Advances in neurobiology最新文献

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system, in which aquaporin-4 immunoglobulin G (AQP4-IgG) targets the water channel aquaporin-4 (AQP4) localized at astrocytic endfeet, thus triggering inflammatory lesions and tissue damage. The pathological characteristics of NMOSD are early loss of oligodendrocytes, extensive demyelination, and axonal injury. The pathogenesis of oligodendrocyte damage in NMOSD includes complement-dependent bystander effect, antibody-dependent cell-mediated cytotoxicity bystander effect, glutamate toxicity, connexin dysregulation, and blood-brain barrier disruption. Remyelination levels in acute NMOSD lesions are low.

Proper physical activity, even at a very light intensity such as walking or slow running, improves brain health related to prefrontal executive function and hippocampal memory. However, the neural mechanism behind the cognitive enhancement that occurs during dynamic aerobic exercise is elusive and remains unclear in humans. Recently, pupillometry has been attracting attention as a kind of readout of the brain's ascending arousal mechanism, especially for brain noradrenergic and cholinergic system activation. Thus, to identify the neural mechanism behind the effects of very-light-intensity exercise, our recent work has focused on pupillometry during aerobic exercise, and we have successfully shown the efficacy of pupil dilation as a biological marker, even during very-light-/light-intensity exercise (below the ventilatory threshold). Interestingly, neuromelanin-MRI contrast in the LC, a marker of LC integrity, predicted the magnitude of exercise-induced pupil dilation and psychological arousal changes at the individual level. In addition, we have found that pupil dilation during exercise predicted the positive impact of acute very-light-/light-intensity exercise on prefrontal executive performance and hippocampal memory performance. The series of exercise pupillometry studies we will discuss here provides essential insights into the neural substrates of the advantages of exercise-induced brain stimulation in humans.

Physical activity has been proven to be beneficial for brain function. Due to a lack of appropriate therapies for the majority of brain diseases, exercise has become a favored alternative to prevent and even treat several of these pathologies. Thus, the mechanisms underlying the neuroprotective actions of exercise are under intense scrutiny. Furthermore, since many patients afflicted with different neurological conditions are not able to perform exercise, development of pharmacological mimics based on knowledge of underlying cellular and molecular mechanisms is of therapeutic interest (Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Cell 134:405-415, 2008). As part of these mechanisms, we will examine the role of insulin-like growth factor I (IGF-I), a pleiotropic neuroprotective signal, and one of the established mediators of the beneficial actions of exercise in the brain. Exercise stimulates the entrance of circulating IGF-I into the brain where it mediates pro-neurogenic, pro-cognitive, and mood modulatory effects known to be associated to exercise. Through its potent cytoprotective actions (anti-apoptotic, anti-oxidant, anti-inflammatory), IGF-I participates in reparative and homeostatic processes associated to exercise. We postulate that circulating IGF-I, a regulator of muscle and bone mass, forms part of an interoceptive system within a humoral branch informing the brain of muscle/bone mass. In this way, IGF-I conveys interoceptive signaling to brain areas involved in orchestrating physical activity to adapt them to available vigor, i.e., muscle strength. Because exercise engages the activity of many brain areas, neuroprotection by exercise-elicited entrance of circulating IGF-I is brain-wide.

Oxidative stress in the brain is associated with the development and progression of neurological disorders, posing antioxidant nutrients as an effective strategy for protecting neuronal cells and potentially slowing cognitive decline. Bioactive compounds from natural sources with antioxidant effects promote brain health. Among various natural compounds, astaxanthin (ASX), a potent red-pigment carotenoid found in various microorganisms and marine animals, is well recognized for its potential health benefits. In this review, we highlight the promising neuroprotective effects of ASX through cellular experiments and animal models. This review can provide novel insights on the therapeutic potential of ASX through its antioxidant, anti-inflammatory, and anti-apoptotic effects against neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In addition to demonstrating the neurotrophic effects of ASX on structural and functional changes in hippocampal neuronal plasticity, this review also discusses its synergistic potential with other interventions, such as exercise.

Monoamine transporters are essential proteins located at presynaptic terminals that play a crucial role in regulating neurotransmission of serotonin, dopamine, and norepinephrine by rapid reuptake of released amines from the synapse. Clinically used antidepressants and widely abused psychostimulants exhibit a high affinity for amine transporters. Function and expression of biogenic amine transporter are altered in subjects suffering from psychiatric diseases such as depression and in psychostimulant use disorder. Therefore, proper functional regulation of monoamine transporters is critical in maintaining normal amine homeostasis. Monoamine transporters possess several potential phosphorylation sites/motifs and exist in a phosphorylated state. Various cellular protein kinases and phosphatases are known to regulate the phosphorylation dynamics of amine transporters, which in turn influences subcellular expression and trafficking, microdomain-specific protein-protein interactions, transporter protein degradation, and overall transport capacity. Dysfunctional amine transporter function, phosphorylation, and association with interacting proteins are evident in neuropsychiatric disease states, including psychostimulant use disorder. However, the neurobiological consequences of in vivo amine transporter phosphorylation and its regulation remain unclear. Recent studies utilizing intact animal models are beginning to connect these molecular mechanisms with observed animal behaviors. This review summarizes current knowledge on the causal role of amine transporter phosphorylation in regulating amine transport and its relevance to animal behavior. Further understanding of phosphorylation-dependent molecular mechanisms governing amine transporter regulation potentially identifies regulatory motif(s) as potential therapeutic targets for treating neuropsychiatric disorders.

