Functions and mechanisms of adenosine and its receptors in sleep regulation.

Sleep is a natural and recurring state of life. Long-term insomnia can lead to physical and mental fatigue, inattention, memory loss, anxiety, depression and other symptoms, imposing immense public health and economic burden worldwide. The sleep and awakening regulation system is composed of many nerve nuclei and neurotransmitters in the brain, and it forms a neural network that interacts and restricts each other to regulate the occurrence and maintenance of sleep-wake. Adenosine (AD) is a neurotransmitter in the central nervous system and a driver of sleep. Meanwhile, the functions and mechanisms underlying sleep-promoting effects of adenosine and its receptors are still not entirely clear. However, in recent years, the increasing evidence indicated that adenosine can promote sleep through inhibiting arousal system and activating sleep-promoting system. At the same time, astrocyte-derived adenosine in modulating sleep homeostasis and sleep loss-induced related cognitive and memory deficits plays an important role. This review, therefore, summarizes the current research on the functions and possible mechanisms of adenosine and its receptors in the regulation of sleep and homeostatic control of sleep. Understanding these aspects will provide us better ideas on clinical problems such as insomnia, hypersomnia and other sleep disorders.

The Interplay between Neurotransmitters and Calcium Dynamics in Retinal Synapses during Development, Health, and Disease.

The intricate functionality of the vertebrate retina relies on the interplay between neurotransmitter activity and calcium (Ca2+) dynamics, offering important insights into developmental processes, physiological functioning, and disease progression. Neurotransmitters orchestrate cellular processes to shape the behavior of the retina under diverse circumstances. Despite research to elucidate the roles of individual neurotransmitters in the visual system, there remains a gap in our understanding of the holistic integration of their interplay with Ca2+ dynamics in the broader context of neuronal development, health, and disease. To address this gap, the present review explores the mechanisms used by the neurotransmitters glutamate, gamma-aminobutyric acid (GABA), glycine, dopamine, and acetylcholine (ACh) and their interplay with Ca2+ dynamics. This conceptual outline is intended to inform and guide future research, underpinning novel therapeutic avenues for retinal-associated disorders.

The association between the neuroendocrine system and the tumor immune microenvironment: Emerging directions for cancer immunotherapy.

This review summarizes emerging evidence that the neuroendocrine system is involved in the regulation of the tumor immune microenvironment (TIME) to influence cancer progression. The basis of the interaction between the neuroendocrine system and cancer is usually achieved by the infiltration of nerve fibers into the tumor tissue, which is called neurogenesis; the migration of cancer cells toward nerve fibers, which is called perineural invasion (PNI), and the neurotransmitters. In addition to the traditional role of neurotransmitters in neural communications, neurotransmitters are increasingly recognized as mediators of crosstalk between the nervous system, cancer cells, and the immune system. Recent studies have revealed that not only nerve fibers but also cancer cells and immune cells within the TIME can secrete neurotransmitters, exerting influence on both neurons and themselves. Furthermore, immune cells infiltrating the tumor environment have been found to express a wide array of neurotransmitter receptors. Hence, targeting these neurotransmitter receptors may promote the activity of immune cells in the tumor microenvironment and exert anti-tumor immunity. Herein, we discuss the crosstalk between the neuroendocrine system and tumor-infiltrating immune cells, which may provide feasible cancer immunotherapy options.

Neurotransmitter systems in the etiology of major neurological disorders: Emerging insights and therapeutic implications.

Neurotransmitters serve as chemical messengers playing a crucial role in information processing throughout the nervous system, and are essential for healthy physiological and behavioural functions in the body. Neurotransmitter systems are classified as cholinergic, glutamatergic, GABAergic, dopaminergic, serotonergic, histaminergic, or aminergic systems, depending on the type of neurotransmitter secreted by the neuron, allowing effector organs to carry out specific functions by sending nerve impulses. Dysregulation of a neurotransmitter system is typically linked to a specific neurological disorder. However, more recent research points to a distinct pathogenic role for each neurotransmitter system in more than one neurological disorder of the central nervous system. In this context, the review provides recently updated information on each neurotransmitter system, including the pathways involved in their biochemical synthesis and regulation, their physiological functions, pathogenic roles in diseases, current diagnostics, new therapeutic targets, and the currently used drugs for associated neurological disorders. Finally, a brief overview of the recent developments in neurotransmitter-based therapeutics for selected neurological disorders is offered, followed by future perspectives in that area of research.

