Efferent Function Research Articles

Spiral ganglion degeneration and hearing loss as a consequence of satellite cell death in saposin B-deficient mice.

Saposin B (Sap B) is an essential activator protein for arylsulfatase A in the hydrolysis of sulfatide, a lipid component of myelin. To study Sap B's role in hearing and balance, a Sap B-deficient (B(-/-)) mouse was evaluated. At both light and electron microscopy (EM) levels, inclusion body accumulation was seen in satellite cells surrounding spiral ganglion (SG) neurons from postnatal month 1 onward, progressing into large vacuoles preceding satellite cell degeneration, and followed by SG degeneration. EM also revealed reduced or absent myelin sheaths in SG neurons from postnatal month 8 onwards. Hearing loss was initially seen at postnatal month 6 and progressed thereafter for frequency-specific stimuli, whereas click responses became abnormal from postnatal month 13 onward. The progressive hearing loss correlated with the accumulation of inclusion bodies in the satellite cells and their subsequent degeneration. Outer hair cell numbers and efferent function measures (distortion product otoacoustic emissions and contralateral suppression) were normal in the B(-/-) mice throughout this period. Alcian blue staining of SGs demonstrated that these inclusion bodies corresponded to sulfatide accumulation. In contrast, changes in the vestibular system were much milder, but caused severe physiologic deficits. These results demonstrate that loss of Sap B function leads to progressive sulfatide accumulation in satellite cells surrounding the SG neurons, leading to satellite cell degeneration and subsequent SG degeneration with a resultant loss of hearing. Relative sparing of the efferent auditory and vestibular neurons suggests that alternate glycosphingolipid metabolic pathways predominate in these other systems.

Medial efferent mechanisms in children with auditory processing disorders.

Auditory processing disorder (APD) affects about 2–5% of children. However, the nature of this disorder is poorly understood. Children with APD typically have difficulties in complex listening situations. One mechanism thought to aid in listening-in-noise is the medial olivocochlear (MOC) inhibition. The purpose of this review was to critically analyze the published data on MOC inhibition in children with APD to determine whether the MOC efferents are involved in these individuals. The otoacoustic emission (OAE) methods used to assay MOC reflex were examined in the context of the current understanding of OAE generation mechanisms. Relevant literature suggests critical differences in the study population and OAE methods. Variables currently known to influence MOC reflex measurements, for example, middle-ear muscle reflexes or OAE signal-to-noise ratio, were not controlled in most studies. The use of potentially weaker OAE methods and the remarkable heterogeneity across studies does not allow for a definite conclusion whether or not the MOC reflex is altered in children with APD. Further carefully designed studies are needed to confirm the involvement of MOC efferents in APD. Knowledge of efferent functioning in children with APD would be mechanistically and clinically beneficial.

Olivocochlear efferent function: issues regarding methods and the interpretation of results.

As studies of the olivocochlear (OC) efferent system have matured, issues have been identified that need to be taken into account in the design of new studies and in the interpretation of existing work. The need for high signal-to-noise ratios (SNRs), multiple alternations of conditions, and avoiding middle-ear-muscle activation have been previously highlighted. Less well-known issues include: Contralateral medial OC (MOC) effects may not be good proxies for ipsilateral (ipsi) MOC effects; MOC-induced changes in otoacoustic emissions (OAEs) may not accurately show MOC-induced changes in auditory-nerve (AN) responses; measuring OAE differences from before to after psychophysical trials yields the transient OAE change but not tonic MOC activation; tonic MOC activation may be measurable by several techniques including by OAE differences in trials in which the subject’s judgment was correct vs. trials that were incorrect; SNRs can be preserved by Bootstrap statistical tests; differences in task difficulty may outweigh differences in subject attention; lateral efferent effects are little understood and may be tied to MOC effects; to assess whether MOC strength predicts protection from acoustic trauma, prospective tests in humans are needed.

