Mechanisms of ionic current changes underlying rhythmic activity recovery after decentralization

Neuronal networks capableof generating rhythmic output in the absence of patterned sensory or central inputs are widely represented in the nervous system where they support a variety of functions, from learning and memory to rhythmic motor activity such as breathing. To perfectly function in a living organism, rhythm-generating networks have to combine the capability of producing a stable output with the plasticity needed to adapt to the changing demands of the organism and environment. This dissertation used the pyloric network of the crab Cancer borealis to identify potential mechanisms that ensure stability and adaptation of rhythm generation by neuronal networks under changing environmental conditions, in particular after the removal of neuromodulatory input to this network (decentralization). For this purpose, changes in ionic currents during the process of network activity recovery after decentralization were studied. The previously unreported phenomenon of coordinated expression of ionic currents within and between network neurons under normal physiological conditions was described. Detailed time course of alterations in current levels and in the coordination of ionic currents during the process of activity recovery after decentralization was determined for pacemaker and follower neurons. During the investigation of the molecular mechanisms underlying the post-decentralization changes, a novel role of central neuromodulators and of the cell-to-cell communication within the network in maintaining ionic current levels and their coordinations was demonstrated. Finally, the involvement of the two mechanisms of network plasticity, namely extrinsic (activity-dependent) and intrinsic (neuromodulator-dependent) regulation, in the recovery process after decentralization was shown. A thorough understanding of the mechanisms that are responsible for the stability and plasticity of neuronal circuits is an important step in learning how to manipulate such networks to cure diseases, enhance performance, build advanced robotic systems, create a functioning computer model of a living organism, etc. The discovery of a novel mechanism of ionic current regulation, i.e. the inter-dependent coordination of different ionic currents, will potentially contribute to this process

Nucleic acid-based therapeutics for the treatment of central nervous system disorders

Nucleic acid-based therapeutics (NBTs) are an emerging class of drugs with potential for the treatment of a wide range of central nervous system conditions. To date, pertaining to CNS indications, there are two commercially available NBTs and a large number of ongoing clinical trials. However, these NBTs are applied directly to the brain due to very low blood brain barrier permeability. In this review, we outline recent advances in chemical modifications of NBTs and NBT delivery techniques intended to promote brain exposure, efficacy, and possible future systemic application

Chapter 3 - Epigenomics of neurological disorders

Neurological disorders, including Alzheimer’s and Parkinson’s diseases, Dravet syndrome, amyotrophic lateral sclerosis, Angelman syndrome, fragile X mental retardation, spinal muscular atrophy, and many others, affect a significant part of world population. The proportion of familial cases in many of these disorders is small, indicating a significant role of environment, de novo mutations, multigenic predispositions, and epigenetic changes in their pathogenesis. Epigenetic changes in particular have been the subject of intense investigation in recent years. Besides epigenetic DNA and histone modification enzymes, long noncoding RNAs (lncRNAs) are emerging as essential components of epigenetic regulation. lncRNAs represent a major interest in the drug development process because they provide access to previously “undruggable” gene targets. Furthermore, lncRNA can be modulated using oligonucleotide-based compounds that have a shortened development pipeline. The synergy of the novel disease mechanisms (epigenetics), new therapeutic target class (lncRNA), an optimal therapeutic modality (oligonucleotide-based compounds), and unmet medical need in sporadic cases of major neurological disorders fuels intensive research in this area. We briefly review these studies

Nucleic Acid-Based Therapeutics in Orphan Neurological Disorders: Recent Developments

