Advances in neurobiology最新文献

The dopamine transporter (DAT) is a plasma membrane protein expressed in dopamine (DA) neurons of the central nervous system and is critical for regulating DA neurotransmission. The DAT is responsible for the reuptake of released DA back into the presynaptic neuron, resulting in the termination of DA transmission. This process also recycles the DA back into the dopaminergic neuron for subsequent release. DAT is the target of psychostimulants including cocaine and amphetamines and has been associated with several neuropsychiatric disorders. Only DAT proteins located on the plasma membrane can remove DA from the extracellular space, and the number of DAT proteins on the cell-surface therefore determines the efficiency of DA clearance. As a result, regulating DAT surface expression is a critical means to regulating the magnitude and duration of DA neurotransmission. This chapter will discuss the different processes and proteins that have been shown to affect DAT surface expression and discuss the relevance to normal DA physiology and diseases that involve aberrant DA signaling.

Some monoamine-uptake inhibitors are among first-line treatments for specific chronic pain conditions. It concerns tricyclic antidepressant drugs, such as amitriptyline or nortriptyline, and the more selective serotonergic and noradrenergic reuptake inhibitors, such as duloxetine. They are recommended for treating neuropathic pain, which is pain caused by a lesion or disease of the somatosensory nervous system, and fibromyalgia, which is a chronic widespread pain. Clinically, their action on pain was proposed to be independent from the one on depression. Research in animal models provided some understanding of the pain-relieving mechanism. The noradrenergic component of monoamine-uptake inhibitors appears to be critical, with the therapeutic effect likely involving targets at peripheral, spinal and supraspinal levels. At least two independent mechanisms would contribute to pain relief. One is spinal, relying on the recruitment of aminergic descending controls of pain, with a downstream key role of the α₂ adrenergic receptors; the other may require more sustained treatment and relies on the noradrenergic recruitment of β₂ adrenergic receptors and a downstream anti-neuroimmune action. Both mechanisms require a functional endogenous opioid system. These insights, however, focused on the sensory component of pain, and the contribution of the supraspinal action of antidepressant drugs needs to be explored in detail.

The concept of "Exercise is Medicine" highlights the preventive effects of physical activity on lifestyle-related diseases, dementia, and mental disorders. However, human studies face limitations in isolating exercise-specific effects due to uncontrolled variables such as diet and living conditions, as well as the constraint of non-invasive methodologies. Animal models offer a valuable alternative, allowing for strict control of experimental conditions and detailed assessment of physiological and neural responses to exercise. While voluntary wheel running has been commonly used, it lacks standardization in exercise intensity and type. To bridge this gap, we developed a treadmill-based rodent exercise model that enables precise control over exercise parameters, including intensity, duration, and distance. By incorporating physiological markers-such as blood lactate and oxygen consumption-commonly used in humans, we succeeded in evaluating rodent fitness and establishing exercise paradigms analogous to those used in human studies. Our findings demonstrate that even light-intensity exercise can significantly enhance brain activation and memory, which may be particularly relevant for aging or low-fitness populations. This approach enables the exploration of shared neurobiological mechanisms and supports the advancement of translational research, facilitating the development of tailored exercise interventions aimed at promoting cognitive health.

In the early 2000s, it became evident that exercise enhances brain function, particularly in the hippocampus, attracting considerable attention. However, at that time, most studies relied on the voluntary wheel running model for experiments, it was unclear whether exercise conditions affected the impact of exercise on the hippocampus. Therefore, aiming to obtain translational insights applicable to humans, we focused on exercise intensity and started with the research investigating whether light-intensity exercise activates hippocampal neural activity in rats. We established an original running model in rats comprising laser Doppler flowmetry for monitoring hippocampal cerebral blood flow (Hip-CBF) and microdialysis for drug treatment. We found that Hip-CBF increased with light-intensity treadmill running, which was elicited by hippocampal neuronal activation and subsequent N-methyl-D-aspartate/nitric oxide (NMDA/NO) signaling. In this chapter, we first retrospectively summarize what we knew and what we did not know during that time, and the impact of our findings that light-intensity exercise can evoke neuronal activity in the rat hippocampus on our subsequent research.

Leukodystrophies are a diverse group of inherited diseases characterised by white matter degenerative pathology. Leukodystrophies have a highly heterogeneous genetic background linked mainly to mutations in oligodendrocyte and astrocyte genes and, to lesser extent, microglia. The most prevalent leukodystrophies are caused by mutations in oligodendrocyte genes that encode the essential myelin proteins PLP1 and GalC in Pelizaeus-Merzbacher disease and Krabbe disease, respectively. Astrocyte leukodystrophies are led by Alexander disease, caused by mutations in the astrocyte gene GFAP. Vanishing white matter disease, the most prevalent inherited white matter pathology in children, is associated with astrocyte atrophy and cystic degeneration of the cerebral white matter. The pathogenic mechanisms in leukodystrophies depend on the genetic mutations and hence are extremely varied, but the diseases have in common white matter atrophy caused by the loss of oligodendrocytes and myelin, with or without marked reactive astrogliosis and microglia activation. The development of a range of animal models with the disruption of specific genes causing leukodystrophies and the use of pluripotent stem cells from people with different forms of leukodystrophy is advancing the understanding of the functional and cellular pathophysiology of these rare diseases.

