Serotoninergic Fibers Research Articles

Current state of knowledge on the centrifugal visual system (including the pinealo-to-retinal connection) in mammals and its hypothesized role in circadian rhythms

The ubiquity of circadian rhythms in living organisms has generally been accepted by researchers over the last century. Indeed, morphology and molecular biology of the circadian clock were described during the last fifty years. This main biological clock is located in the suprachiasmatic nucleus of the hypothalamus. This nucleus is connected with the retina by the retinohypothalamic tract. This way, light regulates the functioning of the biological clock and biological rhythms such as the sleep-wake cycle and other cyclic functions by releasing melatonin from the pineal body (PB) into the general circulation. Melatonin reaches the retina via the bloodstream as humoral feedback. More than a hundred years ago a reverse neuronal connection between the central nervous system and the retina was hypothesized. This so-called centrifugal visual or retinopetal system has been explored in detail in birds, but less information is available in mammals. In this work, the morphology and physiology of mammalian centrifugal visual pathways are reviewed. It is generally accepted that the centrifugal (retinopetal) fibers terminate mainly on the amacrine cells of the retina. Histaminergic fibers terminate on dopaminergic amacrine cells. Serotoninergic synapses were identified on ganglion cells. In addition, serotoninergic fibers were also associated with photoreceptor terminals. Luteinizing hormone releasing hormone fibers have been observed in birds, but not in mammalian retinas. In summary, based on the data available in the literature, it seems that the retinopetal system has a mandatory role in lower vertebrates, but a modulatory role in mammals. There is currently no adequate way to eliminate the centrifugal visual system that would better explain its true function.

Anatomical characterisation of three different psychosurgical targets in the subthalamic area: from the basal ganglia to the limbic system.

Effective neural stimulation for the treatment of severe psychiatric disorders needs accurate characterisation of surgical targets. This is especially true for the medial subthalamic region (MSR) which contains three targets: the anteromedial STN for obsessive compulsive disorder (OCD), the medial forebrain bundle (MFB) for depression and OCD, and the "Sano triangle" for pathological aggressiveness. Blocks containing the subthalamic area were obtained from two human brains. After obtaining 11.7-Tesla MRI, blocks were cut in regular sections for immunohistochemistry. Fluorescent in situ hybridisation was performed on the macaque MSR. Electron microscopic observation for synaptic specialisation was performed on human and macaque subthalamic fresh samples. Images of human brain sections were reconstructed in a cryoblock which was registered on the MRI and histological slices were then registered. The STN contains glutamatergic and fewer GABAergic neurons and has no strict boundary with the adjacent MSR. The anteromedial STN has abundant dopaminergic and serotoninergic innervation with very sparse dopaminergic neurons. The MFB is composed of dense anterior dopaminergic and posterior serotoninergic fibres, and fewer cholinergic and glutamatergic fibres. Medially, the Sano triangle presumably contains orexinergic terminals from the hypothalamus, and neurons with strong nuclear oestrogen receptor-alpha staining with a decreased anteroposterior and mediolateral gradient of staining. These findings provide new insight regarding MSR cells and their fibre specialisation, forming a transition zone between the basal ganglia and the limbic systems. Our 3D reconstruction enabled us to visualize the main histological features of the three targets which should enable better targeting and understanding of neuromodulatory stimulation results in severe psychiatric conditions.

Neuropathic pain: Mechanisms and therapeutic strategies.

