Advances in neurobiology最新文献

Major psychiatric disorders like schizophrenia, depression and anxiety disorders, etc have serious impact on patients' health, but the pathogenesis remains unknown. With an extensive study on glial cells, their functions in psychiatric disorders have attracted much attention in recent years. Oligodendrocyte lineage cells (OLGs), as major myelination cells in the CNS, not only exhibit dynamic changes compatible with alterations in neurologic function but also regulate synaptic development and brain function from multiple aspects by interacting with neurons, astrocytes, and microglia. Concurrently, a growing number of studies have found extensive myelin loss and abnormal alterations of OLGs in the brains of patients with different types of psychiatric disorders. Moreover, impaired development and/or dysfunction of OLGs can lead to neuropsychiatric symptoms such as anxiety, depression, and social disorders by disrupting synaptic transmission or the glial network in animal models. Thus, targeting OLGs may represent a promising strategy for the treatment of psychiatric disorders.

Several magnetic resonance imaging (MRI)-based modalities have provided insight into how acute and chronic exercise and physical activity impact brain health. Structural MRI-based measures provide information regarding brain volume and cortical thickness, diffusion-weighted imaging measures provide indices of white matter and gray microstructure, and cerebrovascular effects that may be assessed through measures of regional cerebral blood flow, and brain activation and neural networks can be indexed using task-based and connectivity-based functional MRI, respectively. In this chapter, a series of studies are described in which these multi-modal MRI outcomes, along with indices of neurocognitive function, have been documented after a brief walking exercise intervention in healthy older adults and those diagnosed with mild cognitive impairment. Finally, we provide some additional insight into the neurophysiological mechanisms that may be foundational for these effects, but are yet not measurable in humans. Multi-modal neuroimaging is a non-invasive method in humans to assess the potential mechanisms whereby acute and chronic exercise may exert benefits to brain function and neural networks related to cognition that may protect older adults from age-related cognitive decline and dementia.

Cognitive decline is a natural part of aging, though its progression varies significantly among individuals. There is a great deal of evidence showing that exercise is one of the most promising lifestyle factors that can both improve cognitive function and reduce the risk of dementia by causing molecular, cellular, structural, and functional changes. In this chapter, based on observational studies and intervention studies, we will briefly outline the effects of physical activity and exercise on cognitive function in older adults, focusing on the potential of light-intensity dance as a practical and enjoyable exercise that many older adults can do.

Physical exercise is a potential medicine for cognitive function and mental health; however, regular exercise is more difficult than taking a pill every day. Developing an exercise environment that promotes a positive affective response to exercise and exercise benefits on the brain may encourage people to participate in physical activities. Listening to music while exercising is a promising candidate for such an "enriched exercise environment." This chapter reviews the studies demonstrating the beneficial effects of music on enhancing mood and cognitive function in both acute and chronic settings. Furthermore, the underlying neural mechanisms involved in the effects of exercise with music are discussed from the following three perspectives: (1) musical reward and pleasure, (2) rhythmic entrainment, and (3) sensory distraction. In addition, the concept of groove, which is "the pleasurable sensation of wanting to move the body to music" was used to explore the characteristics of music that are compatible with exercise. Finally, individual variations on whether combining exercises with music are appropriate and the considerations that should be addressed for implementation in the field are discussed.

The clinical efficacy of psychostimulant drugs, which target monoamine transporters, in treating attention-deficit/hyperactivity disorders (ADHDs) has stimulated interest on the role of transporter proteins like the dopamine (DA) transporter (DAT) in neurotransmission as well as the potential utility of DAT knockout organisms as models for neuropsychiatric disorders. Indeed, the study of DAT-deficient worms, flies, fish, mice, and rats has revealed a conserved role for DAT in the control of motor behavior as well as repetitive behavior, threat aversion, social behavior, and cognition in mammals. However, the disconnect between phenotypes observed in DAT-deficient model organisms and humans, which exhibit an early-onset syndrome characterized by Parkinsonism/dystonia and premature death, challenges the construct validity of DAT knockout models with respect to modeling neurobehavioral disorders. As an alternate approach, several groups have utilized coding variants in the SLC6A3 gene linked to psychiatric conditions, which display divergent molecular phenotypes. This chapter reviews the development and characterization of models of DAT gene deletion and mutation with a particular emphasis on comparing/contrasting the functional impact of DAT deficiency to DAT dysregulation triggered by neuropsychiatric disorder-linked DAT mutants in vivo. Ultimately, the study of DAT knockout and mutant models has revealed novel functions for DA in the mammalian brain, uncovered a dynamic interplay between the monoaminergic systems, highlighted sex differences in the DA system that determine the behavioral trajectory of DAT deregulation, and allowed for the screening of potential leads for therapeutics to treat disorders linked to aberrant dopaminergic neurotransmission.

Myelin is the lipid-rich insulating layer that wraps axons, providing trophic support and ensuring rapid propagation of the electrical impulses that underlie nervous system function. In the CNS, myelin is produced by mature oligodendrocytes (OLs) that arise from oligodendrocyte precursor cells (OPCs). Myelination is regulated by a variety of molecules, including growth factors, hormones, and extracellular molecules, which activate signaling cascades that drive cellular maturation. Key signaling molecules and downstream pathways that control myelination have been identified in cell culture and rodent models. Although much is known about the development of OL and its progenitor cell in vitro and in vivo, how CNS myelin is dynamically formed through OL processes is still unclear. Zebrafish share significant genetic and physiological similarities with mammals, including humans, making them a relevant model for studying complex biological processes like myelination. Due to its transparent larval development, zebrafish facilitates live imaging studies, enabling dynamic visualizations of cellular and molecular processes in real-time studies. In this chapter, we reviewed the latest insights into OL development and myelin formation, with a particular emphasis on the mechanisms regulating dynamic myelination in zebrafish. We highlight the dynamic extension and retraction of myelin sheath segments and the role of neuronal activity in regulating the developmental myelination in zebrafish. In addition, we also discussed the mechanisms of Ranvier node positioning and axon targeting of myelin sheaths in the spinal cord of zebrafish larvae. Finally, we reviewed the recent progress of zebrafish as a demyelinating disease model for drug discovery of pharmacological compounds favoring myelin regeneration.

Multiple sclerosis (MS) is a chronic autoimmune and progressive neurodegenerative disease of the central nervous system (CNS) that has a highly variable clinical manifestation and course. MS targets primarily myelin and oligodendroglia; however, all glial cells and neurons become involved early in the pathology. Thus, inflammation, which is widely thought to be initiated peripherally, expands through the CNS, with astrocytes and microglia entering an activated state not only around and within lesions but also widespread. This chapter will emphasize the pathophysiological changes in oligodendrocytes and myelin as a consequence of the inflammatory cascade driving the disease onset and progression. Learning about the mechanisms of oligodendrocyte and myelin damage beyond the immune attack will be instrumental in protecting these two CNS compartments from damage. In turn, knowledge about the axon-myelin unit will help in devising therapies to prevent axonal degeneration, a key clinical hallmark of MS, as it strongly correlates with the progression of CNS atrophy and symptoms. Finally, exploiting paradigms of oligodendrocyte repopulation and remyelination will definitively contribute to devising treatments for tissue repair and halting MS course. This chapter aims at summarizing the state of the art in all these experimental developments including the available clinical therapies and the current clinical trials.

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.