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ABSTRACT Background Aims Methods Results Conclusions Immunoresistance to botulinum neurotoxin A (BoNT‐A) due to neutralizing antibodies (NAbs) can lead to partial or complete secondary nonresponse (SNR), potentially limiting individuals' aesthetic and/or medical therapeutic options in the short and/or long term. Understanding factors directly or indirectly influencing BoNT‐A immunoresistance risk is crucial.This analysis explored patterns of latent risk factors (biological and behavioral) that may influence the risk of developing BoNT‐A immunoresistance among experienced aesthetic BoNT‐A recipients.Latent class analysis (LCA) was applied to survey data from 363 experienced BoNT‐A recipients from six Asia‐Pacific countries to identify distinct subgroups based on their patterns of risk factor or risk proxy variables. The five risk proxy variables used for modeling capture information on BoNT‐A treatments (treatment indications/locations as proxies for dose), symptoms of declining efficacy, number of aesthetic treatments over the past 3 years, and clinic and BoNT‐A formulation switching behaviors. These represent established risk factors and treatment‐seeking behaviors suggested to influence immunoresistance risk.LCA identified 3 distinct profiles of individuals, which we described based on the observed patterns of risk proxies as: “lower‐risk” (55%), “moderate‐risk” (39%), and “higher‐risk” (6%). Individuals in the “higher‐risk” profile reported higher BoNT‐A exposure, more symptoms of declining efficacy, and distinct patterns of knowledge and attitudes toward BoNT‐A immunoresistance that could account for their treatment‐seeking behaviors.This study suggests that individual behaviors (the “human factor”) have a notable influence on BoNT‐A immunoresistance risk. Gaining deeper insights into these factors could support more targeted and effective interventions to mitigate risk. [ABSTRACT FROM AUTHOR]

Brain‐derived neurotrophic factor (BDNF) is a neurotrophin, acting as a neurotrophic signal and neuromodulator in the central nervous system (CNS). BDNF is synthesized from its precursor proBDNF within the CNS and peripheral tissues. Through activation of NTRK2/TRKB (neurotrophic receptor tyrosine kinase 2), BDNF promotes neuronal survival, synaptic plasticity, and neuronal growth, whereas it inhibits microglial activation and the release of pro‐inflammatory cytokines. BDNF is dysregulated in different neurodegenerative diseases and depressions. However, there is a major controversy concerning BDNF levels in the different stages of multiple sclerosis (MS). Therefore, this review discusses the potential role of BDNF signaling in stages of MS, and how BDNF modulators affect the pathogenesis and outcomes of this disease. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion Neuromodulator injections are minimally invasive procedures performed across the globe. Despite their ubiquity, there is a dearth of information on whether and how needle tips used for neuromodulator procedures are deformed after repeated injections.We investigated the magnitude of needle tip deformation following sequential injection passes (3×, 5×, and 10×) during facial neuromodulator injections with three commonly used needle sizes (30G, 31G, and 32G).Neuromodulator was administered for four different aesthetic indications. Each collected needle was mounted and imaged in a Philips XL‐30 Scanning electron microscope. Images were processed using ImageJ photo analysis software.Forty‐five needle tips were investigated. When comparing the facial regions of interest, a statistically significant difference in deformation percentage was found when injecting 10× (p = 0.044) with greatest damage after injecting the glabella (38.4%), followed by lateral canthus (27.9%), forehead (27.5%), and midface (23.1%). Independent of facial region targeted, the mean percentage of needle deformation at 3× was 14.8%, at 5× 19.6%, and at 10× 29.2% with p < 0.001. Smaller needle size corresponded to smaller percentage of damage.Exchanging needles after more than five injection passes will minimize needle deformation and likely increase injection precision. [ABSTRACT FROM AUTHOR]

GBM, or glioblastoma multiforme, is a brain tumor that poses a great threat to both children and adults, being the primary cause of death related to brain tumors. GBM is often associated with epilepsy, which can be debilitating. Seizures and the development of epilepsy are the primary symptoms that have a severe impact on the quality of life for GBM patients. It is increasingly apparent that the nervous system plays an essential role in the tumor microenvironment for all cancer types, including GBM. In recent years, there has been a growing understanding of how neurotransmitters control the progression of gliomas. Evidence suggests that neurotransmitters and neuromodulators found in the tumor microenvironment play crucial roles in the excitability, proliferation, quiescence, and differentiation of neurons, glial cells, and neural stem cells. The involvement of neurotransmitters appears to play a significant role in various stages of GBM. In this review, the focus is on presenting updated knowledge and emerging ideas regarding the interplay between neurotransmitters and neuromodulators, such as glutamate, GABA, norepinephrine, dopamine, serotonin, adenosine, and their relationship with GBM and the seizures induced by this condition. The review aims to explore the current understanding and provide new insights into the complex interactions between these neurotransmitters and neuromodulators in the context of GBM‐related seizures. [ABSTRACT FROM AUTHOR]