Optogenetic activation of GABAergic neurons in the nucleus accumbens decreases the activity of the ventral pallidum and the expression of cocaine-context-associated memory

GABAergic medium-sized spiny neurons (MSNs) in the nucleus accumbens (NAc) differentially express D1 and D2 dopamine receptors. Both D2- and D1-MSNs in the NAc form projections into the ventral pallidum, whereas only D1-MSNs directly project into midbrain neurons. They are critical in rewarding and aversive learning, and understanding the function of these NAc efferents and the alteration of their targeted brain regions in responding to a reward-associated context is important. In this study, we activated the GABAergic neurons in the NAc of mice expressing channelrhodopsin-2 under the control of the vesicular GABA transporter promoter by an optogenetic approach, and examined its effects on the expression of cocaine-context-associated memory. In vivo optogenetic activation of the NAc GABAergic neurons inhibited the expression of cocaine-conditioned place preference (CPP). When tested 24 h later, these mice exhibited normal cocaine-induced CPP, indicating that the inhibitory effect on the expression of CPP was transient and reversible. Activation of the NAc GABAergic neurons also attenuated the learning of cocaine-induced reinforcement, as indicated by the results of behavioural sensitization. To explore how the cocaine-context-associated information was processed and integrated, we assessed the activity of NAc MSN-targeted brain nuclei and found that the activation of NAc GABAergic neurons during CPP expression resulted in a decrease of c-Fos+ cells in the ventral palladium. Our data suggested that the NAc GABAergic efferents inhibit the ventral palladium activity and negatively regulate the expression of motivational effects induced by cocaine-context-associated cues.

Haliucinacijų etiologijos aspektai

Hallucinations are misperceptions of things or events with one or more senses when an internal or external trigger doesn’t exist. They can be divided into visual, audioverbal, olfactorical, tactile and gustatory. Hallucinations develop due to 3 main pathophysiologicalmechanisms: psychophysiological, psychobiochemical (neurohormone dependent) and psychodynamic. Etiology of these perceptions consists of many things and is not always binned to psychiatric illnesses. These are some of the etiological factors which will be mentioned further bellow: psychosis, delirium, dementia, Charles Bonnet syndrome, Anton syndrome, seizures, migraine, Lhermitte syndrome, sleep disorders and “Alice in Wonderland” syndrome. Audioverbal hallucinations are thought to be a misperceptionof one’s own thoughts which are understood as the speech of someone else. This happens because of distorted function of frontotemporal efferents. These parts of brain are known for their sensorial region activation in the brain and also for the identification and perception of triggers that arise in a person. Furthermore, and increased activity of Wernicke’s region, right putamen, thalamus, and nucleus caudatus was also noticed. During the events of audioverbalhallucinations increased activity of Broca’s region and dorsal cortex of gyrus cinguli were noticed. Subcortical structures might also be the reason or the regulating part of the brain responsiblefor the manifestation of hallucinations which originate in the cortex. Visual hallucinations appear after triggering the primary or associational visual cortex, deafferetion mechanism, when there is some sort of damage to the periferial or central parts of nervous system responsible for visual perceptions. In addition, sleep and wakefulness cycles might be unbalanced and there can be some cognitive disorders.

Obesity and Gut’s Dysbiosis Promote Neuroinflammation, Cognitive Impairment, and Vulnerability to Alzheimer’s disease: New Directions and Therapeutic Implications

Obesity, an epidemic problem in the world is associated with several health problems. An understanding of mechanisms/factors that predispose, delay or protect individuals from obesity and its associated metabolic disturbances and cognitive impairment would be invaluable. The human gut harbors a diverse population of microbial organisms which are symbiotic and important for well being. However, studies on conventional and germ-free animals have shown that alteration in normal commensal gut microbiota and an increase in pathogenic microbiome (termed “dysbiosis”) contribute to gut inflammation, generation of LPS and pro-inflammatory cytokines, gut leakage, and systemic- and neuro-inflammation. The immune mechanisms that are necessary for gut homeostasis may become dysfunctional and lead to bowel inflammation and gut-brain axis dysfunction. These factors are potentially involved in inducing obesity as well. It may be wise to consider the wider hypothesis that gut’s dysbiosis, commencing as a response to fatty food, modulates neuro-inflammation and cognitive dysfunction. This may be enhanced by concomitant noxious factors such as consumption of NSAIDS and alcohol in the elderly. The neurotoxic mechanisms when chronic may enhance vulnerability to dementia of Alzheimer’s type (AD), and perhaps contribute to other dementias as well. Therapeutic strategies for amelioration of cognitive decline and AD are desperately needed. It is pragmatic then that immunologically mediated gut dyshomeostasis is abrogated by available options including Prebiotics, Probiotics, and Synbiotics. Decreasing gut’s dysbiosis may thus attenuate neuroinflammation and provide a potential treatment for obesity-related cognitive impairment. Further, the 'gut-brain axis' or 'brain-gut axis' (depending on whether one considers bottom-up or top-down pathway) is a bi-directional communication system, comprised of neural pathways encompassing enteric nervous system and the vagus. Vagus nerve stimulation in conjunction with α7 nAChR agonists may be an important therapeutic modality in gut pathology to upregulate parasympathetic/vagal efferent function, ameliorate gut-brain axis dysfunction and neuroinflammation, and decrease vulnerability to AD.

