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[Display omitted] • ACP is a relatively novel discovered neuropeptide with only limited known functions. • ACP neurons are present in the brain and thoracic ganglia in adult A. aegypti mosquitoes. • ACP brain neurons project processes posteriorly that permeate the abdominal ganglia. • ACP receptor enrichment in abdominal ganglia indicates ACP acts as a neurotransmitter or neuromodulator. • ACP exhibits sex-specific actions in modulating energy substrate levels in A. aegypti. The adipokinetic hormone/corazonin-related peptide (ACP) is an insect neuropeptide structurally intermediate between corazonin (CRZ) and adipokinetic hormone (AKH). Unlike the AKH and CRZ signaling systems that are widely known for their roles in the mobilization of energy substrates and stress responses, respectively, the main role of ACP and its receptor (ACPR) remains unclear in most arthropods. The current study aimed to localize the distribution of ACP in the nervous system and provide insight into its physiological roles in the disease vector mosquito, Aedes aegypti. Immunohistochemical analysis and fluorescence in situ hybridization localized the ACP peptide and transcript within a number of cells in the central nervous system, including two pairs of laterally positioned neurons in the protocerebrum of the brain and a few ventrally localized neurons within the pro- and mesothoracic regions of the fused thoracic ganglia. Further, extensive ACP-immunoreactive axonal projections with prominent blebs and varicosities were observed traversing the abdominal ganglia. Given the prominent enrichment of ACPR expression within the abdominal ganglia of adult A. aegypti mosquitoes as determined previously, the current results indicate that ACP may function as a neurotransmitter and/or neuromodulator facilitating communication between the brain and posterior regions of the nervous system. In an effort to elucidate a functional role for ACP signaling, biochemical measurement of energy substrates in female mosquitoes revealed a reduction in abdominal fat body in response to ACP that matched the actions of AKH, but interestingly, a corresponding hypertrehalosaemic effect was only found in response to AKH since ACP did not influence circulating carbohydrate levels. Comparatively, both ACP and AKH led to a significant increase in haemolymph carbohydrate levels in male mosquitoes while both peptides had no influence on their glycogen stores. Neither ACP nor AKH influenced circulating or stored lipid levels in both male and female mosquitoes. Collectively, these results reveal ACP signaling in mosquitoes may have complex sex-specific actions, and future research should aim to expand knowledge on the role of this understudied neuropeptide. [ABSTRACT FROM AUTHOR]

Herein, we briefly review the role of nicotinic acetylcholine receptors in regulating important brain activity by controlled release of acetylcholine from subcortical neuron groups, focusing on a microscopic viewpoint and considering the nonlinear dynamics of biological macromolecules associated with neuron activity and how they give rise to advanced brain functions of brain., (© The Author(s) 2023.)

The bed nuclei of the stria terminalis (BST) is recognised as a pivotal integrative centre for monitoring emotional valence. It is implicated in the regulation of diverse affective states and motivated behaviours, and decades of research have firmly established its critical role in anxiety-related behavioural processes. Researchers have recently intricately dissected the BST's dynamic activities, its connection patterns and its functions with respect to specific cell types using multiple techniques such as optogenetics, in vivo calcium imaging and transgenic tools to unmask the complex circuitry mechanisms that underlie anxiety. In this review, we principally focus on studies of anxiety-involved neuromodulators within the BST and provide a comprehensive architecture of the anxiety network-highlighting the BST as a key hub in orchestrating anxiety-like behaviour. We posit that these promising efforts will contribute to the identification of an accurate roadmap for future treatment of anxiety disorders., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Neurotransmitter corelease is emerging as a common theme of central neuromodulatory systems. Though corelease of glutamate or GABA with acetylcholine has been reported within the cholinergic system, the full extent is unknown. To explore synaptic signaling of cholinergic forebrain neurons, we activated choline acetyltransferase expressing neurons using channelrhodopsin while recording post-synaptic currents (PSCs) in layer 1 interneurons. Surprisingly, we observed PSCs mediated by GABAA receptors in addition to nicotinic acetylcholine receptors. Based on PSC latency and pharmacological sensitivity, our results suggest monosynaptic release of both GABA and ACh. Anatomical analysis showed that forebrain cholinergic neurons express the GABA synthetic enzyme Gad2 and the vesicular GABA transporter (Slc32a1). We confirmed the direct release of GABA by knocking out Slc32a1 from cholinergic neurons. Our results identify GABA as an overlooked fast neurotransmitter utilized throughout the forebrain cholinergic system. GABA/ACh corelease may have major implications for modulation of cortical function by cholinergic neurons.