Background: Real‐world data on the outcome of routine treatment for disorders of gut‐brain interaction (DGBI) in secondary care are lacking. Method: A longitudinal study of consecutive adult patients with various DGBI attending this institution's gastroenterology clinic was conducted. Following 2 years of treatment, the proportion of patients with symptom improvement, details of clinical therapy, factors associated with and the impact of 'no symptom improvement' were determined. Results: A total of 289 patients (median age 68 years; 64.7% females; 28.4% irritable bowel syndrome (IBS), 20.1% functional dyspepsia (FD), 8.7% functional constipation (FC), 42.9% overlap syndrome) were recruited. After 2 years, 66.1% patients reported symptom improvement. Patients with overlap syndrome were less likely to have symptomatic improvement compared to those with a single DGBI (Overlap 55.6% vs IBS 74.4% vs FD 72.4% vs FC 76.0%, p = 0.014). Reassurance was associated with symptom improvement (p < 0.001). On multivariate analysis, overlap syndrome remained significantly associated with a poorer outcome (OR 2.27, 95% CI 1.22–4.25, p = 0.010), while providing reassurance was associated with a positive outcome (OR 0.30, 95% CI 0.16–0.56, p < 0.001). Only 25.6% and 14.9% of patients were referred for a low FODMAP diet and psychiatric intervention respectively. DGBI patients who had 'no improvement' were more likely to seek further GI consultations and had more work absenteeism. Conclusion: Two‐thirds of DGBI patients in secondary care showed symptom improvement. Patients who were reassured had better symptom improvement, while those with an overlap syndrome were associated with a poorer outcome, resulting in greater healthcare consultation and work absenteeism. [ABSTRACT FROM AUTHOR]

Artificial optoelectronic synapses with flexibly regulated synaptic weight are crucial to the rapidly evolved artificial visual system. Although three‐terminal devices with transistor geometry have exhibited controllable synaptic response through applying electrical pulses on the gate terminal, the complicated device structure limits its integration with array configurations. In this work, a simple two‐terminal optoelectronic synapses array based on the ZnO/Al2O3/CdS heterojunction with tunable synaptic weight is presented. It can respond to UV and green light stimulation in a neuromorphic manner, allowing the implementation of the basic synaptic function. By introducing the piezo‐phototronic effect, the synaptic weight can be regulated in multilevels, extending the forgetting time by 30.08% and reducing training epochs for image recognition by 36.13%. In addition, the device can extract the target image from massive noisy optical inputs avoiding redundant data memorization. This work provides a novel method to regulate the synaptic weight of the simple two‐terminal device configuration through the piezo‐phototronic effect, showing potential applications for the mimicry of the human visual‐perception system. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The behavior of somatic stem cells is regulated by their niche. Interaction between hematopoietic stem cells (HSCs) and their niches are a representative model to understand stem cell‐niche interplay. Here, we provide an overview of crosstalk between HSCs and their niches in bone marrow and extramedullary organs following the life journey of HSCs from emergence, development, maturation until aging. We highlight the unique differences of HSC niches in different life stages within various organs focusing on recent literature to propose new speculations and hypotheses. [ABSTRACT FROM AUTHOR]