Role of neurotransmitters in immune-mediated inflammatory disorders: a crosstalk between the nervous and immune systems.

Immune-mediated inflammatory diseases (IMIDs) are a group of common heterogeneous disorders, characterized by an alteration of cellular homeostasis. Primarily, it has been shown that the release and diffusion of neurotransmitters from nervous tissue could result in signaling through lymphocyte cell-surface receptors and the modulation of immune function. This finding led to the idea that the neurotransmitters could serve as immunomodulators. It is now manifested that neurotransmitters can also be released from leukocytes and act as autocrine or paracrine modulators. Increasing data indicate that there is a crosstalk between inflammation and alterations in neurotransmission. The primary goal of this review is to demonstrate how these two pathways may converge at the level of the neuron and glia to involve in IMID. We review the role of neurotransmitters in IMID. The different effects that these compounds exert on a variety of immune cells are also reviewed. Current and future developments in understanding the cross-talk between the immune and nervous systems will undoubtedly identify new ways for treating immune-mediated diseases utilizing agonists or antagonists of neurotransmitter receptors.

The immune system as a system of relations.

Progress in neuroimmunology established that the nervous and the immune systems are two functionally related physiological systems. Unique sensory and immune receptors enable them to control interactions of the organism with the inner and the outer worlds. Both systems undergo an experience-driven selection process during their ontogeny. They share the same mediators/neurotransmitters and use synapses for intercellular communication. They keep a memory of previous experiences. Immune cells can affect nervous cells, nervous cells can affect immune cells, and they regulate each other. I however argue that the two systems differ by three major points: 1) Unlike the nervous system, the immune system has a loose anatomical structure, in which molecular and cellular events mostly occur at random; 2) The immune system can respond to molecules of the living world whereas the nervous system can respond to phenomena of the physical world; 3) Responses of the immune system act both on the organism and on the stimulus that triggered the response, whereas responses of the nervous system act on the organism only. The nervous and the immune systems therefore appear as two complementary systems of relations that closely work together, and whose reactivities are well-suited to deal with physical and biological stimuli, respectively. Its ability both to adapt the organism to the living world and to adapt the living world to the organism endows the immune system with powerful adaptive properties that enable the organism to live in peace with itself and with other living beings, whether pathogens or commensals.

Sleep-Wake Neurochemistry.

Behavioral states naturally alternate between wakefulness and the sleep phases rapid eye movement and nonrapid eye movement sleep. Waking and sleep states are complex processes that are elegantly orchestrated by spatially fine-tuned neurochemical changes of neurotransmitters and neuromodulators including glutamate, acetylcholine, γ-aminobutyric acid, norepinephrine, dopamine, serotonin, histamine, hypocretin, melanin concentrating hormone, adenosine, and melatonin. However, as highlighted in this brief overview, no single neurotransmitter or neuromodulator, but rather their complex interactions within organized neuronal ensembles, regulate waking and sleep states. The neurochemical pathways presented here are aimed to provide a conceptual framework for the understanding of the effects of currently used sleep medications.

Significance of mammalian N, N-dimethyltryptamine (DMT): A 60-year-old debate.

N,N-dimethyltryptamine (DMT) is a potent psychedelic naturally produced by many plants and animals, including humans. Whether or not DMT is significant to mammalian physiology, especially within the central nervous system, is a debate that started in the early 1960s and continues to this day. This review integrates historical and recent literature to clarify this issue, giving special attention to the most controversial subjects of DMT's biosynthesis, its storage in synaptic vesicles and the activation receptors like sigma-1. Less discussed topics, like DMT's metabolic regulation or the biased activation of serotonin receptors, are highlighted. We conclude that most of the arguments dismissing endogenous DMT's relevance are based on obsolete data or misleading assumptions. Data strongly suggest that DMT can be relevant as a neurotransmitter, neuromodulator, hormone and immunomodulator, as well as being important to pregnancy and development. Key experiments are addressed to definitely prove what specific roles DMT plays in mammalian physiology.

Neurotransmitters of sleep and wakefulness in flatworms.