Guanosine is a purine nucleoside with important functions in cell metabolism and a protective role in response to degenerative diseases or injury. The past decade has seen major advances in identifying the modulatory role of extracellular action of guanosine in the central nervous system (CNS). Evidence from rodent and cell models show a number of neurotrophic and neuroprotective effects of guanosine preventing deleterious consequences of seizures, spinal cord injury, pain, mood disorders and aging-related diseases, such as ischemia, Parkinson's and Alzheimer's diseases. The present review describes the findings of in vivo and in vitro studies and offers an update of guanosine effects in the CNS. We address the protein targets for guanosine action and its interaction with glutamatergic and adenosinergic systems and with calciumactivated potassium channels. We also discuss the intracellular mechanisms modulated by guanosine preventing oxidative damage, mitochondrial dysfunction, inflammatory burden and modulation of glutamate transport. New and exciting avenues for future investigation into the protective effects of guanosine include characterization of a selective guanosine receptor. A better understanding of the neuromodulatory action of guanosine will allow the development of therapeutic approach to brain diseases. [ABSTRACT FROM AUTHOR]

Acetylcholine is a neuromodulator which is released throughout the central nervous system and plays an essential role in consciousness and cognitive processes including attention and learning. Due to its 'activating' effect on the neuronal and behavioral level its interaction with anesthetics has long been of interest to anesthesiologists. It is widely held that a reduction of the release of acetylcholine by general anesthetics constitutes part of the anesthetic effect. This notion is backed by numerous human and animal studies, but is also in seeming contradiction to findings that acetylcholine activates specific classes of inhibitory neurons: if acetylcholine excites elements within the neuronal network responsible for the release of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), its withdrawal should diminish, not enhance, the effect of anesthetics.Focusing on cortical circuits, we present an overview of recent advances in cellular neurophysiology, particularly the interactions between inhibitory neuron classes, which provide insights on the interaction between acetylcholine and GABA. [ABSTRACT FROM AUTHOR]

Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies. This article is part of a Special Issue entitled SI: Noradrenergic System . [ABSTRACT FROM AUTHOR]

Over the course of each day, animals prioritize different objectives. Immediate goals may reflect fluctuating internal homeostatic demands, prompting individuals to seek out energy supplies or warmth. At other times, the environment may present temporary challenges or opportunities. Homeostatic demands and environmental signals often elicitpersistentchanges in an animal’s behavior to meet needs and challenges over extended periods of time. These changes reflect the underlying motivational state of the animal. The larval zebrafish has been established as an effective genetically tractable vertebrate system to study neural circuits for sensory-motor reflexes. Fewer studies have exploited zebrafish to study brain circuits that control motivated behavior. In part this is because appropriate conceptual frameworks, anatomical knowledge, and behavioral paradigms are not yet well established. This review sketches a general conceptual framework for studying motivated state control in animal models, how this applies to larval zebrafish, and the current knowledge on neuroanatomical substrates for state control in this model. [ABSTRACT FROM PUBLISHER]

Activation of prefrontal cortical (PFC), striatal, and hippocampal dopamine 1-class receptors (D1R and D5R) is necessary for normal spatial information processing. Yet the precise role of the D1R versus the D5R in the aforementioned structures, and their specific contribution to the water-maze spatial learning task remains unknown. D1Rand D5R-specific in situ hybridization probes showed that forebrain restricted D1R and D5R KO mice (F-D1R/D5R KO) displayed D1R mRNA deletion in the medial (m)PFC, dorsal and ventral striatum, and the dentate gyrus (DG) of the hippocampus. D5R mRNA deletion was limited to the mPFC, the CA1 and DG hippocampal subregions. F-D1R/ D5R KO mice were given water-maze training and displayed subtle spatial latency differences between genotypes and spatial memory deficits during both regular and reversal training. To differentiate forebrain D1R from D5R activation, forebrain restricted D1R KO (F-D1R KO) and D5R KO (F-D5R KO) mice were trained on the water-maze task. F-D1R KO animals exhibited escape latency deficits throughout regular and reversal training as well as spatial memory deficits during reversal training. F-D1R KO mice also showed perseverative behavior during the reversal spatial memory probe test. In contrast, F-D5R KO animals did not present observable deficits on the water-maze task. Because F-D1R KO mice showed water-maze deficits we tested the necessity of hippocampal D1R activation for spatial learning and memory. We trained DG restricted D1R KO (DG-D1R KO) mice on the water-maze task. DG-D1R KO mice did not present detectable spatial memory deficit, but did show subtle deficits during specific days of training. Our data provides evidence that forebrain D5R activation plays a unique role in spatial learning and memory in conjunction with D1R activation. Moreover, these data suggest that mPFC and striatal, but not DG D1R activation are essential for spatial learning and memory. [ABSTRACT FROM AUTHOR]