Aim: Octopamine in the Drosophila brain has a neuromodulatory role similar to that of noradrenaline in mammals. After release from Tdc2 neurons, octopamine/tyramine may trigger intracellular Ca 2+ signaling via adrenoceptor-like receptors on neural cells, modulating neurotransmission. Octopamine/tyramine receptors are expressed in neurons and glia, but how each of these cell types responds to octopamine remains elusive. This study aimed to characterize Ca 2+ responses of neurons and astrocytes to neuromodulatory octopamine signals., Methods: We expressed Ca 2+ indicator jGCaMP7b in specific cell type in adult Drosophila brains and performed intracellular Ca 2+ imaging in the brain optic lobes upon bath application of octopamine by confocal microscopy., Results: Octopamine-stimulated Ca 2+ responses in neurons were different from those of glial cells. The amplitude of octopamine-mediated Ca 2+ signals in neurons was 3.4-fold greater than in astrocytes. However, astrocytes were more sensitive to octopamine; the median effective concentration that triggered Ca 2+ responses was nearly 6-fold lower in astrocytes than in neurons. In both cell types, Ca 2+ transients are shaped by G q and G s protein-coupled octopamine/tyramine receptors. Our snRNA-seq database screening uncovered differential expression patterns of these receptors between brain cell types, which may explain the difference in Ca 2+ signaling., Conclusion: In the brain optic lobes, astrocytes, not neurons, appear to be the sole responders to low concentration octopamine signals, and therefore likely drive synaptic plasticity and visual processing. Given the interconnectivity of the optic lobes with other brain regions, octopaminergic signals acting through the optic lobe astrocytes may also influence higher-order brain functions including learning and memory., (© 2025 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Objectives/Hypothesis: Neurogenic cough affects 11% of Americans and causes significant detriment to quality of life. With the advent of novel therapies, the objective of this review is to determine how procedural therapies (e.g., superior laryngeal nerve block) compare to other established pharmacologic and non‐pharmacologic treatments for neurogenic cough. Methods: With the assistance of a medical librarian, a systematic review was performed using PICOS (patients, interventions, comparator, outcome, study design) format: adults with neurogenic cough receiving any pharmacologic or non‐pharmacologic treatment for neurogenic cough compared to adults with neurogenic cough receiving any other relevant interventions, or treated as single cohorts, assessed with cough‐specific quality of life outcomes, in all study designs and case series with ≥ 10 cases. Case reports, review articles, non‐human studies, non‐English language articles, and unavailable full‐text articles were excluded. Results: There were 2408 patients with neurogenic cough in this review, treated with medical therapy (77%), speech therapy (19%), both medical and speech therapy (1%), and procedural therapy (3%). The included studies ranged from low to intermediate quality. Overall, most interventions demonstrated successful improvement in cough. However, the heterogeneity of included study designs precluded direct comparisons between intervention types. Conclusion: This meta‐analysis compared various treatments for neurogenic cough. Procedural therapy should be considered in the armamentarium of neurogenic cough treatments, particularly in patients refractory to, or intolerant of, the side effects of medical therapy. Lastly, this review illuminates key areas for improving neurogenic cough diagnosis, such as strict adherence to diagnostic and treatment guidelines, sophisticated reflux testing, and standardized, consistent outcome reporting. Laryngoscope, 132:107–123, 2022 [ABSTRACT FROM AUTHOR]

Background: It is believed that combination treatment with both neuromodulators (NM) and hyaluronic acid soft-tissue fillers (HA) results in superior aesthetic results and increased patient satisfaction compared to either treatment alone. Aims: To determine whether combined treatment with NM and HA leads to greater patient retention than treatment with NM or HA alone. Patients/Methods: This is a large, multi-center, retrospective review of patient retention rates from 7 aesthetic practices across 5 continents, incorporating over 2600 patients. Patient retention is interpreted as a surrogate marker for overall patient satisfaction. Retention rates were compared at 1, 3, and 5 years for patients who received NM only, HA only, or combination treatment with both NM and HA. Results: Combination therapy significantly increased the probability of retention for each time point (1, 3, and 5 years) compared with NM alone (P < .0001) and HA alone (P < .0001). Conclusion: This large multicenter, global retrospective review demonstrates that patients who received combined HA and NM were more likely to be retained in the same practice over many years than those who received either treatment alone. [ABSTRACT FROM AUTHOR]

