Advances in neurobiology最新文献

Oligodendrocytes (OLs) exhibit complex metabolic interactions essential for neuronal function and CNS health. This chapter analyzes the metabolism of OLs, particularly glucose, lipid, and amino acid metabolism, and their impact on myelin synthesis, maintenance, and CNS resilience. OLs utilize glucose for energy through glycolysis and the pentose phosphate pathway, supporting ATP production and antioxidative defenses. Lipid synthesis, including cholesterol and sphingolipid production, is critical for maintaining myelin integrity and rapid signal conduction. Furthermore, amino acid pathways, such as those involving glutamine and serine, modulate OL differentiation and remyelination. OLs also provide metabolic support to neurons through lactate shuttling and their interactions with astrocytes in the Panglial network, ensuring sustained energy flow. Dysregulation of OL metabolic functions underlies demyelinating diseases, such as multiple sclerosis, neurodegenerative disorders, and neuropsychiatric conditions, highlighting the therapeutic potential of targeting OL metabolism to enhance remyelination and neuroprotection.

The monoamine transporters move substrates across the plasma membrane by an alternating-access mechanism, in which a central substrate-binding site is alternately exposed to either the extracellular milieu or the cytoplasm at any given time. This process is driven by co-transport of sodium ions along the inwardly directed sodium gradient. Alternating access to the central substrate-binding site is facilitated by a stepwise series of changes to the transporter conformation, referred to as the transport cycle. The focus of this chapter is to discuss the conformational dynamics of the monoamine transporters that are orchestrated by the binding of substrate and ions, as part of the transport cycle. Firstly, we describe the substrate-binding event, and how it is fine-tuned to induce the conformational flexibility needed to initiate transport. Secondly, we discuss how sodium fuels the substrate transport as well as how it is aided by potassium and chloride. We also provide a mechanistic description of the cooperativity of the two sodium-binding sites and how they couple allosterically to the intracellular gating mechanism. Thirdly, we go over the amino acid residues of the intra- and extracellular gates and how they affect the transporter conformation.

Recent research highlights the relationship between physical activity and cognitive functions. It has been shown that aerobic and resistance exercises, including a wide range of intensity and duration, can evoke a positive impact on cognitive functions and mental health in various age groups. Also, high-intensity interval training (HIT) has been recognized as an exercise modality inducing desired adaptive changes at the level of physical performance (muscle) as well as cognitive functions (brain). Previous research has also shown HIT to be an effective strategy due to its minimal time commitment and significant multiple health benefits. The mechanism behind the cognitive function facilitation as a result of acute and chronic HIT may involve the induction of neurotransmitters, as well as the synthesis of neuroprotective factors and increased activation of brain areas critical for cognitive functioning. Moreover, HIT also causes robustly increased lactate production, recently identified as the "first myokine" modulating cerebral metabolism. Additionally, HIT may initially disrupt the redox balance where the moderate formation of reactive oxygen species (ROS) may act as a signaling mechanism, also improving cognitive functions. Although research supports the potential of HIT to improve cognitive function, challenges remain due to differences in exercise structure, duration, and intensity of HIT protocols as well as cognitive domains and cognitive testing timing that make it difficult to draw firm conclusions.To summarize, despite many variables that may influence differences in adaptive changes, existing research highlights the potential health benefits of HIT, also suggesting its effectiveness in enhancing human cognitive functions.

The importance of physical activity in neuroscience is gaining increasing recognition. The question arises: What is the specific focus of exercise, and what factors contribute to the observed benefits of exercise in neuroscience? Various forms of exercise have been examined across physiological, psychological, and biochemical experiments within neuroscience. Still, there is a need for greater clarity to identify optimal exercise conditions, including the FITT-VP variables (frequency, intensity, type, and time).This chapter aims to shed light on the positive impacts of high-intensity training (HIT) exercises in facilitating physiological adaptation and exploring the newfound role in brain functions. Key areas explored include (1) exercise neuroscience at the structural level involving synaptic plasticity and neurogenesis; (2) functional level concerning behavioral development; and (3) molecular level addressing potential mechanisms underlying exercise-induced brain plasticity.Overall, high-intensity training emerges as a more cost-effective method for enhancing physiological adaptations, including improvements in aerobic capacity. Additionally, it has been shown to influence brain functions such as hippocampus-dependent learning and memory positively. These findings offer valuable insights into the practicality of high-intensity training for performance improvement and suggest directions for future research.

Exercise has a remarkable capacity to improve brain function by fostering neuronal plasticity, which enables us to better cope with various psychological and cognitive challenges. Numerous studies have demonstrated the neuroprotective effects of exercise. However, the underlying molecular mechanisms of the neuroprotective effects of exercise are not yet fully understood. In particular, the role of exercise-induced secretion of peripheral factors into circulation that influence the brain is understudied. Recent research has shown that extracellular vesicles (EVs), including microvesicles (MVs) and exosomes, are secreted during exercise. The discovery that EVs can mediate intracellular communication by delivering cargo signifies a promising area of research to understand the impact of exercise on the brain. In the present review, we provide an overview of recent advancements in understanding the regulatory mechanisms of EV biogenesis and discuss how EV molecular composition is influenced by exercise. Additionally, we highlight the potential role of EVs as exercise-specific mediators and as a promising therapeutic tool for neurodegenerative diseases, such as Alzheimer's disease.