Evaluation of outer hair cell function and medial olivocochlear efferent system in patients with type II diabetes mellitus.

This study was designed to investigate the function of outer hair cells and medial olivocochlear efferents in type II diabetes mellitus (DM). There were 50 patients with type II DM and 51 age- and sex-matched healthy controls included in the study. Both groups were compared in terms of transient evoked otoacoustic emissions (TEOAEs), distortion product otoacoustic emissions (DPOAEs), and contralateral suppression of TEOAE. Pure tone thresholds of the patients with type II DM were significantly higher than in the controls (P < 0.05). The TEOAE amplitudes at 1 kHz and at 1.5, 2, 3, 4, and 6 kHz signal-to-noise ratio amplitudes on DPOAE testing were significantly lower in the patients than controls (P < 0.05). There was no significant difference between the type II DM and control groups regarding contralateral suppression test results of TEOAEs. Type II DM seems to impact the auditory system at the cochlear level by affecting the functions of outer hair cells, and it results in elevation of the thresholds on audiometry and a decrease in the amplitudes of otoacoustic emissions.

Abstract 18009: Chronic Spinal Cord Stimulation Preserves Cardiac Sympathetic Responses and Normalizes Noradrenergic Gene Expression in Stellate Ganglion in a Canine Heart Failure Model

Background: Myocardial infarction (MI) leads to adverse remodeling of the heart and cardiac neuronal hierarchy, both contributing to the development of heart failure (HF). Our previous work demonstrated that thoracic spinal cord stimulation (SCS) improved parasympathetic efferent function and survival in a canine model of HF induced by MI and mitral regurgitation (MR). The objective of this study was to determine whether SCS also had beneficial effects on the sympathetic element of the cardiac neuronal hierarchy. Methods: A HF model was created in 15 canines by performing sequential surgeries to generate MI and then MR. SCS electrodes and generators were implanted during the first surgery. Seven of the MI/MR animals received SCS (T1-T5; 20 Hz, 200 μsec, 90% of motor threshold) starting one week after MR induction. Generators were not activated in the sham SCS group (n=8). Canines were anesthetized for terminal experiments to record cardiac responses to stellate ganglion stimulation and then to collect the stellate ganglia for RNA analysis by Q-PCR. Results: MI/MR blunted the chronotropic and inotropic responses to stimulation of the right or left stellate ganglia. Treatment with reactive SCS significantly improved functional responses to right or left stellate stimulation. For example, right stellate stimulation evoked the following percent changes in sham SCS vs SCS: Cardiac output, 20.6±3.8 vs 66.2±9.2; LV +dp/dt, 38.3±10.2 vs 112.8±13.1; and LV -dp/dt, 13.8±8.3 vs 72.6±12.1 (P&lt;0.05 for all). RNA analysis of stellate ganglia showed that the sham SCS group had significantly increased expression of tyrosine hydroxylase and vesicular monoamine transporter 2 and decreased expression of α2 adrenergic receptor mRNA compared to the SCS treatment group and an acute control group (n=8). Conclusion: Chronic MI/MR results in impaired functional sympathetic control of cardiac function and corresponding molecular changes in the stellate ganglion reflective of excessive and adverse sympathetic activation. Therapeutic SCS ameliorates adverse changes in sympathetic function and gene expression in canines with MI/MR.