The physiopathology and neurotransmission of pain are of an owe inspiring complexity. Our ability to satisfactorily suppress neuropathic or other forms of chronic pain is limited. The number of pharmacodynamically distinct and clinically available medications is low and the successes achieved modest. Pain Medicine practitioners are confronted with the ethical dichotomy imposed by Hippocrates: On one hand the mandate of primum non nocere, on the other hand, the promise of heavenly joys if successful divinum est opus sedare dolorem. We briefly summarize the concepts associated with nociceptive pain from nociceptive input (afferents from periphery), modulatory output [descending noradrenergic (NE) and serotoninergic (5-HT) fibers] to local control. The local control is comprised of the "inflammatory soup" at the site of pain origin and synaptic relay stations, with an ATP-rich environment promoting inflammation and nociception while an adenosine-rich environment having the opposite effect. Subsequently, we address the transition from nociceptor pain to neuropathic pain (independent of nociceptor activation) and the process of sensitization and pain chronification (transient pain progressing into persistent pain). Having sketched a model of pain perception and processing we attempt to identify the sites and modes of action of clinically available drugs used in chronic pain treatment, focusing on adjuvant (co-analgesic) medication.

Forced Remyelination Promotes Axon Regeneration in a Rat Model of Spinal Cord Injury

Spinal cord injuries result in the loss of motor and sensory functions controlled by neurons located at the site of the lesion and below. We hypothesized that experimentally enhanced remyelination supports axon preservation and/or growth in the total spinal cord transection in rats. Multifocal demyelination was induced by injection of ethidium bromide (EB), either at the time of transection or twice during transection and at 5 days post-injury. We demonstrated that the number of oligodendrocyte progenitor cells (OPCs) significantly increased 14 days after demyelination. Most OPCs differentiated into mature oligodendrocytes by 60-90 dpi in double-EB-injected rats; however, most axons were remyelinated by Schwann cells. A significant number of axons passed the injury epicenter and entered the distant segments of the spinal cord in the double-EB-injected rats. Moreover, some serotoninergic fibers, not detected in control animals, grew caudally through the injury site. Behavioral tests performed at 60-90 dpi revealed significant improvement in locomotor function recovery in double-EB-injected rats, which was impaired by the blockade of serotonin receptors, confirming the important role of restored serotonergic fibers in functional recovery. Our findings indicate that enhanced remyelination per se, without substantial inhibition of glial scar formation, is an important component of spinal cord injury regeneration.

Anxiety and Gene Expression Enhancement in Mice Exposed to Glyphosate-Based Herbicide.

Growing evidence demonstrates that serotonin (5-HT) depletion increases activity in the amygdala and medial prefrontal cortex (mPFC), ultimately leading to anxiety behavior. Previously, we showed that glyphosate-based herbicides (GBHs) increased anxiety levels and reduced the number of serotoninergic fibers within the mPFCs and amygdalas of exposed mice. However, the impact of this 5-HT depletion following GBH exposure on neuronal activity in these structures is still unknown. In this study, we investigated the effects of GBH on immediate early gene (IEG) activation within the mPFCs and amygdalas of treated mice from juvenile age to adulthood and its subsequent effects on anxiety levels. Mice were treated for subchronic (6 weeks) and chronic (12 weeks) periods with 250 or 500 mg/kg/day of GBH and subjected to behavioral testing using the open field and elevated plus maze paradigms. Then, we analyzed the expression levels of c-Fos and pCREB and established the molecular proxies of neuronal activation within the mPFC and the amygdala. Our data revealed that repeated exposure to GBH triggers anxiogenic behavior in exposed mice. Confocal microscopy investigations into the prelimbic/infralimbic regions of the mPFC and in basolateral/central nuclei of the amygdala disclosed that the behavioral alterations are paralleled by a robust increase in the density and labelling intensity of c-Fos- and pCREB-positive cells. Taken together, these data show that mice exposed to GBH display the hyperactivation of the mPFC–amygdala areas, suggesting that this is a potential mechanism underlying the anxiety-like phenotype.

