain (NP) is pain resulting from lesions or disease of the somatosensory system. A cardinal feature of NP is tactile allodynia (a painful response to normally innocuous stimulation). In 2003, a breakthrough strategy for inducing NP was proposed in which microglia of the spinal dorsal horn (SDH) are activated after peripheral nerve injury (PNI) to overexpress P2X4 receptor (P2X4R) and play an important role in inducing tactile allodynia. In 2005, it was reported that stimulation of microglial P2X4Rs evokes the release of brain-derived neurotrophic factor (BDNF), which causes a depolarizing shift of the anion reversal potential (E_anion) of secondary sensory neurons. These findings and other facts suggest the mechanism by which innocuous touch stimuli cause severe pain and the important role of microglia in the mechanism.

This chapter will focus on microglial involvement in neurodevelopmental and neuropsychiatric disorders, particularly autism spectrum disorder (ASD), schizophrenia and major depressive disorder (MDD). We will describe the neuroimmune risk factors that contribute to the etiopathology of these disorders across the lifespan, including both in early life and adulthood. Microglia, being the resident immune cells of the central nervous system, could play a key role in triggering and determining the outcome of these disorders. This chapter will review preclinical and clinical findings where microglial morphology and function were examined in the contexts of ASD, schizophrenia and MDD. Clinical evidence points out to altered microglial morphology and reactivity, as well as increased expression of pro-inflammatory cytokines, supporting the idea that microglial abnormalities are involved in these disorders. Indeed, animal models for these disorders found altered microglial morphology and homeostatic functions which resulted in behaviours related to these disorders. Additionally, as microglia have emerged as promising therapeutic targets, we will also address in this chapter therapies involving microglial mechanisms for the treatment of neurodevelopmental and neuropsychiatric disorders.

Ischemic stroke is a complex brain pathology caused by an interruption of blood supply to the brain. It results in neurological deficits which that reflect the localization and the size of the compromised brain area and are the manifestation of complex pathogenic events triggered by energy depletion. Inflammation plays a prominent role, worsening the injury in the early phase and influencing poststroke recovery in the late phase. Activated microglia are one of the most important cellular components of poststroke inflammation, appearing from the first few hours and persisting for days and weeks after stroke injury. In this chapter, we will discuss the nature of the inflammatory response in brain ischemia, the contribution of microglia to injury and regeneration after stroke, and finally, how ischemic stroke directly affects microglia functions and survival.

Neurodevelopmental disorders (NDDs) encompass various conditions stemming from changes during brain development, typically diagnosed early in life. Examples include autism spectrum disorder, intellectual disability, cerebral palsy, seizures, dyslexia, and attention deficit hyperactivity disorder. Many NDDs are linked to perinatal events like infections, oxygen disturbances, or insults in combination. This chapter outlines the causes and effects of perinatal brain injury as they relate to microglia, along with efforts to prevent or treat such damage. We primarily discuss therapies targeting microglia modulation, focusing on those either clinically used or in advanced development, often tested in large animal models such as sheep, non-human primates, and piglets-standard translational models in perinatal medicine. Additionally, it touches on experimental studies showcasing advancements in the field.

Efforts to reveal the molecular, cellular, and circuit mechanisms of addiction have largely focused on neurons. Yet accumulating data regarding the ability of glial cells to impact synaptic function, circuit activity, and behavior demands that we explore how these nonneuronal cells contribute to substance use disorders and addiction. Important work has shown that glial cells, including microglia, exhibit changes in phenotype following exposure to drugs of abuse and that modification of glial responses can impact behaviors related to drug seeking and drug taking. While these are critical first steps to understanding how microglia can impact addiction, there are still substantial gaps in knowledge that need to be addressed. This chapter reviews some of the key studies that have shown how microglia are affected by and can contribute to addiction. It also discusses areas where more knowledge is urgently needed to reveal new therapeutic and preventative approaches.

Microglia represent the main immunocompetent cell type in the parenchyma of the brain and the spinal cord, with roles extending way beyond their immune functions. While emerging data show the pivotal role of microglia in brain development, brain health and brain diseases, the exact mechanisms through which microglia contribute to complex neuroimmune interactions are still largely unclear. Understanding the communication between microglia and other cells represents an important cornerstone of these interactions, which may provide novel opportunities for therapeutic interventions in neurological or psychiatric disorders. As such, in line with studying the effects of the numerous soluble mediators that influence neuroimmune processes, attention on physical interactions between microglia and other cells in the CNS has increased substantially in recent years. In this chapter, we briefly summarize the latest literature on "microglial contactomics" and its functional implications in health and disease.