Abnormalities in Auditory Efferent Activities in Children with Selective Mutism

Two efferent feedback pathways to the auditory periphery may play a role in monitoring self-vocalization: the middle-ear acoustic reflex (MEAR) and the medial olivocochlear bundle (MOCB) reflex. Since most studies regarding the role of auditory efferent activity during self-vocalization were conducted in animals, human data are scarce. The working premise of the current study was that selective mutism (SM), a rare psychiatric disorder characterized by consistent failure to speak in specific social situations despite the ability to speak normally in other situations, may serve as a human model for studying the potential involvement of auditory efferent activity during self-vocalization. For this purpose, auditory efferent function was assessed in a group of 31 children with SM and compared to that of a group of 31 normally developing control children (mean age 8.9 and 8.8 years, respectively). All children exhibited normal hearing thresholds and type A tympanograms. MEAR and MOCB functions were evaluated by means of acoustic reflex thresholds and decay functions and the suppression of transient-evoked otoacoustic emissions, respectively. Auditory afferent function was tested by means of auditory brainstem responses (ABR). Results indicated a significantly higher proportion of children with abnormal MEAR and MOCB function in the SM group (58.6 and 38%, respectively) compared to controls (9.7 and 8%, respectively). The prevalence of abnormal MEAR and/or MOCB function was significantly higher in the SM group (71%) compared to controls (16%). Intact afferent function manifested in normal absolute and interpeak latencies of ABR components in all children. The finding of aberrant efferent auditory function in a large proportion of children with SM provides further support for the notion that MEAR and MOCB may play a significant role in the process of self-vocalization.

Epidermal Nerve Fibers Modulate Keratinocyte Growth via Neuropeptide Signaling in an Innervated Skin Model

Atopic eczema is a chronic inflammatory skin disease characterized by cutaneous nerve fiber sprouting and epidermal hyperplasia, pointing to an involvement of the peripheral nervous system in cutaneous homeostasis. However, the interaction of sensory neurons and skin cells is poorly understood. Using an innervated skin model, we investigated the influence of sensory neurons on epidermal morphogenesis. Neurons induced the proliferation of keratinocytes, resulting in an increase in the epidermal thickness. Inhibition of calcitonin gene-related peptide (CGRP), but not substance P (SP) signaling, reversed this effect. Human CGRP enhanced keratinocyte proliferation and epidermal thickness in skin models, demonstrating a key role of CGRP in modulating epidermal morphogenesis, whereas SP had only a moderate effect. Innervated skin models composed of atopic skin cells showed increased neurite outgrowth, accompanied by elevated CGRP release. As atopic keratinocytes were sensitized to CGRP owing to higher expression levels of the CGRP receptor components, receptor activity-modifying protein 1 (RAMP1) and receptor component protein (RCP), atopic innervated skin models displayed a thicker epidermis than did healthy controls. We conclude that neural CGRP controls local keratinocyte growth. Our results show that the crosstalk of the cutaneous peripheral nervous system and skin cells significantly influences epidermal morphogenesis and homeostasis in healthy and atopic skin.

Protection from Noise-Induced Hearing Loss by Kv2.2 Potassium Currents in the Central Medial Olivocochlear System

The central auditory brainstem provides an efferent projection known as the medial olivocochlear (MOC) system, which regulates the cochlear amplifier and mediates protection on exposure to loud sound. It arises from neurons of the ventral nucleus of the trapezoid body (VNTB), so control of neuronal excitability in this pathway has profound effects on hearing. The VNTB and the medial nucleus of the trapezoid body are the only sites of expression for the Kv2.2 voltage-gated potassium channel in the auditory brainstem, consistent with a specialized function of these channels. In the absence of unambiguous antagonists, we used recombinant and transgenic methods to examine how Kv2.2 contributes to MOC efferent function. Viral gene transfer of dominant-negative Kv2.2 in wild-type mice suppressed outward K(+) currents, increasing action potential (AP) half-width and reducing repetitive firing. Similarly, VNTB neurons from Kv2.2 knock-out mice (Kv2.2KO) also showed increased AP duration. Control experiments established that Kv2.2 was not expressed in the cochlea, so any changes in auditory function in the Kv2.2KO mouse must be of central origin. Further, in vivo recordings of auditory brainstem responses revealed that these Kv2.2KO mice were more susceptible to noise-induced hearing loss. We conclude that Kv2.2 regulates neuronal excitability in these brainstem nuclei by maintaining short APs and enhancing high-frequency firing. This safeguards efferent MOC firing during high-intensity sounds and is crucial in the mediation of protection after auditory overexposure.

