Cholinergic neuromodulation and Alzheimer's disease: from single cells to network simulations.
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Acetylcholine↗
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Results for “Neuromodulation”
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Neurotransmitters and astroglia lead to neuromodulation.
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Amino Acids↗
Sacral neuromodulation as an effective treatment for refractory pelvic floor dysfunction.
OBJECTIVES: To determine the long-term efficacy and complications of sacral nerve stimulation as an alternative therapy for pelvic floor dysfunction. Pelvic floor dysfunction is a complex problem that can be refractory to current treatment modalities. Conservative therapy rarely results in a durable cure of patients, and various surgical procedures have significant side effects and less than optimal results. METHODS: Sixty-four patients, 54 women and 10 men, with various forms of voiding dysfunction for whom other forms of therapy had failed underwent placement of the Medtronic Implantable Pulse Generator sacral nerve implant. The mean age was 47 years. The presenting complaint was frequency, urgency, and urge incontinence in 44 patients and chronic nonobstructive urinary retention requiring self-catheterization in 20 patients. Forty-one patients also had chronic pelvic and perineal pain associated with their voiding symptoms. The mean duration of symptoms was 69 months. All patients underwent percutaneous nerve evaluation before the permanent implant and demonstrated more than 50% improvement in their symptoms. All patients were evaluated at 1, 3, 6, 12, and 24 months, and yearly thereafter. The assessment of the voiding symptoms was done both subjectively by patient symptoms and objectively using voiding diaries recorded for 3 days. A validated verbal rating pain scale was used to evaluate pain levels. RESULTS: Eighty percent of the patients had 50% or greater improvement in their presenting symptoms and quality of life after the procedure, with a mean follow-up of 24 months. Patients with frequency-urgency showed a reduction in the number of voids per day with a significant increase in voided volumes. Patients with urge incontinence showed a reduction in leaking episodes from 6.4 to 2.0/24 hr, with a decrease in the number of pads used from 3.5 to 1.2/day. Sixteen of 20 patients with urinary retention were able to void with a residual volume of less than 100 mL. Patients with chronic pelvic pain showed a decrease in the severity of pain from a score of 5.8 to 3.7. Complications were minimal and encountered in 18.7% of the patients. CONCLUSIONS: Sacral nerve stimulation is an effective and durable new approach to pelvic floor dysfunction with minimal complications. Test stimulation provides a valuable tool for patient selection.
Adult↗
A theory of cognitive control, aging cognition, and neuromodulation.
A theory is described which links cognitive changes observed in normal aging to an underlying decline in the function of the dopamine (DA) system projection to prefrontal cortex (PFC). The theory postulates that this neural mechanism is integral to the representation, maintenance and updating of context information, and as such impacts cognitive control across a wide range of cognitive domains, including working memory, attention, and inhibition. Behavioral and brain imaging data in support of the theory are discussed, which demonstrate selective impairments in context processing among healthy older adults associated with abnormal PFC activation. These findings highlight the utility of a computational approach to cognitive aging. Current directions for further refinement and validation of the model are outlined.
Aging↗
The mnemon and its juices: neuromodulation of memory processes.
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Acetylcholine↗
Is interferon-alpha a neuromodulator?
Interferons were initially characterized for their ability to 'interfere' with viral replication, slow cell proliferation, and profoundly alter immunity. They are a group of hormone-like molecules synthesized and secreted by macrophages, monocytes, T lymphocytes, glia, and neurons. These cytokines have been shown to have several regulatory roles and diverse biological activities, including control of cellular and humoral immune responses, inflammation, and tumor regression. In addition, there are many reports indicating that interferon-alpha (IFN-alpha) participates in the regulation of various cellular and humoral processes such as the endocrine system modulates behavior, brain activity, temperature, glucose sensitive neurons, feeding pattern and opiate activity. Therefore, IFN-alpha can be considered as a physiological modulator, with only one of its functions being the ability to hinder viral replication intracellularly.
Animals↗
Neuromodulation of enteropathogen internalization in Peyer's patches from porcine jejunum.