Background: Treating the lower face with neuromodulators and targeting the masseter muscle can reduce masseteric hypertrophy but can also change the facial shape. A novel observation after the treatment of the masseter muscle with incobotulinumtoxin Type A was the increase in temporal volume. Aim: Objectively assess temporal volume increase following treatment of masseteric hypertrophy using incobotulinumtoxin Type A. Methods: Nine female patients with a mean age of 35.11 years ± 9.1 [Asian (11.1%) and Caucasian (88.9%)] were treated with incobotulinumtoxin Type A for masseteric hypertrophy. Masseteric prominence and temporal volume were assessed by two independent raters, and temporal fossa volume was measured via 3‐dimensional volumetric imaging. Results: Independent of the neuromodulator injection technique (ie, single‐injection versus multi‐injection), a reduction in masseteric hypertrophy occurred represented by a decrease in the masseter prominence scale. In addition, the treatment resulted in a significant improvement of the temporal volume scale and an increase in the measured volume of the temporal fossa. None of the presented measurements were statistically significantly different between the two utilized injection techniques. Conclusions: This study supports using a full‐face approach when performing aesthetic treatments. Anatomical concepts can help to guide treatments: the compensatory increase in temporalis function after masseter muscle treatment resulted in an increased in temporal fossa volume. The findings presented herein should not be considered as a new concept for treating the temporal fossa but rather as an additional possibility for increasing the temporal volume. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: To evaluate short- and long-term treatment outcomes of amitriptyline for idiopathic cough.Study Design: Retrospective chart review and anonymous survey of a patient cohort.Methods: We evaluated a cohort of adults treated for cough at the Duke Voice Care Center with amitriptyline over a 2- to 3-year period. We characterized demographics, symptoms, treatment variability, and treatment effects from chart review and survey responses. We performed univariate analysis comparing cough improvement to age, gender, symptoms of throat irritation, cough duration, concurrent speech therapy, and dosage.Results: Eighty-nine percent were taking the medication at the first clinical follow-up at a mean 2.6 months, and overall, 67% reported ≥50% improvement. No statistically significant predictors of cough improvement with medication were identified. At follow-up 2 to 3 years later, overall, 53% reported ≥50% improvement, with only 34% of patients still taking amitriptyline. After 2 to 3 years, 65% of patients had titrated the medication to effect, and 33% restarted the medication. Occurrence of side effects was the most frequent reason for stopping the medication.Conclusions: Amitriptyline can be an effective and well-tolerated part of short- and long-term management of idiopathic cough in adults. Titrating the dose and restarting are often necessary. Larger studies and randomized control trials are needed to better understand the outcomes of using amitriptyline to treat idiopathic cough.Level Of Evidence: 4 Laryngoscope, 126:2758-2763, 2016. [ABSTRACT FROM AUTHOR]

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]

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]

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]

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 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.

Proline plays an important role in regulating synaptic neurotransmission in both mammalian and insect nervous systems. The full-length complementary DNA sequences encoding the proline transporter gene ( CsProT) and its alternative spliced transcript ( CsProT-ST) were cloned from the striped stem borer (SSB), Chilo suppressalis, one of the most important rice pests in Asia. The comparison of amino acid sequences showed that CsProT is highly similar to the proline transporter isolated from Manduca sexta (MasProT). The developmental changes of the relative messenger RNA expression levels of CsProT and CsProT-ST genes were examined in SSB. The expression level of CsProT-ST is much higher than that of CsProT in all developmental periods, suggesting that the 3′-end spliced variant is the major transcript instead of CsProT. The highest expression level of both genes in the pupal stage means that proline may be involved in some unclear functions in the metamorphosis from pupa to adulthood. [ABSTRACT FROM AUTHOR]

In the mammalian retina, dopamine binding to the dopamine D4 receptor (D4R) affects a light‐sensitive pool of cyclic AMP by negatively coupling to the type 1 adenylyl cyclase (AC1). AC1 is the primary enzyme controlling cyclic AMP production in dark‐adapted photoreceptors. A previous study demonstrated that expression of the gene encoding AC1, Adcy1, is downregulated in mice lacking Drd4, the gene encoding the D4R. The present investigation provides evidence that D4R activation entrains the circadian rhythm of Adcy1 mRNA expression. Diurnal and circadian rhythms of Drd4 and Adcy1 mRNA levels were observed in wild‐type mouse retina. Also, rhythms in the Ca2+‐stimulated AC activity and cyclic AMP levels were observed. However, these rhythmic activities were damped or undetectable in mice lacking the D4R. Pharmacologically activating the D4R 4 h before its normal stimulation at light onset in the morning advances the phase of the Adcy1 mRNA expression pattern. These data demonstrate that stimulating the D4R is essential in maintaining the normal rhythmic production of AC1 from transcript to enzyme activity. Thus, dopamine/D4R signaling is a novel zeitgeber that entrains the rhythm of Adcy1 expression and, consequently, modulates the rhythmic synthesis of cyclic AMP in mouse retina. [ABSTRACT FROM AUTHOR]