Roux‐en‐Y gastric bypass reverses the effects of diet‐induced obesity to inhibit the responsiveness of central vagal motoneurones

Diet-induced obesity (DIO) has been shown to alter the biophysical properties and pharmacological responsiveness of vagal afferent neurones and fibres, although the effects of DIO on central vagal neurones or vagal efferent functions have never been investigated. The aims of this study were to investigate whether high-fat diet-induced DIO also affects the properties of vagal efferent motoneurones, and to investigate whether these effects were reversed following weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery. Whole-cell patch-clamp recordings were made from rat dorsal motor nucleus of the vagus (DMV) neurones in thin brainstem slices. The DMV neurones from rats exposed to high-fat diet for 12-14 weeks were less excitable, with a decreased membrane input resistance and decreased ability to fire action potentials in response to direct current pulse injection. The DMV neurones were also less responsive to superfusion with the satiety neuropeptides cholecystokinin and glucagon-like peptide 1. Roux-en-Y gastric bypass reversed all of these DIO-induced effects. Diet-induced obesity also affected the morphological properties of DMV neurones, increasing their size and dendritic arborization; RYGB did not reverse these morphological alterations. Remarkably, independent of diet, RYGB also reversed age-related changes of membrane properties and occurrence of charybdotoxin-sensitive (BK) calcium-dependent potassium current. These results demonstrate that DIO also affects the properties of central autonomic neurones by decreasing the membrane excitability and pharmacological responsiveness of central vagal motoneurones and that these changes were reversed following RYGB. In contrast, DIO-induced changes in morphological properties of DMV neurones were not reversed following gastric bypass surgery, suggesting that they may be due to diet, rather than obesity. These findings represent the first direct evidence for the plausible effect of RYGB to improve vagal neuronal health in the brain by reversing some effects of chronic high-fat diet as well as ageing. Vagovagal neurocircuits appear to remain open to modulation and adaptation throughout life, and understanding of these mechanisms may help in development of novel interventions to alleviate environmental (e.g. dietary) ailments and also alter neuronal ageing.

Maturation of the human medial efferent reflex revisited

Past work applying otoacoustic emissions to gauge maturational status of the medial olivocochlear (MOC) reflex in human newborns has produced mixed results. The present study revisits the question while considering the dual nature of the 2f(1) - f(2) distortion product otoacoustic emission (DPOAE) and expanding measures of medial efferent function. Subjects included premature and term-born neonates, 6-month-old infants and young adults. The MOC reflex was elicited with contralateral acoustic stimulation (CAS) while shifts in amplitude and phase of the DPOAE, and its distortion and reflection components, were monitored. Overall, CAS-elicited reductions in DPOAE level did not differ among age groups. For all ages, the MOC reflex was strongest at frequencies below 1.5 kHz, and the reflection component of the DPOAE was most affected, showing maximally reduced amplitude and shallower phase slope when contralateral noise was presented. Results suggest that the MOC reflex likely reaches maturation prior to full-term birth. However, prematurely born neonates show markedly more episodes of CAS-induced DPOAE level enhancement. This may be due to more intrusive component mixing in this age group or disruptions in the formation of the MOC pathway or synapse in the most premature neonates.

Functions and Imaging of Mast Cell and Neural Axis of the Gut

Close association between nerves and mast cells in the gut wall provides the microanatomic basis for functional interactions between these elements, supporting the hypothesis that a mast cell-nerve axis influences gut functions in health and disease. Advanced morphology and imaging techniques are now available to assess structural and functional relationships of the mast cell-nerve axis in human gut tissues. Morphologic techniques including co-labeling of mast cells and nerves serve to evaluate changes in their densities and anatomic proximity. Calcium (Ca(++)) and potentiometric dye imaging provide novel insights into functions such as mast cell-nerve signaling in the human gut tissues. Such imaging promises to reveal new ionic or molecular targets to normalize nerve sensitization induced by mast cell hyperactivity or mast cell sensitization by neurogenic inflammatory pathways. These targets include proteinase-activated receptor (PAR) 1 or histamine receptors. In patients, optical imaging in the gut in vivo has the potential to identify neural structures and inflammation in vivo. The latter has some risks and potential of sampling error with a single biopsy. Techniques that image nerve fibers in the retina without the need for contrast agents (optical coherence tomography and full-field optical coherence microscopy) may be applied to study submucous neural plexus. Moreover, the combination of submucosal dissection, use of a fluorescent marker, and endoscopic confocal microscopy provides detailed imaging of myenteric neurons and smooth muscle cells in the muscularis propria. Studies of motility and functional gastrointestinal disorders would be feasible without the need for full-thickness biopsy.