Jejunal Peyer's patches (JPP) are innervated sites of immune induction and enteropathogen infection. We investigated the role of enteric nerves in modulating pathogen entry into porcine JPP. Presumptive norepinephrine (NE)-containing nerve fibers were localized in JPP domes and follicle-associated villi by secondary immunofluorescence histochemistry. NE or the neuronal conduction blocker saxitoxin increased intracellular internalization of pathogenic Salmonella choleraesuis and Escherichia coli O157:H7, but not nonpathogenic E. coli, into isolated JPP mucosa. NE action was prevented by the alpha-adrenergic antagonist phentolamine. Withdrawal of enteric neural activity or NE administration appears to modulate JPP interactions with pathogenic bacteria.
Animals↗
Gamma-hydroxybutyric acid: an endogenous neuromodulator with abuse potential?
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Animals↗
Beta-amyloid peptides as direct cholinergic neuromodulators: a missing link?
Beta-Amyloid peptide (Abeta) is found in diffuse and focal deposits throughout the brain from Alzheimer's disease (AD) patients. Another feature of AD is the widespread degeneration and dysfunction of the basal-forebrain cholinergic system. Until now, it has been unclear how these features of AD might be related. Recent reports, however, suggest that Abeta can potently inhibit various cholinergic neurotransmitter functions independently of apparent neurotoxicity. This capacity of Abeta might contribute to the vulnerability of selected cholinergic neuronal populations in AD. Moreover, the high potency (picomolar to nanomolar concentrations) of these effects and the secretion of Abeta by brain cells indicate that Abeta-induced cholinergic hypoactivity might have physiological in addition to pathological significance.
Alzheimer Disease↗
Oxytocin release is inhibited by the generation of carbon monoxide from the rat hypothalamus--further evidence for carbon monoxide as a neuromodulator.
Recent evidence suggests that the gas nitric oxide can modulate the secretion of a number of hypothalamic hormones, and may be co-localized particularly to oxytocin-containing neurons. Another gas, carbon monoxide (CO), has also been suggested to play a role in neural signaling in the brain, and the synthetic enzyme responsible for the generation of carbon monoxide has been reported to be present in the rat hypothalamus. In this study, we have therefore investigated whether CO has the ability to modify the release of oxytocin from acute rat hypothalamic explants. Hemin, a specific CO precursor through the enzyme heme oxygenase (the enzymatic pathway synthesizing endogenous CO, was found to inhibit KCl-stimulated oxytocin release, with a maximal effect at 10(-5) M, while showing no effect on basal oxytocin secretion. The stimulation of oxytocin by serotonin 10 ng/ml was also significantly antagonized by hemin 10(-7) M. An inhibitor of heme oxygenase, zinc-protoporphyrin-9, had no effect on basal or stimulated oxytocin release. When hemin and zinc-protoporphyrin-9 were given together, the hemin-induced inhibition of oxytocin was completely antagonized by the enzyme inhibitor. Ferrous hemoglobin A0, a substance known to bind CO with high affinity, had no effect on either basal or stimulated oxytocin release, but when hemin and ferrous hemoglobin A0 were given together the hemin-induced inhibition of oxytocin was completely blocked. These findings provide evidence that endogenous CO may play a role in the control of oxytocin release and that, by analogy with nitric oxide, CO may represent a major new neuroendocrine modulator.
Animals↗
Neuromodulations of the intractable neurologic symptoms
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Journal Article↗
Neuromodulation: an overview.
For over two centuries, electricity has been known to induce modification of neural and nerve fiber activity and has been proposed to be used to treat some neurological dysfunctions. The new era of the use of electrical current in the treatment of neurological symptoms began in 1967 with the use of totally implanted devices that deliver a controlled amount of electricity on a precise structure within the nervous systems and was first used to control pain. Extensive research has been carried out ever since to elucidate the mechanism of action of this treatment and extend its indication for the treatment of the other neurological symptoms. So far, there is evidence that the treatment is safe and efficient for long periods of time, as it does not induce permanent damage to the stimulated structure. Most likely, electrical current at the parameters used for therapeutic purpose induces an inhibition of the structure on which it is applied. However, this may be accompanied by either inhibition or excitation of anatomically related structures. For this reason, it seems more convenient to refer to this type of therapy as neuromodulation.A review of the historical development of this fascinating area is presented, with special attention to the evidence derived from experimental work on the parameters that electrical current must maintain to avoid damage to the underlying tissue.