Disruption of brainstem monoaminergic fibre tracts in multiple sclerosis as a putative mechanism for cognitive fatigue: a fixel-based analysis

In multiple sclerosis (MS), monoaminergic systems are altered as a result of both inflammation-dependent reduced synthesis and direct structural damage. Aberrant monoaminergic neurotransmission is increasingly considered a major contributor to fatigue pathophysiology. In this study, we aimed to compare the integrity of the monoaminergic white matter fibre tracts projecting from brainstem nuclei in a group of patients with MS (n = 68) and healthy controls (n = 34), and to investigate its association with fatigue. Fibre tracts integrity was assessed with the novel fixel-based analysis that simultaneously estimates axonal density, by means of ‘fibre density’, and white matter atrophy, by means of fibre ‘cross section’. We focused on ventral tegmental area, locus coeruleus, and raphe nuclei as the main source of dopaminergic, noradrenergic, and serotoninergic fibres within the brainstem, respectively. Fourteen tracts of interest projecting from these brainstem nuclei were reconstructed using diffusion tractography, and compared by means of the product of fibre-density and cross-section (FDC). Finally, correlations of monoaminergic axonal damage with the modified fatigue impact scale scores were evaluated in MS. Fixel-based analysis revealed significant axonal damage – as measured by FDC reduction – within selective monoaminergic fibre-tracts projecting from brainstem nuclei in MS patients, in comparison to healthy controls; particularly within the dopaminergic-mesolimbic pathway, the noradrenergic-projections to prefrontal cortex, and serotoninergic-projections to cerebellum. Moreover, we observed significant correlations between severity of cognitive fatigue and axonal damage within the mesocorticolimbic tracts projecting from ventral tegmental area, as well as within the locus coeruleus projections to prefrontal cortex, suggesting a potential contribution of dopaminergic and noradrenergic pathways to central fatigue in MS. Our findings support the hypothesis that axonal damage along monoaminergic pathways contributes to the reduction/dysfunction of monoamines in MS and add new information on the mechanisms by which monoaminergic systems contribute to MS pathogenesis and fatigue. This supports the need for further research into monoamines as therapeutic targets aiming to combat and alleviate fatigue in MS.

Serotonin Expression in the Song Circuitry of Adult Male Zebra Finches

Serotonin is an important neurotransmitter of the brain, but its role in song control remains to be fully demonstrated. Using male zebra finches (Taeniopygia guttata) that have song learning and production capabilities, we analysed the serotonin expression levels in the song nuclei and adjacent areas (peri-song nuclei) using immunohistochemistry. Key song nuclei were identified using combinations of Hoechst, choline acetyltransferase, and a neurofilament (NN18) marker in reference to the ZEBrA atlas. Mean serotonin expression was highest in interfacial nucleus (Nif) and lower in the other song nuclei in the following order (in order of highest first): interfacial nucleus (Nif) > Area X > dorsomedial part of the intercollicular nucelus (DM) > robust nucleus of the archistriatum (RA) > lateral magnocellular nucleus of the anterior neostriatum (LMAN) > ventral respiratory group (VRG) > dorsolateral nucleus of the medial thalamus (DLM) > the nucleus HVC (proper name) > tracheosyringeal motor nucleus (nXIIts). However, the mean serotonin expression (in order of highest first) in the peri-song nuclei regions was: peri-DM > peri-nXIIts > supra-peri-HVC > peri-RA > peri-DLM > peri-Area X > infra-peri-HVC > peri-VRG > peri-LMAN > peri-Nif. Interestingly, serotoninergic fibers immunostained for serotonin or the serotonin transporter can be found as a basket-like peri-neuronal structure surrounding cholinergic cell bodies, and appear to form contacts onto dopaminergic neurones. In summary, serotonin fibers are present at discrete song nuclei, and peri-song nuclei regions, which suggest serotonin may have a direct and/or modulatory role in song control.

Concomitant in Vivo Voltammetric and Electrophysiological Analysis Indicate that Nociceptin/Orphanin FQ Affects Dopamine and then Serotonin Activities in Brain Substancia Nigra.

