International review of neurobiology最新文献

Amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases are characterised by dysfunction of a host of RNA-binding proteins (RBPs) and a severely disrupted RNA metabolism. Recently, RBP-harbouring phase-separated complexes, ribonucleoprotein (RNP) granules, have come into the limelight as "crucibles" of neuronal pathology in ALS. RNP granules are indispensable for the multitude of regulatory processes underlying cellular RNA metabolism and serve as critical organisers of cellular biochemistry. Neurons, highly specialised cells, heavily rely on RNP granules for efficient trafficking, signalling and stress responses. Multiple RNP granule components, primarily RBPs such as TDP-43 and FUS, are affected by ALS mutations. However, even in the absence of mutations, RBP proteinopathies represent pathophysiological hallmarks of ALS. Given the high local concentrations of RBPs and RNAs, their weakened or enhanced interactions within RNP granules disrupt their homeostasis. Thus, the physiological process of phase separation and RNP granule formation, vital for maintaining the high-functioning state of neuronal cells, becomes their Achilles heel. Here, we will review the recent literature on the causes and consequences of abnormal RNP granule functioning in ALS and related disorders. In particular, we will summarise the evidence for the network-level dysfunction of RNP granules in these conditions and discuss considerations for therapeutic interventions to target RBPs, RNP granules and their network as a whole.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and interaction, as well as restricted and repetitive patterns of behavior. Despite extensive research, effective pharmacological interventions for ASD remain limited. Cannabidiol (CBD), a non-psychotomimetic compound of the Cannabis sativa plant, has potential therapeutic effects on several neurological and psychiatric disorders. CBD interacts with the endocannabinoid system, a complex cell-signaling system that plays a crucial role in regulating various physiological processes, maintaining homeostasis, participating in social and behavioral processing, and neuronal development and maturation with great relevance to ASD. Furthermore, preliminary findings from clinical trials indicate that CBD may have a modulatory effect on specific ASD symptoms and comorbidities in humans. Interestingly, emerging evidence suggests that CBD may influence the gut microbiota, with implications for the bidirectional communication between the gut and the central nervous system. CBD is a safe drug with low induction of side effects. As it has a multi-target pharmacological profile, it becomes a candidate compound for treating the central symptoms and comorbidities of ASD.

This chapter provides a succinct overview of several recommendations for the design and analysis of treatments for AUD with a specific focus on increasing rigor and generalizability of treatment studies in order to increase the reach of AUD treatment. We recommend that researchers always register their trials in a clinical trial registry and make the protocol accessible so that the trial can be replicated in future work, follow CONSORT reporting guidelines when reporting the results of the trial, carefully describe all inclusion and exclusion criteria as well as the randomization scheme, and always use an intent to treat design with attention to analysis of missing data. In addition, we recommend that researchers pay closer attention to recruitment and engagement strategies that increase enrollment and retention of historically marginalized and understudied populations, and we end with a plea for more consideration of implementation science approaches to increase the dissemination and implementation of AUD treatment in real-world settings.

The non-motor symptoms of Parkinson's disease (PD) have gained increasing attention in recent years due to their significant impact on patients' quality of life. Among these non-motor symptoms, cognitive dysfunction has emerged as an area of particular interest where the clinical aspects are covered in Chapter 2 of this volume. This chapter explores the rationale for investigating the underlying neurobiology of cognitive dysfunction by utilising translational animal models of PD, from rodents to non-human primates. The objective of this chapter is to review the various animal models of cognition that have explored the dysfunction in animal models of Parkinson's disease. Some of the more advanced pharmacological studies aimed at restoring these cognitive deficits are reviewed, although this chapter highlights the lack of systematic approaches in dealing with this non-motor symptom at the pre-clinical stages.

Sleep disturbances are highly prevalent among patients with Parkinson's disease (PD) and often appear from the early-phase disease or prodromal stages. In this chapter, we will discuss the current evidence addressing the links between sleep dysfunctions in PD, focusing most closely on those data from animal and mathematical/computational models, as well as in human-based studies that explore the electrophysiological and molecular mechanisms by which PD and sleep may be intertwined, whether as predictors or consequences of the disease. It is possible to clearly state that leucine-rich repeat kinase 2 gene (LRRK2) is significantly related to alterations in sleep architecture, particularly affecting rapid eye movement (REM) sleep and non-REM sleep, thus impacting sleep quality. Also, decreases in gamma power, observed after dopaminergic lesions, correlates negatively with the degree of injury, which brings other levels of understanding the impacts of the disease. Besides, abnormal synchronized oscillations among basal ganglia nuclei can be detrimental for information processing considering both motor and sleep-related processes. Altogether, despite clear advances in the field, it is still difficult to definitely establish a comprehensive understanding of causality among all the sleep dysfunctions with the disease itself. Although, certainly, the search for biomarkers is helping in shortening this road towards a better and faster diagnosis, as well as looking for more efficient treatments.