An animal's behavior is modulated by learning; however, the behavioral component modulated by learning and the mechanisms of this modulation have not been fully understood. We show here that two types of neural signalings are required for the modulation of different behavioral components in non-associative odor learning in the nematode Caenorhabditis elegans . We have previously found that C. elegans avoid the repulsive odor 2-nonanone, and preexposure to the odor for 1 h enhances the avoidance behavior as a type of non-associative learning. Systematic quantitative analyses of behavioral components revealed that the odor preexposure caused increases in average duration of straight migration (“runs”) only when the animals were migrating away from the odor source within a certain range of bearing, which likely corresponds to odor decrement. Further, genetic analyses revealed that the genes for neuropeptide or dopamine signalings are both required for the enhanced odor avoidance. Neuropeptide signaling genes were required for the preexposure-dependent increase in run duration. In contrast, dopamine signaling genes were required not for the increase in run duration but likely for maintenance of run direction. Our results suggests that multiple behavioral components are regulated by different neuromodulators even in non-associative learning in C. elegans . [ABSTRACT FROM AUTHOR]

Cleaning behavior is known as a classic example of cooperation between unrelated individuals. Although much is known of the behavioral processes underlying cooperative behavior, the physiological pathways mediating cooperation remain relatively obscure. Here, we show that altering the activity of serotonin on wild cleaner wrasses Labroides dimidiatus has causal effects on both social and cooperative activities. These cleaners cooperate by removing ectoparasites from visiting "client" reef fishes but prefer to eat client mucus, which constitutes "cheating." We found that enhancing serotonin made cleaner wrasses more motivated to engage in cleaning behavior and more likely to provide physical contact to clients (tactile stimulation) without spending more time cleaning or cheating more often. Blocking serotonin-mediated response resulted in an apparent decrease in cleaners' cheating levels and in an increase in cleaners' aggressiveness toward smaller conspecifics. Our results provide first evidence that serotonin is a neuromodulatory driver of cooperative behavioral activities and contribute to the understanding of neural pathways of cooperation. [ABSTRACT FROM AUTHOR]

Serotonin is probably best known for its role in conveying a sense of contentedness and happiness. It is one of the most unique and pharmacologically complex monoamines in both the peripheral and central nervous system (CNS). Serotonin has become in focus of interest for the treatment of depression with multiple serotonin-mimetic and modulators of adult neurogenesis used clinically. Here we will take a broad view of serotonin from development to its physiological role as a neurotransmitter and its contribution to homeostasis of the adult rodent hippocampus. This chapter reflects the most significant findings on cellular and molecular mechanisms from neuroscientists in the field over the last two decades. We illustrate the action of serotonin by highlighting basic receptor targeting studies, and how receptors impact brain function. We give an overview of recent genetically modified mouse models that differ in serotonin availability and focus on the role of the monoamine in antidepressant response. We conclude with a synthesis of the most recent data surrounding the role of serotonin in activity and hippocampal neurogenesis. This synopsis sheds light on the mechanisms and potential therapeutic model by which serotonin plays a critical role in the maintenance of mood. [ABSTRACT FROM AUTHOR]

Adenosine modulates dopamine in the brain via A1 and A2A receptors, but that modulation has only been characterized on a slow time scale. Recent studies have characterized a rapid signaling mode of adenosine that suggests a possible rapid modulatory role. Here, fast-scan cyclic voltammetry was used to characterize the extent to which transient adenosine changes modulate stimulated dopamine release (5 pulses at 60 Hz) in rat caudate-putamen brain slices. Exogenous adenosine was applied and dopamine concentration monitored. Adenosine only modulated dopamine when it was applied 2 or 5 s before stimulation. Longer time intervals and bath application of 5 μM adenosine did not decrease dopamine release. Mechanical stimulation of endogenous adenosine 2 s before dopamine stimulation also decreased stimulated dopamine release by 41 ± 7%, similar to the 54 ± 6% decrease in dopamine after exogenous adenosine application. Dopamine inhibition by transient adenosine was recovered within 10 min. The A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked the dopamine modulation, whereas dopamine modulation was unaffected by the A2A receptor antagonist SCH 442416. Thus, transient adenosine changes can transiently modulate phasic dopamine release via A1 receptors. These data demonstrate that adenosine has a rapid, but transient, modulatory role in the brain. [ABSTRACT FROM AUTHOR]