STUDY OBJECTIVES: Sleep is a prominent behavioral and biochemical state observed in all animals studied, including platyhelminth flatworms. Investigations into the biochemical mechanisms associated with sleep-and wakefulness-are important for understanding how these states are regulated and how that regulation changed with the evolution of new types of animals. Unfortunately, beyond a handful of vertebrates, such studies on invertebrates are rare. METHODS: We investigated the effect of seven neurotransmitters, and one pharmacological compound, that modulate either sleep or wakefulness in mammals, on flatworms (Girardia tigrina). Flatworms were exposed via ingestion and diffusion to four neurotransmitters that promote wakefulness in vertebrates (acetylcholine, dopamine, glutamate, histamine), and three that induce sleep (adenosine, GABA, serotonin) along with the H1 histamine receptor antagonist pyrilamine. Compounds were administered over concentrations spanning three to five orders of magnitude. Flatworms were then transferred to fresh water and video recorded for analysis. RESULTS: Dopamine and histamine decreased the time spent inactive and increased distance traveled, consistent with their wake-promoting effect in vertebrates and fruit flies; pyrilamine increased restfulness and GABA showed a nonsignificant trend towards promoting restfulness in a dose-dependent manner, in agreement with their sleep-inducing effect in vertebrates, fruit flies, and Hydra. Similar to Hydra, acetylcholine, glutamate, and serotonin, but also adenosine, had no apparent effect on flatworm behavior. CONCLUSIONS: These data demonstrate the potential of neurotransmitters to regulate sleep and wakefulness in flatworms and highlight the conserved action of some neurotransmitters across species.

Mapping circuit dynamics during function and dysfunction.

Neural circuits can generate many spike patterns, but only some are functional. The study of how circuits generate and maintain functional dynamics is hindered by a poverty of description of circuit dynamics across functional and dysfunctional states. For example, although the regular oscillation of a central pattern generator is well characterized by its frequency and the phase relationships between its neurons, these metrics are ineffective descriptors of the irregular and aperiodic dynamics that circuits can generate under perturbation or in disease states. By recording the circuit dynamics of the well-studied pyloric circuit in Cancer borealis, we used statistical features of spike times from neurons in the circuit to visualize the spike patterns generated by this circuit under a variety of conditions. This approach captures both the variability of functional rhythms and the diversity of atypical dynamics in a single map. Clusters in the map identify qualitatively different spike patterns hinting at different dynamic states in the circuit. State probability and the statistics of the transitions between states varied with environmental perturbations, removal of descending neuromodulatory inputs, and the addition of exogenous neuromodulators. This analysis reveals strong mechanistically interpretable links between complex changes in the collective behavior of a neural circuit and specific experimental manipulations, and can constrain hypotheses of how circuits generate functional dynamics despite variability in circuit architecture and environmental perturbations.

Dopaminergic mushroom body neurons in Drosophila: Flexibility of neuron identity in a model organism?

In classical neuroscience, Dale´s principle postulates that neuronal identity is conferred by the specific neurotransmitter that it releases. However, the brain might be more tractable to specific situations regardless of specific specialisation which may contradict this principle. Hence, this constrained approach of how we perceive and study the nervous system must be revisited and revised, specifically by studying the dopaminergic system. We presume a relatively flexible change in the dopaminergic system due to neuronal activity or environmental changes. While the parallel between the reward system of mammals and insects is generally well accepted, herein, we extend the idea that the insect nervous system might also possess incredible plasticity, similar to the mammalian system. In this review, we critically evaluate the available information about the reward system in vertebrates and invertebrates, emphasising the dopaminergic neuronal plasticity, a challenge to the classical Dale's principle. Thus, neurotransmitter switching significantly disrupts the static idea of neural network organisation and suggests greater possibilities for a dynamic response to the current life context of organisms.

Determinants of synapse diversity revealed by super-resolution quantal transmission and active zone imaging.

Neural circuit function depends on the pattern of synaptic connections between neurons and the strength of those connections. Synaptic strength is determined by both postsynaptic sensitivity to neurotransmitter and the presynaptic probability of action potential evoked transmitter release (Pr). Whereas morphology and neurotransmitter receptor number indicate postsynaptic sensitivity, presynaptic indicators and the mechanism that sets Pr remain to be defined. To address this, we developed QuaSOR, a super-resolution method for determining Pr from quantal synaptic transmission imaging at hundreds of glutamatergic synapses at a time. We mapped the Pr onto super-resolution 3D molecular reconstructions of the presynaptic active zones (AZs) of the same synapses at the Drosophila larval neuromuscular junction (NMJ). We find that Pr varies greatly between synapses made by a single axon, quantify the contribution of key AZ proteins to Pr diversity and find that one of these, Complexin, suppresses spontaneous and evoked transmission differentially, thereby generating a spatial and quantitative mismatch between release modes. Transmission is thus regulated by the balance and nanoscale distribution of release-enhancing and suppressing presynaptic proteins to generate high signal-to-noise evoked transmission.