Renal blood flow, fractional excretion of sodium and acute kidney injury

Global renal blood flow is considered pivotal to renal function. Decreased global renal blood flow (decreased perfusion) is further considered the major mechanism of reduced glomerular filtration rate responsible for the development of acute kidney injury (AKI) in critically ill patients. Additionally, urinary biochemical tests are widely taught to allow the differential diagnosis of prerenal (functional) AKI and intrinsic [structural AKI (so-called acute tubular necrosis)]. In this review we will examine recent evidence regarding these two key clinical paradigms. Recent animal experiments and clinical studies in humans using cine-phase contrast magnetic resonance technology are not consistent with the decreased perfusion paradigm. They suggest instead that changes in the intra-renal circulation including modification in efferent arteriolar function and intra-renal shunting are much more likely to be responsible for AKI, especially in sepsis. Similarly, recent human studies indicate the urinary biochemistry has limited diagnostic or prognostic ability and is dissociated form biomarker and microscopic evidence of tubular injury. Intra-renal microcirculatory changes are likely more important than changes in global blood flow in the development of AKI. Urinary biochemistry is not a clinically useful diagnostic or prognostic tool in critically ill patients at risk of or with AKI.

The vagus nerve and the inflammatory reflex—linking immunity and metabolism

The vagus nerve has an important role in regulation of metabolic homeostasis, and efferent vagus nerve-mediated cholinergic signalling controls immune function and proinflammatory responses via the inflammatory reflex. Dysregulation of metabolism and immune function in obesity are associated with chronic inflammation, a critical step in the pathogenesis of insulin resistance and type 2 diabetes mellitus. Cholinergic mechanisms within the inflammatory reflex have, in the past 2 years, been implicated in attenuating obesity-related inflammation and metabolic complications. This knowledge has led to the exploration of novel therapeutic approaches in the treatment of obesity-related disorders.

The Neuro-Ophthalmology of Multiple Sclerosis

Multiple sclerosis (MS) is a disease marked by focal demyelinating inflammatory plaques throughout the CNS. Neuro-ophthalmologic sequelae are common in MS and may arise from the disease itself or from treatment of the disease. Both afferent and efferent functions may be affected. Despite much progress, our understanding of the pathophysiology of MS, and the efficacy of our available treatments, remain inadequate. Here, we review the chief neuro-ophthalmologic abnormalities associated with MS and discuss the emerging diagnostic and therapeutic advances that are likely to further our understanding of MS and its treatment.

Disruption of subcellular Arc/Arg 3.1 mRNA expression in striatal efferent neurons following partial monoamine loss induced by methamphetamine

The immediate-early gene Arc (activity-regulated cytoskeleton-associated protein) is provocative in the context of neuroplasticity because of its experience-dependent regulation and mRNA transport to and translation at activated synapses. Normal rats have more preproenkephalin-negative (ppe-neg; presumed striatonigral) neurons with cytoplasmic Arc mRNA than ppe-positive (ppe-pos; striatopallidal) neurons, despite equivalent numbers of these neurons showing novelty-induced transcriptional activation of Arc. Furthermore, rats with partial monoamine loss induced by methamphetamine (METH) show impaired Arc mRNA expression in both ppe-neg and ppe-pos neurons relative to normal animals following response-reversal learning. In this study, Arc expression induced by exposure to a novel environment was used to assess transcriptional activation and cytoplasmic localization of Arc mRNA in striatal efferent neuron subpopulations subsequent to METH-induced neurotoxicity. Partial monoamine depletion significantly altered Arc expression. Specifically, basal Arc expression was elevated, but novelty-induced transcriptional activation was abolished. Without novelty-induced Arc transcription, METH-pre-treated rats also had fewer neurons with cytoplasmic Arc mRNA expression, with the effect being greater for ppe-neg neurons. Thus, METH-induced neurotoxicity substantially alters striatal efferent neuron function at the level of Arc transcription, suggesting a long-term shift in basal ganglia neuroplasticity processes subsequent to METH-induced neurotoxicity. Such changes potentially underlie striatally based learning deficits associated with METH-induced neurotoxicity.