Background and Objective: Long-course (LC) antidepressants for the treatment of disorders of gut-brain interaction, such as refractory functional dyspepsia (rFD), pose patients at risk of antidepressant discontinuation syndrome (ADS). Short-course (SC) therapy of rapid-acting antidepressant may reduce discontinuation syndromes while maintaining efficacy for dyspeptic symptoms. However, the evidence-based research is lacking. This study aims to determine whether SC therapy with antidepressants could decrease the risk of ADS with comparable treatment efficacy to LC therapy in rFD., Methods: This randomized clinical trial with rFD patients was conducted at a tertiary hospital in China. Participants ( N = 240) were randomly allocated to receive flupentixol-melitracen (FM) plus omeprazole therapy for 2 (SC group) or 4 (LC group) weeks, respectively. Scores for Leeds Dyspepsia Questionnaire (LDQ), Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 for Depression (PHQ-9) were assessed at baseline and every 2 weeks, ending at 4 weeks after treatment. ADS was assessed after drug cessation. Medication possession ratio (MPR) for FM was calculated., Results: The severity and incidence of ADS of patients in SC group were significantly lower than those in LC group (0.60 ± 0.62 vs. 1.71 ± 1.58 and 3.64 vs. 39.45%; both P < 0.0001). The MPR values for FM were significantly higher in patients of SC group than in LC group ( P < 0.0001). Scores for LDQ, GAD-7 and PHQ-9 decreased in patients of both groups, and the symptom improvement in SC group was comparable to that in LC group after treatment., Conclusions: Compared to 4-week FM therapy, the 2-week FM therapy reduces the risk of ADS with non-inferior treatment efficacy in patients with rFD., Clinical Trial Registration: Clinical trials.gov, identifier NCT05099913., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Cheng, Wu, Xu, Qiu, Wang, Yan and Chen.)

Every day, we shift among various states of sleep and arousal to meet the many demands of our bodies and environment. A central puzzle in neurobiology is how the brain controls these behavioral states, which are essential to an animal’s well-being and survival. Mammalian models have predominated sleep and arousal research, although in the past decade, invertebrate models have made significant contributions to our understanding of the genetic underpinnings of behavioral states. More recently, the zebrafish has emerged as a promising model system for sleep and arousal research. Here we review experimental evidence that the zebrafish, a diurnal vertebrate, exhibits fundamental behavioral and neurochemical characteristics of mammalian sleep and arousal. We also propose how specific advantages of the zebrafish can be harnessed to advance the field. These include tractable genetics to identify and manipulate molecular and cellular regulators of behavioral states, optical transparency to facilitate in vivo observation of neural structure and function, and amenability to high-throughput drug screens to discover novel therapies for neurological disorders.

Neuroendocrine tuberoinfundibular dopamine (TIDA) neurons tonically inhibit pituitary release of the hormone, prolactin. Through the powerful actions of prolactin in promoting lactation and maternal behaviour while suppressing sexual drive and fertility, TIDA neurons play a key role in reproduction. We summarize insights from recent in vitro studies into the membrane properties and network behaviour of TIDA neurons including the observations that TIDA neurons exhibit a robust oscillation that is synchronized between cells and depends on intact gap junction communication. Comparisons are made with phasic firing patterns in other neuronal populations. Modulators involved in the control of lactation – including serotonin, thyrotropin-releasing hormone and prolactin itself – have been shown to change the electrical behaviour of TIDA cells. We propose that TIDA discharge mode may play a central role in tuning the amount of dopamine delivered to the pituitary and hence circulating prolactin concentrations in different reproductive states and pathological conditions. [ABSTRACT FROM AUTHOR]

Millions of people worldwide suffer from diseases that result from a failure of central pathways to regulate behavioral and physiological processes. Advances in genetics and pharmacology have already allowed us to appreciate that rather than this dysregulation being systemic throughout the brain, it is usually rooted in specific subsets of dysfunctional cells within discrete neurological circuits. This article discusses the advent of opto- and chemogenetic tools and how they are providing the means to dissect these circuits with a degree of temporal and spatial sensitivity not previously possible. We also highlight the potential applications for treating disease and the key developments likely to have the greatest impact over the next 5 years. [ABSTRACT FROM AUTHOR]

Highlights: [•] Transcripts encoding Calanus NOS, HO and CBS proteins were identified. [•] All deduced enzymes appear to be full-length homologs of vertebrate neural isoforms. [•] Calanus CBS is the first crustacean member of this enzyme family to be identified. [•] The identified Calanus HO is the second known crustacean member of this family. [•] RNA-Seq mapping suggests stage-specific expression of gas transmitter transcripts. [ABSTRACT FROM AUTHOR]

Multiscale computational models can provide systemic evaluation and prediction of neuropharmacological drug effects. To date, little computational modeling work has been done to bridge from intracellular to neuronal circuit level. A complex model that describes the intracellular dynamics of the presynaptic terminal of a serotonergic neuron has been previously proposed. By systematically perturbing the model's components, we identify the slow and fast dynamical components of the model, and the reduced slow or fast mode of the model is computationally significantly more efficient with accuracy not deviating much from the original model. The reduced fast-mode model is particularly suitable for incorporating into neurobiologically realistic spiking neuronal models, and hence for large-scale realistic computational simulations. We also develop user-friendly software based on the reduced models to allow scientists to rapidly test and predict neuropharmacological drug effects at a systems level. [ABSTRACT FROM PUBLISHER]