Dopamine, a co-regulatory component, bridges the central nervous system and the immune system.

Dopamine (DA) is a crucial neurotransmitter that plays an important role in maintaining physiological function in human body. In the past, most studies focused on the relationship between the dopaminergic system and neurological-related diseases. However, it has been found recently that DA is an immunomodulatory mediator and many immune cells express dopamine receptors (DRs). Some immune cells can synthesize and secrete DA and then participate in regulating immune function. DRs agonists or antagonists can improve the dysfunction of immune system through classical G protein signaling pathways or other non-receptor-dependent pathways. This article will discuss the relationship between the dopaminergic system and the immune system. It will also review the use of DRs agonists or antagonists to treat chronic and acute inflammatory diseases and corresponding immunomodulatory mechanisms.

Autonomic control of pancreatic beta cells: What is known on the regulation of insulin secretion and beta-cell proliferation in rodents and humans.

Insulin secretion and pancreatic beta-cell proliferation are tightly regulated by several signals such as hormones, nutrients, and neurotransmitters. However, the autonomic control of beta cells is not fully understood. In this review, we describe mechanisms involved in insulin secretion as well as metabolic and mitogenic actions on its target tissues. Since pancreatic islets are physically connected to the brain by nerves, parasympathetic and sympathetic neurotransmitters can directly potentiate or repress insulin secretion and beta-cell proliferation. Finally, we highlight the role of the autonomic nervous system in metabolic diseases such as diabetes and obesity.

Neurosteroid replacement therapy for catamenial epilepsy, postpartum depression and neuroendocrine disorders in women.

Neurosteroids are involved in the pathophysiology of many neuroendocrine disorders in women. This review describes recent advancements in pharmacology of neurosteroids and emphasizes the benefits of neurosteroid replacement therapy for the management of neuroendocrine disorders such as catamenial epilepsy (CE), postpartum depression (PPD) and premenstrual brain conditions. Neurosteroids are endogenous modulators of neuronal excitability. A variety of neurosteroids are present in the brain including allopregnanolone (AP), allotetrahydro-deoxycorticosterone and androstanediol. Neurosteroids interact with synaptic and extrasynaptic GABAA receptors in the brain. AP and related neurosteroids, which are positive allosteric modulators of GABAA receptors, are powerful anticonvulsants, anxiolytic, antistress and neuroprotectant agents. In CE, seizures are most often clustered around a specific menstrual period in women. Neurosteroid withdrawal-linked plasticity in extrasynaptic receptors has been shown to play a key role in catamenial seizures, anxiety and other mood disorders. Based on our extensive research spanning two decades, we have proposed and championed neurosteroid replacement therapy as a rational strategy for treating disorders marked by neurosteroid-deficiency, such as CE and other related ovarian or menstrual disorders. In 2019, AP (renamed as brexanolone) was approved for treating PPD. A variety of synthetic neurosteroids are in clinical trials for epilepsy, depression and other brain disorders. Recent advancements in our understanding of neurosteroids have entered a new era of drug discovery and one that offers a high therapeutic potential for treating complex brain disorders.

Viés da Escalada, Daemons de Otimização, e a Influência da Narrativa Social Aceleracionista / Hill-Climbing Bias, Optimization Daemons, and the Influence of Accelerated Social Narratives

O fenômeno de aceleração social, intimamente ligado a nossa modernização tecnológica e os sistemas políticos e sociais que adotamos, vem sendo alvo de questionamentos por parte da teoria crítica por diversos filósofos e sociólogos, principalmente em relação a se tal "aceleração" seja algo que, possa ser justificável pelo bem comum da sociedade. De fato, as rápidas mudanças que ocorreram no último século causaram uma tremenda mudança em nossos estilos-de-vida, e na maneira como experienciamos o mundo. Que a nossa sociedade mudou e continua a mudar é um fato evidente quando olhamos criticamente para o passado e presente, e comparamos diferentes épocas da história humana. Neste ensaio tentaremos explorar algumas possíveis hipóteses que fundamentem o comportamento aceleracionista em certos fatores e mecanismo biológicos que caracterizam os sistemas de motivação e saciação humanos. Também tentaremos mostrar como certos fenômenos sociais podem auxiliar em fortalecer este tipo de comportamento, e suas possíveis origens evolutivas. Este estudo tem como objetivo principal fundamentar a Tese Aceleracionista em evidências neurofisiológicas, cognitivo-comportamentais, evolutivas e sociais.