Electric Stimulation Therapy↗
Endogenous zinc as a retinal neuromodulator: evidence from the skate (Raja erinacea).
The effects of zinc on skate (Raja erinacea) bipolar cell responses to glutamatergic agonists were examined using whole-cell voltage-clamp recording. Isolated ON bipolar cell currents mediated by the metabotropic agonist trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (30 microM), L-2-amino-4-phosphonobutyrate (3-10 microM) and glutamate (0.3-10 microM) were blocked when zinc (1 microM) was added to the test solution. Similarly, isolated OFF bipolar cell responses to the ionotropic agonist kainate (300 microM) were blocked by zinc (1 microM). The effects of zinc were further studied using electroretinogram (ERG) recording. Skate eyecup preparations were superfused with picrotoxin (200 microM) to block GABAergic input. When histidine (100 microM), a zinc chelator, was added to the superfusate, ERG ON responses increased. This suggests that endogenous zinc plays a neuromodulatory role in the retina and is consistent with zinc's suppressive effect on isolated bipolar cells.
Aminobutyrates↗
Prolonged non-adrenergic inhibition of cardiac vagal action following sympathetic stimulation: neuromodulation by neuropeptide Y?
After short periods of intense sympathetic activation, the action of the vagus nerve on heart rate is inhibited for periods of many minutes to several hours. This effect is not abolished by effective blockade of alpha- or beta-adrenoceptors and is not duplicated by administration of noradrenaline or isoprenaline. A similar, long lasting vagal inhibition is caused by administration of neuropeptide Y, a probable cotransmitter in sympathetic nerves.
Animals↗
Neuromodulation of reciprocal glutamatergic inhibition between antagonistic motoneurons by 5-hydroxytryptamine (5-HT) in crayfish walking system.
In an in vitro preparation of the crayfish thoracic locomotor system, paired intracellular recordings were performed from antagonistic depressor (Dep) and levator (Lev) motoneurons (MNs) that control the second joint of walking legs. Connections between these two groups of MNs consist mainly of inhibitory connections and weak electrotonic synapses. Injection of depolarizing current into a Lev MN results in a hyperpolarization in a Dep MN, and vice versa. This reciprocal glutamatergic inhibition, is not changed in the presence of the sodium channel blocker tetrodotoxin (TTX) and therefore is likely supported by a direct connection between MNs. By contrast, reciprocal inhibition is largely reduced in the presence of 5-hydroxytryptamine (5-HT; 10 microM). Direct micro-application of glutamate pressure-ejected close to an intracellularly recorded MN, evoked an inhibitory response in that MN, accompanied by a decrease of input resistance. These two effects were dramatically reduced in the presence of 5-HT. Thus 5-HT could be involved in mechanisms of dynamic reconfigurations of the neural network controlling leg movements in crayfish.
Animals↗
Differential expression of suppressors of cytokine signaling-1, -2, and -3 in the rat hippocampus after seizure: implications for neuromodulation by gp130 cytokines.
Numerous studies have investigated the expression of various cytokine families in the CNS after brain injury. The gp130 or interleukin (IL)-6-type cytokines have received a great deal of focus, and it is clear that they exhibit an acute and robust upregulation in various brain injury models. We are interested to determine, however, whether endogenously expressed cytokines in the CNS act in a direct neuromodulatory manner. In an accompanying study, we examined the expression of five gp130 cytokines and their receptors in the lithium-pilocarpine model of status epilepticus. We follow up that study here by trying to determine if gp130 signal transduction occurs in hippocampal principal neurons after seizure. Therefore, using the expression of suppressors of cytokine signaling (SOCS)-1 and -3 as indices of gp130 signal transduction, we performed a detailed in situ hybridization seizure time-course study in the adult rat hippocampus. For comparison, we also examined SOCS-2, which is involved in insulin-like growth factor signaling. We found that while SOCS-1 and -3 were faintly expressed under basal conditions, only SOCS-3 exhibited a rapid, robust, and transient induction. This occurred first in non-principal cells, which appeared to be glial, peaking at approximately 12 h post-seizure. Subsequently, a robust induction of SOCS-3 occurred in pyramidal and granule neurons, peaking at approximately 24 h. SOCS-2 displayed a relatively higher level of basal expression, particularly in CA3, and a mild and transient downregulation by 24 h. These findings corroborate the hypothesis that seizure-induced gp130 cytokines play a direct neuromodulatory role in the hippocampus. Since in our previous study we did not detect cytokine receptor expression in non-principal cells, it is unclear what elicits SOCS-3 expression in this population.