Human d-amino acid oxidase (; hDAAO) is a peroxisomal flavoenzyme significantly enriched in the mammalian brain. hDAAO has been proposed to play (with serine racemase; ) an essential role in the catabolism of d-serine, an 'atypical' key signalling molecule that acts as allosteric activator of the N-methyl- d-aspartate-type glutamate receptor ( NMDAr). hDAAO and its interacting partner pLG72 have been related to schizophrenia, a highly disabling psychiatric disorder in which a dysfunction of NMDA-mediated neurotransmission is widely assumed to occur. We previously demonstrated that the d-serine cellular concentration depends on hDAAO and pLG72 expression levels and that newly-synthesized hDAAO interacts with its modulator in the cytosol, being progressively destabilized and inactivated. To obtain insight into the mechanisms regulating cellular d-serine levels, we investigated the degradation pathways of hDAAO and pLG72 in U87 glioblastoma cells stably expressing enhanced yellow fluorescent protein- hDAAO (peroxisomal), hDAAO-enhanced yellow fluorescent protein (cytosolic) or pLG72-enhanced cyan fluorescent protein (mitochondrial) proteins. hDAAO is a long-lived protein: the peroxisomal fraction of this flavoprotein is degraded via the lysosomal/endosomal pathway (and blocking this pathway increases the cellular hDAAO activity and decreases d-serine levels), whereas the cytosolic portion is ubiquitinated and targeted to the proteasome. By contrast, pLG72 shows a rapid turnover ( t1/2 ≈ 25-40 min) and is degraded via the proteasome system, albeit not ubiquitinated. Overexpression of pLG72 increases the turnover of hDAAO, in turn playing a protective role against excessive d-serine depletion. [ABSTRACT FROM AUTHOR]

Highlights: [•] H2S is mainly formed by astrocytes and released in response to neuronal excitation. [•] H2S mediated the dilation of cerebral vessels. [•] H2S counteracts glutamate mediated excitotoxicity. [•] H2S plays the role of anti-oxidation, anti-inflammatory and anti-apoptotic effect. [•] H2S elevates intracellular Ca2+ concentration in neurons and glia. [ABSTRACT FROM AUTHOR]

Over the years, accumulating evidence has indicated that D-serine represents the main endogenous ligand of NMDA (N-methyl-D-aspartate) receptors. In the brain, the concentration of D-serine stored in cells is defined by the activity of two enzymes: serine racemase (responsible for both the synthesis and degradation) and d-amino acid oxidase (which catalyses D-serine degradation). The present review is focused on human damino acid oxidase, discussing the mechanisms involved in modulating enzyme activity and stability, with the aim to substantiate the pivotal role of D-amino acid oxidase in brain D-serine metabolism. [ABSTRACT FROM AUTHOR]

Although neuromodulation is well established for the treatment of non-neurogenic lower urinary tract symptoms, recent literature supports its use in the patient having LUTS associated with a neurologic condition. Sacral neuromodulation, in particular, may see new use as a modality to facilitate neurologic remodeling in spinal cord injured patients as well as children. As a therapeutic option, sacral neuromodulation and dorsal genital nerve stimulation may one day become more effective and more efficient utilizing the concept of closed- loop feedback, where electro-neurogram and bladder pressure data are incorporated into stimulation routines. In addition, some older therapies are reviewed that have recently demonstrated success in this patient population. [ABSTRACT FROM AUTHOR]

Neuronal firing pattern, which includes both the frequency and the timing of action potentials, is a key component of information processing in the brain. Although the relationship between neuronal output (the firing pattern) and function (during a task/behavior) is not fully understood, there is now considerable evidence that a given neuron can show very different firing patterns according to brain state. Thus, such neurons assembled into neuronal networks generate different rhythms (e.g. theta, gamma, sharp wave ripples), which sign specific brain states (e.g. learning, sleep). This implies that a given neuronal network, defined by its hard-wired physical connectivity, can support different brain state-dependent activities through the modulation of its functional connectivity. Here, we review data demonstrating that not only the firing pattern, but also the functional connections between neurons, can change dynamically. We then explore the possible mechanisms of such versatility, focusing on the intrinsic properties of neurons and the properties of the synapses they establish, and how they can be modified by neuromodulators, i.e. the different ways that neurons can use to switch from one mode of communication to the other.

A major puzzle in the field of computational neuroscience is how to relate system-level learning in higher organisms to synaptic plasticity. Recently, plasticity rules depending not only on pre- and post-synaptic activity but also on a third, non-local neuromodulatory signal have emerged as key candidates to bridge the gap between the macroscopic and the microscopic level of learning. Crucial insights into this topic are expected to be gained from simulations of neural systems, as these allow the simultaneous study of the multiple spatial and temporal scales that are involved in the problem. In particular, synaptic plasticity can be studied during the whole learning process, i.e. on a time scale of minutes to hours and across multiple brain areas. Implementing neuromodulated plasticity in large-scale network simulations where the neuromodulatory signal is dynamically generated by the network itself is challenging, because the network structure is commonly defined purely by the connectivity graph without explicit reference to the embedding of the nodes in physical space. Furthermore, the simulation of networks with realistic connectivity entails the use of distributed computing. A neuromodulated synapse must therefore be informed in an efficient way about the neuromodulatory signal, which is typically generated by a population of neurons located on different machines than either the pre- or post-synaptic neuron. Here, we develop a general framework to solve the problem of implementing neuromodulated plasticity in a time-driven distributed simulation, without reference to a particular implementation language, neuromodulator or neuromodulated plasticity mechanism. We implement our framework in the simulator NEST and demonstrate excellent scaling up to 1024 processors for simulations of a recurrent network incorporating neuromodulated spike-timing dependent plasticity.

