Pharmacological Regulation Of Neural Circuit Formation In Hipsc Derived Neurons And Mini Brains

Emerging evidence suggests that altered neural connectivity, particularly at the level of synaptic connections, contributes to the pathology of many neurodevelopmental and neurodegenerative diseases. For instance, post-mortem Autistic patient brain samples have increased numbers of excitatory to inhibitory synaptic connections, referred to as an E/I imbalance [42]. Contrastingly, post-mortem brain samples from patients diagnosed with Alzheimer's disease have decreased numbers of synaptic connections [42]. In order to understand the mechanisms that underlie the formation of these synaptic circuits, we develop 3-D human cortical organoids ('mini-brains') from human-induced pluripotent stem cells (hIPSCs). Previous research demonstrates that rearrangements of the actomyosin cytoskeleton drive neural circuit formation, in particular the development and maturation of actin-enriched spines at excitatory synapses. This thesis work investigates how pharmacological regulation of actomyosin activity affects neuronal connectivity during neurite formation in 2-D and excitatory synapse formation in 3-D 'mini-brains'. The Rho-Kinase (ROCK) inhibitor, Y-27632, both inhibits non-muscle myosin II (NM-II) and leads to a corresponding increase in Rac-driven actin polymerization. In 2-D, Y-27632 promotes neurite formation. Specifically, Y-27632 increases the number, length, and branching of neurites in hIPSC-derived neurons. Furthermore, Y-27632 increases neurite persistence, while decreasing neurite protrusion and retraction rates. However, in 3-D, acute Y-27632 treatment increases excitatory synapse area, consistent with an increase in Rac-driven actin polymerization [39]. Thus, Y-27632 increases both neurite outgrowth and excitatory synapse formation and may serve as a potential therapeutic for neurodegenerative diseases associated with synapse loss such as Alzheimer's disease. This study demonstrates the need for physiologically-relevant brain models, such as 3-D cortical organoids, to assess the impact of drug therapies on developing neural circuits to potentially treat neurodevelopmental and neurodegenerative disorders.

The International Workingmen’s Association was the prototype of all organizations of the Labour movement and the 150th anniversary of its birth (1864-2014) offers an important opportunity to rediscover its history and learn from its legacy. The International helped workers to grasp that the emancipation of labour could not be won in a single country but was a global objective. It also spread an awareness in their ranks that they had to achieve the goal themselves, through their own capacity for organization, rather than by delegating it to some other force; and that it was essential to overcome the capitalist system itself, since improvements within it, though necessary to pursue, would not eliminate exploitation and social injustice. This book reconsider the main issues broached or advanced by the International – such as labor rights, critiques of capitalism and the search for international solidarity – in light of present-day concerns. With the recent crisis of capitalism, that has sharpened more than before the division between capital and labour, the political legacy of the organization founded in London in 1864 has regained profound relevance, and its lessons are today more timely than ever. This book was published as a special issue of Socialism and Democracy.

This book summarizes early pioneering achievements in the field of human neural stem cell (hNSC) research and combines them with the latest advances in stem cell technology, including reprogramming and gene editing. The powerful potential of hNSC to generate and repair the developing and adult CNS has been confirmed by numerous experimental in vitro and in vivo studies. The book presents methods for hNSC derivation and discusses the mechanisms underlying NSC in vitro fate decisions and their in vivo therapeutic mode of action. The long-standing dogma that the human central nervous system (CNS) lacks the ability to regenerate was refuted at the end of the 20th century, when evidence of the presence of neurogenic zones in the adult human brain was found. These neurogenic zones are home to human neural stem cells (hNSCs), which are capable of self-renewing and differentiating into neurons, astrocytes and oligodendrocytes. NSCs isolated from human CNS have a number of clinical advantages, especially the innate potential to differentiate into functional neural cells. Nevertheless, their full clinical exploitation has been hindered by limited access to the tissue and low expansion potential. The search for an alternative to CNS sources of autologous, therapeutically competent hNSCs was the driving force for the many studies proving the in vitro plasticity of different somatic stem cells to generate NSCs and their functional progeny. Now the era of induced pluripotent stem cells has opened entirely new opportunities to achieve research and therapeutic goals with the aid of hNSCs.