Over the decades, preclinical models have been developed and refined to investigate the rewarding effects of addictive substances and the neurobiological underpinnings of alcohol and other drug use disorders. This chapter delves into the methodological foundations, advantages, and limitations of leading animal models used to study alcohol use disorders (AUDs). Some models focus on the early stages of alcohol use and abuse. For instance, conditioned place preference assesses associative learning between a specific context and the effects of the drug, while locomotor sensitization measures increased locomotor activity following repeated drug exposure. In contrast, contingent models such as operant and non-operant alcohol self-administration protocols gauge voluntary intake, preference, motivation, and seeking behavior for alcohol solutions among experimental subjects. Additionally, we discuss the chronic intermittent alcohol vapor model, extensively utilized to induce a phenotype resembling dependence through non-contingent inhalation of alcohol vapor, resulting in elevated blood alcohol concentrations. Given the focus on pharmacological treatments for AUDs, we explore how different animal models can be employed to evaluate potential therapies and extrapolate findings to alcohol-related behaviors in humans. This chapter aims to provide readers with a comprehensive understanding of various animal models for AUDs, aiding in the interpretation of preclinical studies and the selection of suitable models for future research endeavors.

This chapter reviews the neuroanatomy of the nociceptive system and its functional organization. We describe three main compartments of the nervous system that underlie normal nociception and the resulting pain percept: Peripheral, Spinal Cord, and Brain. We focus on how ascending nociceptive processing streams traverse these anatomical compartments, culminating in the multidimensional experience of pain. We also describe neuropathic pain conditions, in which nociceptive processing is abnormal, not only because of the primary effects of a lesion or disease affecting peripheral nerves or the central nervous system (CNS), but also due to secondary effects on ascending pathways and brain networks. We discuss how the anatomical components (circuits/networks) reorganize under various etiologies of neuropathic pain and how these changes can give rise to pathological pain states.

Amyotrophic lateral sclerosis (ALS) is a heterogeneous progressive neurodegenerative disorder with available treatments such as riluzole and edaravone extending survival by an average of 3-6 months. The lack of highly effective, widely available therapies reflects the complexity of ALS. Omics technologies, including genomics, transcriptomic and proteomics have contributed to the identification of biological pathways dysregulated and targeted by therapeutic strategies in preclinical and clinical trials. Integrating clinical, environmental and neuroimaging information with omics data and applying a systems biology approach can further improve our understanding of the disease with the potential to stratify patients and provide more personalised medicine. This chapter will review the omics technologies that contribute to a systems biology approach and how these components have assisted in identifying therapeutic targets. Current strategies, including the use of genetic screening and biosampling in clinical trials, as well as the future application of additional technological advances, will also be discussed.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder in which selective death of motor neurons leads to muscle weakness and paralysis. Most research has focused on understanding and treating monogenic familial forms, most frequently caused by mutations in SOD1, FUS, TARDBP and C9orf72, although ALS is mostly sporadic and without a clear genetic cause. Rodent models have been developed to study monogenic ALS, but despite numerous pre-clinical studies and clinical trials, few disease-modifying therapies are available. ALS is a heterogeneous disease with complex underlying mechanisms where several genes and molecular pathways appear to play a role. One reason for the high failure rate of clinical translation from the current models could be oversimplification in pre-clinical studies. Here, we review advances in pre-clinical models to better capture the heterogeneous nature of ALS and discuss the value of novel model systems to guide translation and aid in the development of precision medicine.

Amyotrophic lateral sclerosis (ALS) has traditionally been considered a neuron-centric disease. This view is now outdated, with increasing recognition of cell autonomous and non-cell autonomous contributions of central and peripheral nervous system glia to ALS pathomechanisms. With glial research rapidly accelerating, we comprehensively interrogate the roles of astrocytes, microglia, oligodendrocytes, ependymal cells, Schwann cells and satellite glia in nervous system physiology and ALS-associated pathology. Moreover, we highlight the inter-glial, glial-neuronal and inter-system polylogue which constitutes the healthy nervous system and destabilises in disease. We also propose classification based on function for complex glial reactive phenotypes and discuss the pre-requisite for integrative modelling to advance translation. Given the paucity of life-enhancing therapies currently available for ALS patients, we discuss the promising potential of harnessing glia in driving ALS therapeutic discovery.