No generic function for the minicolumn—i.e., one that would apply equally well to all cortical areas and species—has yet been proposed. I propose that the minicolumn does have a generic functionality, which only becomes clear when seen in the context of the function of the higher-level, subsuming unit, the macrocolumn. I propose that: a) a macrocolumn’s function is to store sparse distributed representations of its inputs and to be a recognizer of those inputs; and b) the generic function of the minicolumn is to enforce macrocolumnar code sparseness. The minicolumn, defined here as a physically localized pool of ~20 L2/3 pyramidals, does this by acting as a winner-take-all (WTA) competitive module, implying that macrocolumnar codes consist of ~70 active L2/3 cells, assuming ~70 minicolumns per macrocolumn. I describe an algorithm for activating these codes during both learning and retrievals, which causes more similar inputs to map to more highly intersecting codes, a property which yields ultra-fast (immediate, first-shot) storage and retrieval. The algorithm achieves this by adding an amount of randomness (noise) into the code selection process, which is inversely proportional to an input’s familiarity. I propose a possible mapping of the algorithm onto cortical circuitry, and adduce evidence for a neuromodulatory implementation of this familiarity-contingent noise mechanism. The model is distinguished from other recent columnar cortical circuit models in proposing a generic minicolumnar function in which a group of cells within the minicolumn, the L2/3 pyramidals, compete (WTA) to be part of the macrocolumnar code.

High-frequency cortical potentials in electroencephalographic (EEG) scalp recordings have low amplitudes and may be confounded with scalp muscle activities. EEG data from an eyes-closed emotion imagination task were linearly decomposed using independent component analysis (ICA) into maximally independent component (IC) processes. Joint decomposition of IC log spectrograms into source- and frequency-independent modulator (IM) processes revealed three distinct classes of IMs that separately modulated broadband high-frequency (~15-200 Hz) power of brain, scalp muscle, and likely ocular motor IC processes. Multi-dimensional scaling revealed significant but spatially complex relationships between mean broadband brain IM effects and the valence of the imagined emotions. Thus, contrary to prevalent assumption, unitary modes of spectral modulation of frequencies encompassing the beta, gamma, and high gamma frequency ranges can be isolated from scalp-recorded EEG data and may be differentially associated with brain sources and cognitive activities.

The brain uses a strategy of labor division, which may allow it to accomplish more elaborate and complicated tasks, but in turn, imposes a requirement for central control to integrate information among different brain areas. Anatomically, the divergence of long-range neuromodulator projections appears well-suited to coordinate communication between brain areas. Oscillatory brain activity is a prominent feature of neural transmission. Thus, the ability of neuromodulators to modulate signal transmission in a frequency-dependent manner adds an additional level of regulation. Here, we review the significance of frequency-dependent signal modulation in brain function and how a neuronal network can possess such properties. We also describe how a neuromodulator, dopamine, changes frequency-dependent signal transmission, controlling information flow from the entorhinal cortex to the hippocampus.

The acquisition and expression of conditioned fear depends on prefrontal-amygdala circuits. Auditory fear conditioning increases the tone responses of lateral amygdala neurons, but the increase is transient, lasting only a few hundred milliseconds after tone onset. It was recently reported that that the prelimbic (PL) prefrontal cortex transforms transient lateral amygdala input into a sustained PL output, which could drive fear responses via projections to the lateral division of basal amygdala (BL). To explore the possible mechanisms involved in this transformation, we developed a largescale biophysical model of the BL-PL network, consisting of 850 conductance-based Hodgkin-Huxley-type cells, calcium-based learning, and neuromodulator effects. The model predicts that sustained firing in PL can be derived from BL-induced release of dopamine and norepinephrine that is maintained by PL-BL interconnections. These predictions were confirmed with physiological recordings from PL neurons during fear conditioning with the selective β-blocker propranolol and by inactivation of BL with muscimol. Our model suggests that PL has a higher bandwidth than BL, due to PL's decreased internal inhibition and lower spiking thresholds. It also suggests that variations in specific microcircuits in the PL-BL interconnection can have a significant impact on the expression of fear, possibly explaining individual variability in fear responses. The human homolog of PL could thus be an effective target for anxiety disorders. [ABSTRACT FROM AUTHOR]