This volume connects current ideas and concepts about sleep functions and circadian rhythms with the search for novel target-selective sleep-wake therapeutics. To do so, it provides a timely, state-of-the-art overview of sleep-wake mechanisms in health and disease, ongoing developments in drug discovery, and their prospects for the clinical treatment of sleep-disordered patients. It particularly focuses on the concept that sleep and wakefulness mutually affect each other, and the future therapeutic interventions with either sleep- or wake-promoting agents that are expected to not only improve the quality of sleep but also the waking behavior, cognition, mood and other sleep-associated physiological functions. The chapter 'Sleep Physiology, Circadian Rhythms, Waking Performance and the Development of Sleep-Wake Therapeutics' available open access under a CC BY 4.0 license at link.springer.com

Jasper's Basic Mechanisms, Fourth Edition, is the newest most ambitious and now clinically relevant publishing project to build on the four-decade legacy of the Jasper's series. In keeping with the original goal of searching for "a better understanding of the epilepsies and rational methods of prevention and treatment.", the book represents an encyclopedic compendium neurobiological mechanisms of seizures, epileptogenesis, epilepsy genetics and comordid conditions. Of practical importance to the clinician, and new to this edition are disease mechanisms of genetic epilepsies and therapeutic approaches, ranging from novel antiepileptic drug targets to cell and gene therapies.

In recent years, the need to develop acceptable alternatives to conventional animal testing for neurotoxicity and developmental neurotoxicity has been increasingly recognized, and much effort is being directed toward the development of alternative models, utilizing mostly mammalian cells in culture but also non-mammalian model systems. In Vitro Neurotoxicology: Methods and Protocols presents a series of cellular, biochemical, and molecular methodological protocols in the area of in vitro neurotoxicology, with an emphasis on mammalian cell culture systems. Opening with a section on methodologies for preparing several cellular systems of variable complexity, amenable for in vitro neurotoxicological studies, the thorough volume continues with coverage of methods to measure cellular death and major mechanisms, methods for assessing mechanisms of nervous system cell toxicity related to impairment of cell signaling, while a final section illustrates additional methods for assessing important nervous system processes such as cell proliferation, neuritogenesis, and synaptogenesis. Written in the highly successful Methods in Molecular BiologyTM series format, chapters include introductions to their respective subjects, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Comprehensive and cutting-edge, In Vitro Neurotoxicology: Methods and Protocols serves researchers with an interest in assessing or characterizing the potential neurotoxicity of environmental contaminants, drugs, or other chemicals.

This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact.

Spinal Cord Injury (SCI) Repair Strategies provides researchers the latest information on potential regenerative approaches to spinal cord injury, specifically focusing on therapeutic approaches that target regeneration, including cell therapies, controlled drug delivery systems, and biomaterials. Dr. Giuseppe Perale and Dr. Filippo Rossi lead a team of authoritative authors in academia and industry in this innovative reference on the field of regenerative medicine and tissue engineering. This book presents all the information readers need to understand the current and potential array of techniques, materials, applications and their benefits for spinal cord repair. Covers current and future repair strategies for spinal cord injury repair Focuses on key research trends, clinics, biology and engineering Provides fundamentals on regenerative engineering and tissue engineering

This detailed volume collects protocols for experimentation into how neurons connect to produce the extraordinary functionalities of the nervous system. Contributed by experts and pioneers in their respective techniques, the book covers synapses in the brain and in culture, their constituents, their structures, their dynamics, and the assemblies they form, all in the structure of a laboratory guide. Written for the highly successful Methods in Molecular Biology series, chapters include brief introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and practical, Synapse Development: Methods and Protocols serves as an ideal guide to minimizing the barrier to entry for the integration of new approaches with existing expertise, producing syntheses that will foster novel perspectives on the many ways in which synapses form, transform, and transmit.