Nociceptin/orphanin-FQ (NOCI) together with its receptor NOP are widely expressed in cortical and subcortical motor areas and it is known that NOCI acts as an anxiolytic attenuating the behavioral inhibition of animals acutely exposed to stressful/anxiogenic conditions. Influence of NOCI upon the dopaminergic system has been observed in the ventral tegmental area and in the nucleus accumbens as well as an inhibitory action of NOCI is described upon serotoninergic mechanisms at cells and terminal levels. In particular, it is known that serotoninergic fibers from the raphe system project to the substancia nigra (SN) and that this modulation is behaviourally relevant. In the present work, the effect of exogenous NOCI injected into the SN upon DA and 5-HT levels have been analyzed by means of differential pulse voltammetry and nafion-carbon fiber microelectrodes. Electrophysiological monitoring of multicell activity was concomitantly performed with the same microsensor. It appeared that both levels of these biogenic amines were specularly altered, with possibly a driving influence of the DA activity upon the serotoninergic function(s).

Motor Recovery after Chronic Spinal Cord Transection in Rats: A Proof-of-Concept Study Evaluating a Combined Strategy.

The chronic phase of Spinal Cord (SC) injury is characterized by the presence of a hostile microenvironment that causes low activity and a progressive decline in neurological function; this phase is non-compatible with regeneration. Several treatment strategies have been investigated in chronic SC injury with no satisfactory results. OBJECTIVE- In this proof-of-concept study, we designed a combination therapy (Comb Tx) consisting of surgical glial scar removal plus scar inhibition, accompanied with implantation of mesenchymal stem cells (MSC), and immunization with neural-derived peptides (INDP). This study was divided into three subsets, all in which Sprague Dawley rats were subjected to a complete SC transection. Sixty days after injury, animals were randomly allocated into two groups for therapeutic intervention: control group and animals receiving the Comb-Tx. Sixty-three days after treatment we carried out experiments analyzing motor recovery, presence of somatosensory evoked potentials, neural regeneration-related genes, and histological evaluation of serotoninergic fibers. Comb-Tx induced a significant locomotor and electrophysiological recovery. An increase in the expression of regeneration-associated genes and the percentage of 5-HT+ fibers was noted at the caudal stump of the SC of animals receiving the Comb-Tx. There was a significant correlation of locomotor recovery with positive electrophysiological activity, expression of GAP43, and percentage of 5-HT+ fibers. Comb-Tx promotes motor and electrophysiological recovery in the chronic phase of SC injury subsequent to a complete transection. Likewise, it is capable of inducing the permissive microenvironment to promote axonal regeneration.

Supraspinal projections: origins and their terminals in the mouse spinal cord

Event Abstract Back to Event Supraspinal projections: origins and their terminals in the mouse spinal cord Huazheng Liang1, 2*, Emma Schofield1 and George Paxinos1, 2 1 Neuroscience Research Australia, Brain Structure and Function Group, Australia 2 The University of New South Wales, School of Medical Sciences, Australia The present study explored the origins of supraspinal projections in the mouse by injecting FG into the cervical cord. The majority of FG labelled cell groups were similar to those found in large mammals. The precuneiform and the epirubrospinal nuclei were found to project to the spinal cord for the first time. Next, we investigated the vestibulospinal projections arising from the lateral vestibular nucleus (LVe). FG labeled neurons at the caudal level of LVe formed two clusters. The boundary between LVe and MVe was tentatively defined. BDA injections into LVe led to the revelation of vestibulospinal fibers mainly in laminae 6-9 with an ipsilateral predominance. In the lumbar and sacral cord, collaterals extended from the ipsilateral to the contralateral side and mainly terminated in laminae 6-8. Next, termination pattern of raphespinal fibers arising from the hindbrain raphe nuclei was studied. These fibers terminate in both the dorsal and ventral horns in addition to lamina 10. There was a shift of fibers in the ventral horn towards the dorsal and lateral part of the gray matter. Fibers from the adjacent gigantocellular reticular nuclei show similar termination pattern as those from the raphe nuclei with slight difference. CLARITY experiments revealed that serotoninergic fibers are present in all laminae and form bundles regularly in a short distance along the rostrocaudal axis in the medial part of the ventral horn and extend towards the lateral motor neuron column. Keywords: Dorsal horn, ventral horn, Supraspinal projection, raphespinal fibers, vestibulospinal fibers Conference: 14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016. Presentation Type: YIC06: Young Investigator Colloquium 6 Topic: 14th Meeting of the Asian-Pacific Society for Neurochemistry Citation: Liang H, Schofield E and Paxinos G (2016). Supraspinal projections: origins and their terminals in the mouse spinal cord. Conference Abstract: 14th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00075 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Aug 2016; Published Online: 11 Aug 2016. * Correspondence: Dr. Huazheng Liang, Neuroscience Research Australia, Brain Structure and Function Group, Randwick, NSW, Australia, h.liang@neura.edu.au Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Huazheng Liang Emma Schofield George Paxinos Google Huazheng Liang Emma Schofield George Paxinos Google Scholar Huazheng Liang Emma Schofield George Paxinos PubMed Huazheng Liang Emma Schofield George Paxinos Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Evidences of Existence of Serotoninergic Nerves, Enhancing Duodenal Motility