Monoamines are important neuromodulators that respond to social cues and that can, in turn, modify social responses. Yet we know very little about the ontogeny of monoaminergic systems and whether they contribute to the development of social behavior. Anurans are an excellent model for studying the development of social behavior because one of its primary components, phonotaxis, is expressed early in life. To examine the effect of social signals on monoamines early in ontogeny, we presented juvenile Mexican spadefoot toads ( Spea multiplicata) with a male mating call or no sound and measured norepinephrine, epinephrine, dopamine, serotonin, and a serotonin metabolite, across the brain using high-pressure liquid chromatography. Our results demonstrate that adult-like monoaminergic systems are in place shortly after metamorphosis. Perhaps more interestingly, we found that mating calls increased the level of monoamines in the juvenile tegmentum, a midbrain region involved in sensory-motor integration and that contributes to brain arousal and attention. We saw no such increase in the auditory midbrain or in forebrain regions. We suggest that changes in monoamine levels in the juvenile tegmentum may reflect the effects of social signals on arousal state and could contribute to context-dependent modulation of social behavior. [ABSTRACT FROM AUTHOR]

Crustaceans can store excess copper in the hepatopancreas, an organ playing a role in digestive activ-ity as well as in neurosecretory control. Here, we studied the effect of copper exposure on the level of histamine, an indicator of food spoilage in edible crustaceans. Histamine is also a neuromodulator in the intestinal nervous system of crustaceans, and a human allergen. Marbled crayfish (Procambarus fallax forma virginalis) were exposed to average measured values of 0.031 mg Cu/1 and 0.38 mg Cu/1, respectively, for 14 days and then transferred to copper-free water for another 14 days. Concentrations of copper and histamine in the hepatopancreas and muscle were evaluated at different time points. His-tamine levels were significantly higher in hepatopancreas and muscle tissues at the highest exposure level, but only after transfer of the animals to copper-free water. The increased histamine concentra-tion following copper exposure may be explained by a (delayed) stress response, and by up-regulated histidine synthesis induced by copper, followed by decarboxylation to histamine. [ABSTRACT FROM AUTHOR]

The article discusses a study conducted to examine the use of neuromodulating medications like amitriptyline, gabapentin, pregabalin and baclofen in treating chronic, idiopathic cough. It is stated that the study evaluated eight relevant articles out of forty-six to evaluate different dosing and medication protocols and it was found that neuromodulating medications provide benefits to chronic, idiopathic cough patients.

Merkel cells are an enigmatic group of rare cells found in the skin of vertebrates. Most make contacts with somatosensory afferents to form Merkel cell-neurite complexes, which are gentle-touch receptors that initiate slowly adapting type I responses. The function of Merkel cells within the complex remains debated despite decades of research. Numerous anatomical studies demonstrate that Merkel cells form synaptic-like contacts with sensory afferent terminals. Moreover, recent molecular analysis reveals that Merkel cells express dozens of presynaptic molecules that are essential for synaptic vesicle release in neurons. Merkel cells also produce a host of neuroactive substances that can act as fast excitatory neurotransmitters or neuromodulators. Here, we review the major neurotransmitters found in Merkel cells and discuss these findings in relation to the potential function of Merkel cells in touch reception. [ABSTRACT FROM AUTHOR]

The in vivo chemogenetic property of mercuric ions (Hg 2+ ) was investigated as a specific hypercalcemia actuator in snail's spinal cord cell manipulation by extracellular field potential biosensing analysis. For this purpose, a three-microelectrode system with working, counter, and pseudo reference electrodes was blindly implanted into the snail's spinal cord to electrically stimulate (triggering) the action potential with a staircase electrical voltage at a very low frequency level, along with measurement of the electrical current, as a detection system. Under optimum conditions, using the one-factor-at-a-time method, a wide linear range between 1.0 × 10 -14 and 1.0 × 10 -1 mol L -1 with correlation coefficients ( R 2 ) >0.98 and a response time ( t 90 ) of maximum 10.0 s were approximated. Percentages of relative standard deviation were estimated to be 3.08 (reproducibility, n = 50) and 7.31 (repeatability, n = 15). The detection limit was estimated to be sub 2.1 × 10 -16 mol L -1 based on the X b - + 3S b definition. The reliability of this phenomenon was evidenced by the estimation of recovery percentages (between 95 and 107%) during spiking Hg 2+ standard solutions. The probable mechanism behind this process could be attributed to the following: (i) the neuronal ephaptic coupling during electrical synchronization by a specific brain-triggered wave as a neuronal motor toolkit and (ii) chemical synchronization using a Hg 2+ hypercalcemia actuator (biosensor). Linear correlation has been evidenced during interactions between Hg 2+ and a calcium ionic channel's protein with a gram molecular weight of 66.2 ± 0.3 KCU. This process, therefore, caused an opening of the Ca 2+ channel gates and majorly released the Ca 2+ (hypercalcemia) that was detected as the main source of the measured electrical current. At this condition, ultratrace levels of Hg 2+ ions not only were considered as nontoxic reagents but also had chemically regulating effects as ephaptic synchronizers to the neuron cells. This report may pave the way for using mercury ions at an ultratrace level for clinical controlling purposes during neuronal spinal cord cell manipulation.