In this chapter we will show how electrophysiological recordings were used to gain insights into the transport kinetics and pharmacology of monoamine transporters (MATs). We will discuss data obtained from whole cell patch clamp recordings that allow for real time monitoring of MAT function. A notable property of MATs is that they carry so-called uncoupled currents. We will begin this chapter by reviewing the experimental evidence that has led to the conclusion that the currents carried by MATs are largely uncoupled and, therefore, not directly related to substrate transport. We will discuss how this has made it difficult to understand the operation of MATs. We will also explain why the existence of these currents has led to the proposition that MATs do not operate by alternate access but rather by a single file diffusion mechanism. However, we will show that ultimately the uncoupled currents carried by MATs can be most parsimoniously explained within the framework of the alternate access mechanism. We will review the existing evidence that MATs, like most other transporters, undergo a cycle during which they visit outward and inward-facing conformations (i.e., the transport cycle). We will outline what we have learned about the transport cycle of MATs from electrophysiological recordings. Thereafter, we will describe how electrophysiological recordings can be utilized to understand how drugs that target MATs affect their operation. To this end, we will discuss the binding modes of three different MAT ligands: (i) amphetamines, (ii) ibogaine, and (iii) zinc.

While moderate exercise has been demonstrated to enhance executive function, this beneficial effect may vary depending on the exercise environment. For instance, the decline in blood oxygen levels (hypoxemia) associated with ascent to high altitude has been shown not only to induce acute mountain sickness but also to potentially cause decreased cognitive performance. Therefore, exercise under hypoxic conditions may reduce oxygen delivery to various tissues, thereby attenuating the executive function-enhancing effects of exercise. Previous studies have examined the impact of exercise in hypoxic environments on cognitive function using cognitive task paradigms; however, a consensus has not been reached. One contributing factor to this lack of consensus is the insufficient investigation of how exercise in hypoxic environments affects neural activity in brain regions specific to cognitive function tasks. This limitation stems from the practical difficulties of utilizing positron emission tomography (PET) and magnetic resonance imaging (MRI) systems in hypoxic environments. We addressed these challenges by employing functional near-infrared spectroscopy (fNIRS), which requires only a compact experimental system, is portable, and can be readily installed in gym settings. Our findings revealed that exercise in hypoxic environments induces decreasing cognitive performance, specifically cognitive fatigue, by reducing task-specific neural activity. This chapter provides an overview of our research methodology and results.

Understanding exercise intensity is essential for optimizing training outcomes and minimizing health risks. This chapter introduces key physiological and subjective parameters used to assess exercise intensity, including heart rate reserve (HRR), oxygen uptake reserve (VO2R), maximal oxygen consumption (VO2max), and ratings of perceived exertion (RPE). Standardized classifications from organizations such as the American College of Sports Medicine (ACSM) are presented, alongside practical methods like the Talk Test for field applications. Incremental exercise testing is highlighted for identifying physiological thresholds, including lactate and ventilatory thresholds, which serve as critical markers for personalized training. Additionally, recent advances in neuroimaging-including electroencephalography (EEG), near-infrared spectroscopy (NIRS), and functional magnetic resonance imaging (fMRI)-are reviewed to explore how different exercise intensities affect brain activity. Evidence suggests that even low to moderate-intensity exercise can positively influence cognitive function and cerebral blood flow. The integration of wearable technologies has further enabled real-time monitoring of both physiological and neurocognitive responses. Overall, this chapter underscores the importance of individualized, evidence-based approaches in exercise prescription and highlights emerging methods for linking exercise intensity with brain function.

The dopamine transporter (DAT) plays a critical role in the central nervous system and has been implicated in numerous psychiatric disorders. The ligand-based approaches are instrumental to decipher the structure-activity relationship (SAR) of DAT ligands, especially the quantitative SAR (QSAR) modeling. By gathering and analyzing data from literature and databases, we systematically assemble a diverse range of ligands binding to DAT, aiming to discern the general features of DAT ligands and uncover the chemical space for potential novel DAT ligand scaffolds. The aggregation of DAT pharmacological activity data, particularly from databases like ChEMBL, provides a foundation for constructing robust QSAR models. The compilation and meticulous filtering of these data, establishing high-quality training data sets with specific divisions of pharmacological assays and data types, along with the application of QSAR modeling, prove to be a promising strategy for navigating the pertinent chemical space. Through a systematic comparison of DAT QSAR models using training data sets from various ChEMBL releases, we underscore the positive impact of enhanced data set quality and increased data set size on the predictive power of DAT QSAR models.

Myelin sheaths formed by oligodendrocytes (OLs) wrap around neuronal axons and allow for saltatory conduction of nerve impulses, significantly increasing the speed of electrical signal transmission. The development of oligodendrocyte lineage consists of several coordinated steps. Briefly, oligodendrocyte precursor cells (OPCs) are first generated from neural precursor cells of certain neuroepithelial regions, and then they proliferate and migrate to other regions of the central nervous system (CNS), where they differentiate into oligodendrocytes and form myelin sheaths around the axons of neurons. These developmental processes are tightly and precisely regulated during animal development by a cohort of intracellular molecular and extracellular signals.