The review is devoted to the mechanism of duodenal motility activation caused by sympathetic nerves. The authors havefound that stimulation of the sympathetic trunk in the thoracic cavity in dogs in most cases provide not inhibitory but excitatory motor responses of the duodenum. Excitatory effects were eliminated during 5HT-receptors blockade by promedol and lysergol. Analysis ofpublications showed that sympathetic trunk contains serotoninergic fibers, providing excitatory motor responses of the duodenum to electrical nerve stimulation. According to histochemical and physiological studies, amount of serotonergic fibers in the sympathetic trunk is several times more than the adrenergic. This means that the body has sertoninergic nerves. Serotoninergic nerve as well as the sympathetic is a collective notion. There are: sympathetic trunks, their ramifications and branches that innervate the internal organs. Since promedol blocks serotonergic nerves, this is plausible cause of constipation in patients after surgical treatment along with the application of this drug.

Serotonin increases synaptic activity in olfactory bulb glomeruli.

Serotoninergic fibers densely innervate olfactory bulb glomeruli, the first sites of synaptic integration in the olfactory system. Acting through 5HT2A receptors, serotonin (5HT) directly excites external tufted cells (ETCs), key excitatory glomerular neurons, and depolarizes some mitral cells (MCs), the olfactory bulb's main output neurons. We further investigated 5HT action on MCs and determined its effects on the two major classes of glomerular interneurons: GABAergic/dopaminergic short axon cells (SACs) and GABAergic periglomerular cells (PGCs). In SACs, 5HT evoked a depolarizing current mediated by 5HT2C receptors but did not significantly impact spike rate. 5HT had no measurable direct effect in PGCs. Serotonin increased spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) in PGCs and SACs. Increased sEPSCs were mediated by 5HT2A receptors, suggesting that they are primarily due to enhanced excitatory drive from ETCs. Increased sIPSCs resulted from elevated excitatory drive onto GABAergic interneurons and augmented GABA release from SACs. Serotonin-mediated GABA release from SACs was action potential independent and significantly increased miniature IPSC frequency in glomerular neurons. When focally applied to a glomerulus, 5HT increased MC spontaneous firing greater than twofold but did not increase olfactory nerve-evoked responses. Taken together, 5HT modulates glomerular network activity in several ways: 1) it increases ETC-mediated feed-forward excitation onto MCs, SACs, and PGCs; 2) it increases inhibition of glomerular interneurons; 3) it directly triggers action potential-independent GABA release from SACs; and 4) these network actions increase spontaneous MC firing without enhancing responses to suprathreshold sensory input. This may enhance MC sensitivity while maintaining dynamic range.

Distribution of raphespinal fibers in the mouse spinal cord.