Major depressive disorder and anxiety disorders are common and disabling conditions that affect millions of people worldwide. Despite being different disorders, symptoms of depression and anxiety frequently overlap in individuals, making them difficult to diagnose and treat adequately. Therefore, compounds capable of exerting beneficial effects against both disorders are of special interest. Noteworthily, vitamin D deficiency has been associated with an increased risk of developing depression and anxiety, and individuals with these psychiatric conditions have low serum levels of this vitamin. Indeed, in the last few years, vitamin D has gained attention for its many functions that go beyond its effects on calcium-phosphorus metabolism. Particularly, antioxidant, anti-inflammatory, pro-neurogenic, and neuromodulatory properties seem to contribute to its antidepressant and anxiolytic effects. Therefore, in this review, we highlight the main mechanisms that may underlie the potential antidepressant and anxiolytic effects of vitamin D. In addition, we discuss preclinical and clinical studies that support the therapeutic potential of this vitamin for the management of these disorders.

Incobotulinum toxin A (IncoBoNT-A) is effective in preventing ultraviolet B (UVB)-induced hyperpigmentation. This prospective, randomized, controlled study aimed to evaluate the effect of IncoBoNT-A on the treatment of UVB-induced hyperpigmentation in 15 volunteers. Five hyperpigmentation squares (2 × 2 cm) were induced by local UVB on the abdomen at baseline. At Day 7, each site was randomized to receive no treatment (control), normal saline, or intradermal IncoBoNT-A injection with 1:2.5, 1:5, and 1:7.5 dilutions (12, 6, and 4 units, respectively). The mean lightness index (L*), hyperpigmentation improvement score evaluated by blinded dermatologists, and participant satisfaction scores were obtained at Days 21, 28, and 35. At Day 21, improvements in mean L* of 1:2.5, 1:5, and 1:7.5 IncoBoNT-A-treated, saline-treated, and control sites were 14.30%, 12.28%, 6.62%, 0.32%, and 4.98%, respectively ( p = 0.86). At Day 28, the improvement in mean L* in IncoBoNT-A-treated groups was superior to that in the other groups. In terms of the hyperpigmentation improvement score, 12 participants (80%) experienced better outcomes with the IncoBoNT-A-injected site compared with the other sites. IncoBoNT-A, especially at higher concentrations, showed some positive effects on the treatment of UVB-induced hyperpigmentation. This may serve as an adjuvant treatment for hyperpigmentary conditions that are aggravated by UVB.

Neuronal firing pattern, which includes both the frequency and the timing of action potentials, is a key component of information processing in the brain. Although the relationship between neuronal output (the firing pattern) and function (during a task/behavior) is not fully understood, there is now considerable eyidence that a given neuron can show very different firing patterns according to brain state. Thus, such neurons assembled into neuronal networks generate different rhythms le.g., theta, gamma and sharp wave ripples), which sign specific brain states leg., learning, sleep). This implies that a given neuronal network, defined by its hard-wired physical connectivity, can support different brain state-dependent activities through the modulation of its functional connectivity. Here, we review data demonstrating that not only the firing pattern, but also the functional connections between neurons, can change dynamically. We then explore the possible mechanisms of such versatility, focusing on the intrinsic properties of neurons and the properties of the synapses they establish, and how they can be modified by neuromodulators, i.e., the different ways that neurons can use to switch from one mode of communication to the other. [ABSTRACT FROM AUTHOR]

The article illustrates the process of sacral neuromodulation (SNM) therapy, which was developed in the early 1980s and is used for the treatment of patients with refractory lower urinary tract dysfuction. It notes that the mechanism of action of SNM therapy involves the modulation of spinal cord reflexes and brain networks by peripheral afferents. The significant steps of SNM through the use of the minimally invasive two-stage tined lead procedure is explored.

Abstract: It is thought that the adjustment of intraspecific aggression is an essential factor in the development of a social structure. To understand the natural laws for organizing the social structure, we focus on the fighting behavior of crickets, Gryllus bimaculatus, and investigate the neuronal mechanisms to adjust aggressiveness associated with a neuromodulatory biological amine: serotonin (5-HT). In this paper, we present a working theory of a neurophysiological mechanism based on the past biological studies on the 5-HT hypothesis, and a mathematical model of the mechanism. We analyzed this model and concluded that this neurophysiological mechanism makes the forgetting process slower. Next, we fitted our theoretical forgetting curve to an experimental curve and estimated the parameters of our model. These estimated values were in agreement with common belief in biological science. [Copyright &y& Elsevier]