Oligodendroglia are the only cell lineage of the central nervous system (CNS) responsible for producing myelin. They originate from precursor cells known as oligodendrocyte precursor cells (OPCs), which are born around the ventricular zones of the brain and spinal cord and migrate throughout the developing CNS, and many of them ultimately differentiate into mature myelinating oligodendrocytes. Recent research has shown that OPCs and oligodendrocytes possess distinct characteristics when compared either to other types of glial cells in the CNS or to each other. Under different physiological and pathophysiological conditions, the processes of development or regeneration, the features, and, in some cases, even the functions of oligodendroglia can be modified. These changes can contribute to disease progression and affect the functional status of the nervous system. For instance, experience-dependent "adaptive" myelination plays a crucial role in the plasticity of neuronal circuits and influences learning processes; additionally, the non-myelinating functions of oligodendroglia expand their pathological potential, allowing them to regulate neuronal development and activity, angiogenesis, astrocyte maturation, and neuroinflammation. This chapter serves as a comprehensive introduction to oligodendroglia by presenting evidence from fundamental studies and fresh insights into their development, physiological and pathophysiological attributes, as well as the newly discovered non-myelinating functions.

Some neuronal populations in the brain have the ability to release multiple neurotransmitters, which may be packaged in the same vesicle, or released by distinct subsets of vesicles. Here, we review current knowledge on the molecular mechanisms by which multiple neurotransmitters can be stored in the same cell and the functional implications that this has for information processing throughout the brain and the control of movement execution by basal ganglia and cortical motor circuits.

Monoamine transmission is critical for regulating numerous physiological processes, including stress, learning, motor activity, and reward. Over the past few decades, the adoption of fast scan cyclic voltammetry has unveiled an intricate interplay between monoamine release and uptake dynamics, particularly concerning monoamine transporter involvement in reward and reinforcement processes for drugs of abuse. This review discusses how fast scan cyclic voltammetry has revolutionized our understanding of the processes that govern monoamine release and uptake, emphasizing the heterogeneity in transporter function across terminal regions, the influence of autoreceptors on monoamine transmission, and the complex interactions between drugs of abuse and monoamine transporters. While much of the review focuses on what is known about dopamine transporters-due to the wealth of evidence on dopamine transmission-we also emphasize significant gaps in knowledge regarding the serotonin and norepinephrine transporters. Finally, we highlight remaining questions about the dynamic nature of monoaminergic transporter efficiency and suggest new areas of investigation to gain a more comprehensive understanding of the biochemical mechanisms through which monoamine transporters regulate behavior.

Cognitive dysfunction in type 2 diabetes mellitus (T2DM) poses a significant peril not only to compromised human well-being but also to the onset of dementia, Alzheimer's disease, and depression. Given the present research findings utilizing animal models, various potential biochemical mechanisms have been reported for hippocampus-based cognitive dysfunction in T2DM. This chapter focuses on the relationship between cognitive dysfunction in T2DM and dysregulation of the hippocampal astrocyte-neuron lactate shuttle, with specific emphasis on monocarboxylate transporter 2 (MCT2). Furthermore, it provides a summary of the evidence suggesting the potentiality of exercise as a viable therapeutic intervention, encompassing not solely glycemic control but also the amelioration of cognitive dysfunction in T2DM.

Dopamine (DA) is an important modulatory neurotransmitter that is involved in daily activities such as movement, memory, and reward-oriented learning of essential behaviors and needs. DA signaling is initiated by the release of DA into the synaptic cleft that will bind to dopamine receptors to mediate the physiological response. To terminate the DA response, the DA is taken up by the dopamine transporter (DAT), a surface membrane protein. Psychostimulants, like cocaine and amphetamine, both target DAT and interfere with the DA uptake process, resulting in an increased amount of DA in the synaptic cleft. Continuous use of psychostimulants can lead to psychostimulant use disorders (PUDs), which are marked by uncontrollable psychostimulant craving and misuse. Because of the unmet need for treatment options for PUDs, novel strategies for discovering therapies are essential. Over the years, DAT-targeting ligands have been identified with atypical properties such as reduced abuse liability compared to cocaine. These compounds have been proposed to bind to different sites from cocaine and/or prefer and stabilize specific conformations of DAT. In addition, some of these compounds can interfere with psychostimulant-DAT binding and may have therapeutic potential in treating PUDs. This chapter introduces the role of DAT in PUDs, presents the mechanism of action of novel DAT-binding ligands, and discusses the therapeutic potential of atypical DAT-binding ligands for PUDs.