Myelin plasticity, the capacity for dynamic changes in myelination and myelin structure, challenges the long-held view of myelin as a static entity post-development. Emerging evidence highlights its pivotal role in adapting neural circuits during learning, memory, and recovery from injury or disease. This chapter explores the cellular and molecular mechanisms underlying myelin plasticity, focusing on activity-dependent and experience-driven myelination mediated by oligodendrocytes, which are potentially modified by astrocytes and microglia. This study examines how neuronal activity regulates oligodendrocyte differentiation and myelin remodelling, affecting conduction velocity and circuit synchronization. The implications of myelin plasticity in cognition, ageing, and pathologies such as multiple sclerosis and stroke are discussed alongside experimental models that elucidate its processes. Finally, the importance of sleep in myelin maintenance and plasticity is discussed. Elucidating the mechanisms underlying myelin plasticity and maintenance may uncover new therapeutic opportunities for treating diseases and injuries that disrupt myelin and neuronal activity.

Neurodegenerative diseases are clinically, pathologically and genetically heterogeneous disorders characterised by progressive dysfunction and neuronal loss and the deposition of disease-specific proteinaceous aggregates in neurons and/or glia, showing a hierarchical involvement of brain regions. Research into disease mechanisms underlying neurodegenerative disorders has focused on the proteinaceous neuronal aggregates in vulnerable brain regions leading to neuronal dysfunction and degeneration and onset of clinical symptoms. However, emerging evidence highlights the importance of glia, including oligodendroglia, in the pathogenesis of neurodegenerative diseases, which have been underappreciated and frequently considered secondary to neuronal involvement. Pathologically altered proteins depositing in oligodendroglia comprise phosphorylated tau, α-synuclein, transactive response DNA-binding protein-43 (TDP-43) and occasionally FET/FUS. However, only primary oligodendroglial tau and α-synuclein deposits are considered for neuropathological diagnosis and classification of some tauopathies and synucleinopathies, respectively. Oligodendroglial tau pathology is also seen in ageing-related tau oligodendrogliopathy (ARTOG). This chapter provides an overview of neurodegenerative proteinopathies and protein pathologies affecting oligodendroglia.

Oligodendroglia are highly specialised to myelinate axons and ensure rapid electrical conduction of action potentials in the central nervous system (CNS). The oligodendroglial cell lineage comprises mature myelinating oligodendrocytes, together with oligodendrocyte precursor cells (OPCs) and immature premyelinating oligodendrocytes, their numerical density depending on developmental age. In early embryonic and postnatal development, OPCs and immature oligodendrocytes predominate, whereas in the adult CNS, mature myelinating oligodendrocytes comprise over 90% of the lineage, with OPCs making up a small but significant population (3-9%). Adult OPCs provide for myelin repair and plasticity throughout life. Oligodendroglial cells express diverse ion channels and neurotransmitter receptors, together with transporters and gap junctions, which enables these cells to sense and respond to their environment and fulfil their myelinating function as well as providing metabolic and homeostatic support for axons.

This review aims to elucidate the positive effects of exercise on cognitive function and explore the underlying mechanisms. Extensive evidence supports the assertion that exercise positively influences neuroplasticity, learning and memory, and mitigates cognitive decline. Nevertheless, comprehending the intricate factors influencing the efficacy of exercise in cognitive improvement remains challenging. Further investigations are imperative to determine the optimal personalized exercise regimen, including the frequency, intensity, type, dosage, and duration, as a non-pharmacological, safe, and cost-effective approach to maximize cognitive benefits. This pursuit holds significant promise for advancing our understanding of exercise as a practical intervention to promote cognitive well-being.

Adult hippocampal neurogenesis (AHN) is the process of generating new neurons in the adult hippocampal dentate gyrus (DG). Exercise promotes AHN and improves hippocampal function through neuroplastic enhancement. The underlying regulatory factors of this process are currently being vigorously studied. However, many previous studies have used a rodent wheel-running model, in which the exercise condition (e.g., volume, intensity, duration) cannot be controlled. In contrast, treadmill running (TR) allows the precise regulation of conditions such that animals can run according to specific experimental aims. Understanding the intensity-dependent effects of exercise on AHN and hippocampal functions, and the underlying mechanisms, is crucial for the development of exercise prescriptions for humans in diverse educational and clinical fields. Based on the lactate threshold (LT), an inflection point at which blood lactate accumulation drastically rises during incremental exercise, exercise can be defined as minimal-stress light-intensity exercise (below LT) and exercise-derived-stress vigorous-intensity exercise (above LT). This chapter begins with a brief overview of AHN, followed by a discussion of LT-based exercise effects on AHN and hippocampal function as they vary with exercise intensity, primarily following the findings from the TR models, and closing with the molecular factors involved in AHN and hippocampal function regulation.