Modulation of microglia function for treatment of neurodegenerative and neuropsychiatric disorders is an emerging field of neuroscience drug development. This is largely attributed to human genetic association studies combined with biological evidence indicating that the innate immune system acts as a causal contributor superimposed on the reactive component of neuronal loss in neurological dysfunction. The identification of disease risk gene variants that encode immune-modulatory proteins in microglia provides tools to evaluate how microglia cellular function or dysfunction affect neuronal health. The development of clinical stage therapeutic compounds that modify myeloid cell function enables us to investigate how modulating microglia function could become a transformational approach to mitigate neurological disorders. Improving our ability to boost microglia-promoting homeostatic and reparative functions hopefully will translate into achieving a better outcome for patients affected by neurological diseases. In this chapter, we aim to provide an overview of the microglial emerging therapies and targets being studied in current clinical trials.

New in vitro models provide an exciting opportunity to study live human microglia. Previously, a major limitation in understanding human microglia in health and disease has been their limited availability. Here, we provide an overview of methods to obtain human stem cell or blood monocyte-derived microglia-like cells that provide a nearly unlimited source of live human microglia for research. We address how understanding microglial ontogeny can help modeling microglial identity and function in a dish with increased accuracy. Moreover, we categorize stem cell-derived differentiation methods into embryoid body based, growth factor driven, and coculture-driven approaches, and review novel viral approaches to reprogram stem cells directly into microglia-like cells. Furthermore, we review typical readouts used in the field to verify microglial identity and characterize functional microglial phenotypes. We provide an overview of methods used to study microglia in environments more closely resembling the (developing) human CNS, such as cocultures and brain organoid systems with incorporated or innately developing microglia. We highlight how microglia-like cells can be utilized to reveal molecular and functional mechanisms in human disease context, focusing on Alzheimer's disease and other neurodegenerative diseases as well as neurodevelopmental diseases. Finally, we provide a critical overview of challenges and future opportunities to more accurately model human microglia in a dish and conclude that novel in vitro microglia-like cells provide an exciting potential to bring preclinical research of microglia to a new era.

Parkinson's disease (PD) is a neurodegenerative disorder with a complex and multifactorial pathogenesis. This chapter delves into the critical role of astrocytes in PD. Once viewed as supporting cells in the central nervous system, astrocytes have emerged as key players in both maintaining neuronal health and contributing to neurodegeneration in PD. Their functions play a dual role in the progression of PD, ranging from protective functions like secretion of neurotrophic factors and clearance of α-synuclein to detrimental functions like promotion of neuroinflammation. This chapter is structured into three primary sections: the morphological and functional organization of astrocytes, astrocytic calcium signaling, and the role of astrocyte heterogeneity in PD. We provide a detailed exploration of astrocytic organelles, bidirectional astrocyte-neuron interactions, and the impact of astrocytic secretions such as antioxidant molecules and neurotrophic factors. Furthermore, we discuss the influence of astrocytes on non-neuronal cells, including interactions with microglia and the blood-brain barrier (BBB). By examining the multifaceted roles of astrocytes, in this chapter, we aim to bridge basic astrocyte biology with the clinical complexities of PD, offering insights into novel therapeutic strategies. The inclusion of astrocyte biology in our broader research approach will aid in the development of more effective treatment strategies for PD.

Engagement of astrocytes within the brain's reward circuitry has been apparent for approximately 30 years, when noncontingent drug administration was observed to lead to cytological markers of reactive astrocytes. Since that time, advanced approaches in rodent behavior and astrocyte monitoring have revealed complex interactions between astrocytes with drug type, animal sex, brain region, and dose and duration of drug administration. A number of studies now collectively reveal that rodent drug self-administration followed by prolonged abstinence results in decreased features of structure and synaptic colocalization of astrocytes. In addition, stimulation of astrocytes in the nucleus accumbens with DREADD receptors or pharmacological compounds opposes drug-seeking behavior. These findings provide a clear path for ongoing investigation into astrocytes as mediators of drug action in the brain and underscore the potential therapeutic utility of astrocytes in the regulation of drug craving and relapse vulnerability.