The possibility of rational design and the resulting faster and more cost-efficient development cycles of nucleic acid-based therapeutics (NBTs), such as antisense oligonucleotides, siRNAs, and gene therapy vectors, have fueled increased activity in developing therapies for orphan diseases. Despite the difficulty of delivering NBTs beyond the blood-brain barrier, neurological diseases are significantly represented among the first targets for NBTs. As orphan disease NBTs are now entering the clinical stage, substantial efforts are required to develop the scientific background and infrastructure for NBT design and mechanistic studies, genetic testing, understanding natural history of orphan disorders, data sharing, NBT manufacturing, and regulatory support. The outcomes of these efforts will also benefit patients with "common" diseases by improving diagnostics, developing the widely applicable NBT technology platforms, and promoting deeper understanding of biological mechanisms that underlie disease pathogenesis. Furthermore, with successes in genetic research, a growing proportion of "common" disease cases can now be attributed to mutations in particular genes, essentially extending the orphan disease field. Together, the developments occurring in orphan diseases are building the foundation for the future of personalized medicine. In this review, we will focus on recent achievements in developing therapies for orphan neurological disorders

Developments in lncRNA drug discovery: where are we heading?

Introduction: The central dogma of molecular biology, which states that the only role of long RNA transcripts is to convey information from gene to protein, was brought into question in recent years due to discovery of the extensive presence and complex roles of long noncoding RNAs (lncRNAs). Furthermore, lncRNAs were found to be involved in pathogenesis of multiple diseases and thus represent a new class of therapeutic targets. Translational efforts in the lncRNA field have been augmented by progress in optimizing the chemistry and delivery platforms of lncRNA-targeting modalities, including oligonucleotide-based drugs and CRISPR-Cas9. Areas covered: This review covers the current advances in characterizing diversity and biological functions of lncRNA focusing on their therapeutic potential in selected therapeutic areas. Expert opinion: Due to accelerating parallel progress in lncRNA biology and lncRNA-compatible therapeutic modalities, it is likely that lncRNA-dependent mechanisms of pathogenesis will soon be targeted in various disorders, including neurological, psychiatric, cardiovascular, infectious diseases, and cancer. Significant efforts, however, are still required to better understand the biology of both lncRNAs and lncRNA-targeting drugs. Further work is needed in the areas of lncRNA nomenclature, database representation, intra/interfield communication, and education of the community at large

Activity and Neuromodulatory Input Contribute to the Recovery of Rhythmic Output After Decentralization in a Central Pattern Generator

Central pattern generators (CPGs) are neuronal networks that control vitally important rhythmic behaviors including breathing, heartbeat, and digestion. Understanding how CPGs recover activity after their rhythmic activity is disrupted has important theoretical and practical implications. Previous experimental and modeling studies indicated that rhythm recovery after central neuromodulatory input loss (decentralization) could be based entirely on activity-dependent mechanisms, but recent evidence of long-term conductance regulation by neuromodulators suggest that neuromodulator-dependent mechanisms may also be involved. Here we examined the effects of altering activity and the neuromodulatory environment before decentralization of the pyloric CPG in Cancer borealis on the initial phase of rhythmic activity recovery after decentralization. We found that pretreatments altering the network activity through shifting the ionic balance or the membrane potential of pyloric pacemaker neurons reduced the delay of recovery initiation after decentralization, consistent with the recovery process being triggered already during the pretreatment period through an activity-dependent mechanism. However, we observed that pretreatment with neuromodulators GABA and proctolin, acting via metabotropic receptors, also affected the initial phase of the recovery of pyloric activity after decentralization. Their distinct effects appear to result from interactions of their metabotropic effects with their effects on neuronal activity. Thus we show that the initial phase of the recovery process can be accounted for by the existence of distinct activity-and neuromodulator-dependent pathways. We propose a computational model that includes activity- and neuromodulator-dependent mechanisms of the activity recovery process, which successfully explains the experimental observations and predicts the results of key biological experiments

Nucleic acid-based therapeutics for the treatment of central nervous system disorders

Nucleic acid-based therapeutics (NBTs) are an emerging class of drugs with potential for the treatment of a wide range of central nervous system conditions. To date, pertaining to CNS indications, there are two commercially available NBTs and a large number of ongoing clinical trials. However, these NBTs are applied directly to the brain due to very low blood brain barrier permeability. In this review, we outline recent advances in chemical modifications of NBTs and NBT delivery techniques intended to promote brain exposure, efficacy, and possible future systemic application