Animals↗
Neurotransmitters and neuromodulators during early human development.
BACKGROUND: Neurotransmitters such as monoamines appear in the embryo before the neurones are differentiated. They may have other functions than neurotransmission during embryogenesis such as differentiation and neuronal growth. For example, serotonin may act as a morphogen. A number of neuropeptides are expressed during ontogenesis, but their function has been difficult to establish. Maybe some of them remain as evolutionary residues. Fast-switching neurotransmitters like the excitatory amino acids and the more ionotropic receptors dominate in the human brain, but appear probably later during evolution as well as during ontogeny. METHODS: The distribution of catecholamines during development has been analysed with a fluorescence method, while most of the other neurotransmitters have been mapped with immunohistochemical methods. The classical method to determine the physiological role of a neurotransmitter or modulator is to study the physiological effect of its antagonist, blocking the endogenous activity. By transgenic technique, the genes encoding for enzymes involved in the synthesis of neurotransmitters can be knocked-out. MAJOR FINDINGS: Pharmacological blocking of endogenous activity has, for example, demonstrated that adenosine suppresses fetal respiration. Knocking out the dopamine beta-hydroxylase gene results in fetal death, suggesting that noradrenaline is essential for survival. Some neurotransmitters change their effect during embryogenesis, e.g. GABA which is excitatory in the embryo, but inhibitory after birth due to a switch from a high to low chloride content in the nerve cells. It is possible that this is of importance for the wiring of neuronal network in early life. NMDA receptors dominate in the foetus, while kainate and AMPA receptors appear later. At birth, there is a surge of neurotransmitters such as catecholamines, which may be of importance for the neonatal adaptation. CONCLUSIONS: Neurotransmitters and modulators are not only important for the neural trafficking in the embryo, but also for the development of the neuronal circuits. Prenatal or neonatal stress (hypoxia), as well as various drugs, may disturb the wiring and cause long-term behavioural effects (fetal and neonatal programming).
Adult↗
An immunohistochemical study of putative neuromodulators and transmitters in the centrifugal visual system of the quail (Coturnix japonica).
The aim of the present study was to analyze the neurochemical properties of the centrifugal visual system (CVS) of the quail using an immunohistochemical approach by testing 16 neuropeptides (angiotensin: ANG, bradykinin: BK, cholecystokinin, dynorphin, L and M-enkephalin, beta-endorphin: beta-END, galanin, alpha-neoendorphin, neurokinin A, neuropeptide Y (NPY), ocytocin, somatostatin, substance P, vasopressin, vasoactive intestinal polypeptide) and three neurotransmitters or their synthetic enzymes (choline acetyltransferase: ChAT, tyrosine hydroxylase: TH, serotonin: 5-HT and nitric oxide synthase: NOS, including the histochemical nicotinamide adenine dinucleotide phosphate diaphorase technique). For each substance, the somatic and afferent fiber and terminal labeling was analyzed within the nucleus isthmo-opticus (NIO) and the ectopic area (EA) and compared with that of retinopetal cell bodies labeled retrogradely with RITC following its intraocular injection (double-labeling procedure). The results showed that none of the centrifugal neurons were reactive to any of the substances tested. In contrast, all with the exception of ANG, BK and beta-END, labeled fibers and terminals within the EA and only four (ChAT, 5-HT, NPY and NOS) within the NIO. Possible sources of these immunoreactive fibers terminating in the NIO and EA were investigated by mapping the somatic immunolabeling of the different substances within brainstem regions previously shown by Miceli and other authors to project upon the centrifugal neurons. The data suggests that, besides the rapid retino-tecto-NIO-retinal loop, which facilitates the transfer of meaningful or more relevant information within particular portions of the visual field, the multiple afferent input which stems from various brainstem regions utilizes a wide range of neuroactive substances. Some of these afferent projections upon the centrifugal neurons appear to belong to nonspecific systems which might play a role in modulating the excitability of centrifugal neurons as a function of arousal.
Animals↗