BackgroundSerotonergic raphespinal neurons and their fibers have been mapped in large mammals, but the non-serotonergic ones have not been studied, especially in the mouse. The present study aimed to investigate the termination pattern of fibers arising from the hindbrain raphe and reticular nuclei which also have serotonergic neurons by injecting the anterograde tracer BDA into them.ResultsWe found that raphespinal fibers terminate in both the dorsal and ventral horns in addition to lamina 10. There is a shift of the fibers in the ventral horn towards the dorsal and lateral part of the gray matter. Considerable variation in the termination pattern also exists between raphe nuclei with raphe magnus having more fibers terminating in the dorsal horn. Fibers from the adjacent gigantocellular reticular nucleus show similar termination pattern as those from the raphe nuclei with slight difference. Immunofluorescence staining showed that raphespinal fibers were heterogeneous and serotoninergic fibers were present in all laminae but mainly in laminae 1, 2, medial lamina 8, laminae 9 and 10. Surprisingly, immunofluorescence staining on clarified spinal cord tissue revealed that serotoninergic fibers formed bundles regularly in a short distance along the rostrocaudal axis in the medial part of the ventral horn and they extended towards the lateral motor neuron column area.ConclusionSerotonergic and non-serotonergic fibers arising from the hindbrain raphe and reticular nuclei had similar termination pattern in the mouse spinal cord with subtle difference. The present study provides anatomical foundation for the multiple roles raphe and adjacent reticular nuclei play.Electronic supplementary materialThe online version of this article (doi:10.1186/s12990-015-0046-x) contains supplementary material, which is available to authorized users.

Serotonin regulates contractile activity of the uterus in non-pregnant rabbits

Serotonin (5-HT) can stimulate the cholinergic system of the uterus by indirect actions on the modulation of reflexes and a direct action on smooth muscles. We investigated the role of 5-HT in the regulation of the cholinergic activity in the uterine parts of non-pregnant rabbits. The right vagus or pelvic nerve and the left sympathetic trunk were stimulated by an electrical field, and the uterine contractile activity was evaluated by measuring the amplitude and frequency of slow wave electromyogram (EMG), with the surface of microelectrodes applied to the uterus bottom, body, and cervix, respectively. Double stimulation of the vagus or pelvic nerve and the sympathetic trunk increased the frequency and the amplitude of the slow wave EMG in all the uterine parts. Furthermore, the administration of exogenous 5-HT increased the vagus or pelvic induced EMG activity in all parts of the uterus. Overall our results demonstrate that 5-HT enhances the vagus contractile activity with a magnitude of the effect decreasing from the bottom to the cervix, whereas 5-HT enhances the pelvic nerve contractile functions with a magnitude of the response increasing from the bottom to the cervix. The administration of droperidol, a 5-HT3 and 4 receptor inhibitor, and spiperone, a 5-HT2 receptor antagonist, inhibited the effect of the serotoninergic fibers of the sympathetic trunk to increase the vagus and pelvic nerve EMG activity. These data suggest that 5-HT stimulation of the parasympathetic nerves results in the induction of uterine contraction via the activation of 5-HT2, 3, and 4 receptor subfamilies.

Neuronal localization of the 5-HT2 receptor family in the amygdaloid complex.

The amygdaloid complex (or amygdala), a heterogeneous structure located in the medial portion of the temporal lobe, is composed of deep, superficial, and “remaining” nuclei. This structure is involved in the generation of emotional behavior, in the formation of emotional memories and in the modulation of the consolidation of explicit memories for emotionally arousing events. The serotoninergic fibers originating in the dorsal and medial raphe nuclei are critically involved in amygdalar functions. Serotonin (5-hydroxytryptamine, 5-HT) regulates amygdalar activity through the activation of the 5-HT2 receptor family, which includes three receptor subtypes: 5-HT2A, 5-HT2B, and 5-HT2C. The distribution and the functional activity of the 5-HT2 receptor family has been studied more extensively than that of the 5-HT2A receptor subtypes, especially in the deep nuclei. In these nuclei, the 5-HT2A receptor is expressed on both pyramidal and non-pyramidal neurons, and could play a critical role in the formation of emotional memories. However, the exact role of the 5-HT2A receptor subtypes, as well as that of the 5-HT2B and 5-HT2C receptor subtypes, in the modulation of the amygdalar microcircuits requires additional study. The present review reports data concerning the distribution and the functional roles of the 5-HT2 receptor family in the amygdala.