20. The peripheral nervous system and focal bony erosions in arthritis

Sympathetic and sensory nerve fibers innervate bone and joint adjacent tissue. Apart from transmitting signals to the brain (afferent function), they also play an important role in bone homeostasis (efferent function). Under certain conditions sympathetic nerve fibers are able to change their phenotype from noradrenergic to cholinergic. Anti-inflammatory effects mediated by the α7 subunit-containing nicotinic acetylcholine receptor have been described (work of Tracey’s group). We asked whether this transition might occur near focal erosions during collagen-induced arthritis (CIA) in mice or in co-culture experiments of murine sympathetic ganglia and osteoclast progenitor cells. Limbs from 30 immunized C57Bl/6J mice were collected at distinct time points covering all stages of the disease. Sections of limbs from CIA experiments as well as sympathetic ganglia from co-culture experiments were stained for tyrosine hydroxylase (TH), the key enzyme for catecholamine synthesis (noradrenergic fibers), and vesicular acetylcholine transporter (VAChT, cholinergic fibers) by immunofluorescence. In mouse joint sections, an increase in the ratio of cholinergic to adrenergic nerve fiber density at day 35 after immunization was observed. However, most of the nerve fibers were located in joint adjacent skin or muscle tissue, only few in synovium or directly in the erosion. Co-culture experiments of sympathetic ganglia and osteoclast progenitors obtained from healthy mice showed increased cholinergic activity as compared to experiments with cells from mice with CIA. Taken together, these results suggest that cholinergic innervation in the joint region is upregulated under inflammatory conditions and that catecholaminergic nerve fibers are influenced by osteoclast progenitor cells.

27 AFFERENT AND EFFERENT MECHANISMS ASSOCIATED WITH NEUROMODULATION OF THE BLADDER MICTURITION REFLEX IN THE RAT

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Basic Research I1 Apr 201227 AFFERENT AND EFFERENT MECHANISMS ASSOCIATED WITH NEUROMODULATION OF THE BLADDER MICTURITION REFLEX IN THE RAT Xin Su, Angela M. Nickles, and Dwight E. Nelson Xin SuXin Su Minneapolis, MN More articles by this author , Angela M. NicklesAngela M. Nickles Minneapolis, MN More articles by this author , and Dwight E. NelsonDwight E. Nelson Minneapolis, MN More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.070AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Spinal nerve stimulation (SNS, 10Hz) suppresses bladder micturition reflex contraction (BRC), either eliminating BRC or reducing the contraction frequency in a current dependent manner. Here we evaluate whether this suppression may be associated with increased bladder capacity (e.g. through afferent functions) or suppression of detrusor contractions (efferent functions). METHODS In female rats (urethane, i.p. 1.2g/kg), a monopolar electrode was placed under L6 spinal nerves. A bladder cannula was placed via the urethra for saline infusion and intravesical pressure recording. Saline infusion induced BRC. If SNS completely abolished BRC, we determined whether additional infusion could overcome bladder inhibition. RESULTS SNS attenuated the frequency but not amplitude of BRC. Two x motor threshold (2*Tmot), 3*Tmot, 4*Tmot and 6*Tmot significantly (p<0.05, vs. control, n=23) decreased the frequency of BRC during stimulation to 65.56 ± 17% (n=9), 10.64 ± 8% (n=8), 6.25 ± 6% (n=7), and 0% of controls (n=7), respectively. High intensity SNS abolished BRC. Additional saline re-established the BRC with a similar frequency but lower amplitude despite the presence of electrical stimulation (Fig 1A). During this time SNS produced a significant inhibition of the amplitude but not frequency of BRC (n=5, p<0.05, Fig 1B/C). CONCLUSIONS Bladder inhibitory effects of SNS are a consequence of an increased bladder capacity since SNS attenuates the frequency but not amplitude of BRC and the ‘shutdown' of the BRC can be re-established by additional saline infusion. Consistent with this, we previously reported that SNS increases voiding threshold and inter-contraction interval but not voiding pressure (Su et al., IPPS, 2011). However since SNS suppresses the amplitude of the re-established BRC, SNS may also directly depress detrusor contractility. These data suggest that SNS neuromodulation may act through two distinct stimulation modes. Lower stimulation intensities appear to be mediated through the afferent limb of the neural circuit and increase the bladder capacity. Higher intensities may additionally act through efferent neural pathways and attenuate amplitude of detrusor contractions as well as by increasing bladder capacity. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e10-e11 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Xin Su Minneapolis, MN More articles by this author Angela M. Nickles Minneapolis, MN More articles by this author Dwight E. Nelson Minneapolis, MN More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...