The phenomenon of social acceleration is closely linked to our technological modernization and the political and social systems we have adopted, and it has been questioned by several philosophers and sociologists, especially in relation to whether such acceleration is something that can be justified for the common good of society. In fact, the rapid changes that have occurred in the last century have caused a tremendous change in our lifestyles, and in the way we experience the world. That society have changed and continues to change is an evident fact when we look critically to the past and our present and compare different times in human history. In this essay we will try to explore some possible hypotheses that underpin accelerated behavior, in certain biological factors and mechanisms that characterize human motivation and satiation systems. We will also try to show how certain social phenomena can help to strengthen this type of behavior, and its possible evolutionary origins. The main objective of this study is to base the Accelerationist Thesis on neurophysiological, cognitive-behavioral, evolutionary and also social evidence.

Simultaneous fMRI and fast-scan cyclic voltammetry bridges evoked oxygen and neurotransmitter dynamics across spatiotemporal scales.

The vascular contributions of neurotransmitters to the hemodynamic response are gaining more attention in neuroimaging studies, as many neurotransmitters are vasomodulatory. To date, well-established electrochemical techniques that detect neurotransmission in high magnetic field environments are limited. Here, we propose an experimental setting enabling simultaneous fast-scan cyclic voltammetry (FSCV) and blood oxygenation level-dependent functional magnetic imaging (BOLD fMRI) to measure both local tissue oxygen and dopamine responses, and global BOLD changes, respectively. By using MR-compatible materials and the proposed data acquisition schemes, FSCV detected physiological analyte concentrations with high temporal resolution and spatial specificity inside of a 9.4 T MRI bore. We found that tissue oxygen and BOLD correlate strongly, and brain regions that encode dopamine amplitude differences can be identified via modeling simultaneously acquired dopamine FSCV and BOLD fMRI time-courses. This technique provides complementary neurochemical and hemodynamic information and expands the scope of studying the influence of local neurotransmitter release over the entire brain.

Serotonin modulates melatonin synthesis as an autocrine neurotransmitter in the pineal gland.

The pineal gland secretes melatonin principally at night. Regulated by norepinephrine released from sympathetic nerve terminals, adrenergic receptors on pinealocytes activate aralkylamine N-acetyltransferase that converts 5-hydroxytryptamine (5-HT, serotonin) to N-acetylserotonin, the precursor of melatonin. Previous studies from our group and others reveal significant constitutive secretion of 5-HT from pinealocytes. Here, using mass spectrometry, we demonstrated that the 5-HT is secreted primarily via a decynium-22-sensitive equilibrative plasma membrane monoamine transporter instead of by typical exocytotic quantal secretion. Activation of the endogenous 5-HT receptors on pinealocytes evoked an intracellular Ca2+ rise that was blocked by RS-102221, an antagonist of 5-HT2C receptors. Applied 5-HT did not evoke melatonin secretion by itself, but it did potentiate melatonin secretion evoked by submaximal norepinephrine. In addition, RS-102221 reduced the norepinephrine-induced melatonin secretion in strips of pineal gland, even when no exogenous 5-HT was added, suggesting that the 5-HT that is constitutively released from pinealocytes accumulates enough in the tissue to act as an autocrine feedback signal sensitizing melatonin release.

The roles of serotonin in cell adhesion and migration, and cytoskeletal remodeling.

Serotonin is well known as a neurotransmitter. Its roles in neuronal processes such as learning, memory or cognition are well established, and also in disorders such as depression, schizophrenia, bipolar disorder, and dementia. However, its effects on adhesion and cytoskeletal remodelling which are strongly affected by 5-HT receptors, are not as well studied with some exceptions for e.g. platelet aggregation. Neuronal function is strongly dependent on cell-cell contacts and adhesion-related processes. Therefore the role played by serotonin in psychiatric illness, as well as in the positive and negative effects of neuropsychiatric drugs through cell-related adhesion can be of great significance. In this review, we explore the role of serotonin in some of these aspects based on recent findings.