The effects of adenosine on neurotransmission have been widely studied by monitoring transmitter release. However, the effects of adenosine on vesicle recycling are still unknown. We used fluorescence microscopy of FM2-10-labeled synaptic vesicles in combination with intracellular recordings to examine whether adenosine regulates vesicle recycling during high-frequency stimulation at mouse neuromuscular junctions. The A1 adenosine receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine) increased the quantal content released during the first endplate potential, suggesting that vesicle exocytosis can be restricted by endogenous adenosine, which accordingly decreases the size of the recycling vesicle pool. Staining protocols designed to label specific vesicle pools that differ in their kinetics of release showed that all vesicles retrieved in the presence of 8-cyclopentyl-1,3-dipropylxanthine were recycled towards the fast-release pool, favoring its loading with FM2-10 and suggesting that endogenous adenosine promotes vesicle recycling towards the slow-release pool. In accordance with this effect, exogenous applied adenosine prevented the replenishment of the fast-release vesicle pool and, thus, hindered its loading with the dye. We had found that, during high-frequency stimulation, Ca2+ influx through L-type channels directs newly formed vesicles to a fast-release pool (Perissinotti et al., 2008). We demonstrated that adenosine did not prevent the effect of the L-type blocker on transmitter release. Therefore, activation of the A1 receptor promotes vesicle recycling towards the slow-release pool without a direct effect on the L-type channel. Further studies are necessary to elucidate the molecular mechanisms involved in the regulation of vesicle recycling by adenosine. [ABSTRACT FROM AUTHOR]

The feedback actions of ovarian oestradiol during the female reproductive cycle are among the most unique in physiology. During most of the cycle, oestradiol exerts homeostatic, negative feedback upon the release of gonadotrophin-releasing hormone (GnRH). Upon exposure to sustained elevated oestradiol levels, however, there is a switch in the feedback effects of this hormone to positive, resulting in induction of a surge in the release of GnRH that serves as a neuroendocrine signal to initiate the ovulatory cascade. We review recent developments stemming from studies in an animal model exhibiting daily switches between positive and negative feedback that have probed the neurobiological mechanisms, including changes in neural networks and intrinsic properties of GnRH neurones, underlying this switch in oestradiol action. [ABSTRACT FROM AUTHOR]

The optic gland, which is analogous to the anterior pituitary in the context of gonadal maturation, is found on the upper posterior edge of the optic tract of the octopus Octopus vulgaris. In mature octopus, the optic glands enlarge and secrete a gonadotrophic hormone. A peptide with structural features similar to that of vertebrate gonadotophin-releasing hormone (GnRH) was isolated from the brain of octopus and was named oct-GnRH. Oct-GnRH showed luteinising hormone-releasing activity in the anterior pituitary cells of the Japanese quail Coturnix coturnix. Oct-GnRH immunoreactive signals were observed in the glandular cells of the mature optic gland. Oct-GnRH stimulated the synthesis and release of sex steroids from the ovary and testis, and elicited contractions of the oviduct. Oct-GnRH receptor was expressed in the gonads and accessory organs, such as the oviduct and oviducal gland. These results suggest that oct-GnRH induces the gonadal maturation and oviposition by regulating sex steroidogenesis and a series of egg-laying behaviours via the oct-GnRH receptor. The distribution and expression of oct-GnRH in the central and peripheral nervous systems suggest that oct-GnRH acts as a multifunctional modulatory factor in feeding, memory processing, sensory, movement and autonomic functions. [ABSTRACT FROM AUTHOR]

Abstract Nitric oxide (NO) acts as an orthograde neurotransmitter in the central nervous system by stimulating guanylyl cyclase and increasing cGMP. We previously demonstrated this pathway for an identified synaptic follower neuron in the cerebral ganglion of the mollusc Aplysia californica. Here, we investigated the NO–cGMP pathway in other Aplysia central neurons using cGMP immunocytochemistry and intracellular recordings. NO-induced cGMP immunoreactivity in a few neurons in the abdominal, pleural and buccal ganglia, including identified neurons L11 and R15 in the abdominal ganglion and neuron Bng in the buccal ganglion. NO depolarized all these neurons but none of the four nonimmunoreactive neurons tested. In neuron L11, NO-induced depolarization, tonic spiking and a reduction in membrane conductance at resting potential. The NO effect was mimicked by applying the membrane permeable analogue, 8-Br-cGMP in L11. Neuron R15 was depolarized and its activity shifted from spike/bursts to tonic spiking. These NO effects were blocked by applying the guanylyl cyclase inhibitor ODQ and mimicked by 8-Br-cGMP. Neuron Bng was depolarized and produced spikes tonically. These results provide evidence that the NO–cGMP pathway is linked to membrane ionic channels in cGMP-IR neurons, and the channels may be different in specific neurons. [ABSTRACT FROM AUTHOR]

The tripeptide glutathione (GSH) has been thoroughly investigated in relation to its role as antioxidant and free radical scavenger. In recent years, novel actions of GSH in the nervous system have also been described, suggesting that GSH may serve additionally both as a neuromodulator and as a neurotransmitter. In the present article, we describe our studies to explore further a potential role of GSH as neuromodulator/neurotransmitter. These studies have used a combination of methods, including radioligand binding, synaptic release and uptake assays, and electrophysiological recording. We report here the characteristics of GSH binding sites, the interrelationship of GSH with the NMDA receptor, and the effects of GSH on neural activity. Our results demonstrate that GSH binds via its γ-glutamyl moiety to ionotropic glutamate receptors. At micromolar concentrations GSH displaces excitatory agonists, acting to halt their physiological actions on target neurons. At millimolar concentrations, GSH, acting through its free cysteinyl thiol group, modulates the redox site of NMDA receptors. As such modulation has been shown to increase NMDA receptor channel currents, this action may play a significant role in normal and abnormal synaptic activity. In addition, GSH in the nanomolar to micromolar range binds to at least two populations of binding sites that appear to be distinct from all known excitatory amino acid receptor subtypes. GSH bound to these sites is not displaceable by glutamatergic agonists or antagonists. These binding sites, which we believe to be distinct receptor populations, appear to recognize the cysteinyl moiety of the GSH molecule. Like NMDA receptors, the GSH binding sites possess a coagonist site(s) for allosteric modulation. Furthermore, they appear to be linked to sodium ionophores, an interpretation supported by field potential recordings in rat cerebral cortex that reveal a dose-dependent depolarization to applied GSH that is blocked by the absence of sodium but not by lowering calcium or by NMDA or (S)-2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate antagonists. The present data support a reevaluation of the role of GSH in the nervous system in which GSH may be involved both directly and indirectly in synaptic transmission. A full accounting of the actions of GSH may lead to more comprehensive understanding of synaptic function in normal and disease states. [ABSTRACT FROM AUTHOR]

Is There an Answer? is intended to serve as a forum in which readers to IUBMB Life may pose questions of the type that intrigue biochemists but for which there may be no obvious answer or one may be available but not widely known or easily accessible. Readers are invited to e-mail ascenzi@uniroma3.it if they have questions to contribute or if they can provide answers to questions that are provided here from time to time. In the latter case, instructions will be sent to interested readers. Answers should be, whenever possible, evidence-based and provide relevant references. Paolo Ascenzi [ABSTRACT FROM AUTHOR]

Abstract Corticotropin-releasing factor (CRF)-like proteins act via two G-protein-coupled receptors (CRF-R1 and CRF-R2) playing important neuromodulatory roles in stress responses and synaptic plasticity. The cerebellar expression of corticotropin-releasing factor-like ligands has been well documented, but their receptor localization has not. This is the first combination of a light microscopic and ultrastructural study to localize corticotropin-releasing factor receptors immunohistologically in the developing rat cerebellum. Both CRF-R1 and CRF-R2 were expressed in climbing fibres from early stages (post-natal day 3) to the adult, but CRF-R2 immmunoreactivity was only prominent throughout the molecular layer in the posterior cerebellar lobules. CRF-R1 immunoreactivity was concentrated in apical regions of Purkinje cell somata and later in primary dendrites exhibiting a diffuse cytoplasmic appearance. In Purkinje cells, CRF-R1 immunoreactivity was never membrane bound post-synaptically in dendritic spines while CRF-R2 immunoreactivity was found on plasmic membranes of Purkinje cells from post-natal day 15 onwards. We conclude that the localization of these receptors in cerebellar afferents implies their pre-synaptic control of the release of corticotropin-releasing factor-like ligands, impacting on the sensory information being transmitted from afferents. Furthermore, the fact that CRF-R2 is membrane bound at synapses, while CRF-R1 is not, suggests that ligands couple to CRF-R2 via synaptic transmission and to CRF-R1 via volume transmission. Finally, the distinct expression profiles of receptors along structural domains of Purkinje cells suggest that the role for these receptors is to modulate afferent inputs. [ABSTRACT FROM AUTHOR]