Role of Serotonin Receptors in Regulation of Contractile Activity of Urinary Bladder in Rabbits

To evaluate the role of different serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes on urinary bladder contraction, pharmacologic analysis of electromotor activity (EMA) variation was performed using a rabbit bladder model. Measurements of EMA were performed on 3 urinary bladder portions: top, body, and trigone. The experiments were performed on 24 Shinshilla rabbits of both sexes, 5-6 months old, and weighing 2.5-4.0 kg. The bladder was isolated. Noninvasive electrodes were superimposed on the surface of the top, body, and trigone of the bladder. Contact between the electrode tips and the bladder surface was achieved. The bladder EMA was measured using bipolar silver electrodes for extracellular recordings. The stimulation of the serotoninergic fibers and parasympathetic nerve resulted in increased bladder EMA frequency and amplitude (72% and 25%, respectively). The increase in bladder EMA was prevented by administration of selective inhibitors of serotonin receptor subtypes such as droperidol, spiperone, and sumatriptan. Exogenous serotonin administered to the rabbits after vagus nerve excitation increased the typical EMA of the bladder body smooth muscle. The serotoninergic system has been widely implicated in the control of urinary bladder function. In the present study, we have demonstrated that preganglionic fibers and ganglionic serotoninergic neurons, expressing the 5-HT3 and 5-HT4 receptors, and the effector smooth muscle cells, expressing 5-HT1 and 5-HT2 receptors, are actively involved in the regulation of the bladder contractile activity in rabbits.

Early Endogenous Activation of CB1 and CB2 Receptors after Spinal Cord Injury Is a Protective Response Involved in Spontaneous Recovery

Spinal cord injury (SCI) induces a cascade of processes that may further expand the damage (secondary injury) or, alternatively, may be part of a safeguard response. Here we show that after a moderate-severe contusive SCI in rats there is a significant and very early increase in the spinal cord content of the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (anandamide, AEA). Since 2-AG and AEA act through CB1 and CB2 cannabinoid receptors, we administered at 20 minutes after lesion a single injection of their respective antagonists AM281 and AM630 alone or in combination to block the effects of this early endocannabinoid accumulation. We observed that AM281, AM630 or AM281 plus AM630 administration impairs the spontaneous motor recovery of rats according to the Basso-Beattie-Bresnahan (BBB) locomotor scale. However, blockade of CB1, CB2 or both receptors produced different effects at the histopathological level. Thus, AM630 administration results at 90 days after lesion in increased MHC-II expression by spinal cord microglia/monocytes and reduced number of serotoninergic fibres in lumbar spinal cord (below the lesion). AM281 exerted the same effects but also increased oedema volume estimated by MRI. Co-administration of AM281 and AM630 produced the effects observed with the administration of either AM281 or AM630 and also reduced white matter and myelin preservation and enhanced microgliosis in the epicentre. Overall, our results suggest that the endocannabinoids acting through CB1 and CB2 receptors are part of an early neuroprotective response triggered after SCI that is involved in the spontaneous recovery after an incomplete lesion.

Identification of Minimal Neuronal Networks Involved in Flexor-Extensor Alternation in the Mammalian Spinal Cord

Neural networks in the spinal cord control two basic features of locomotor movements: rhythm generation and pattern generation. Rhythm generation is generally considered to be dependent on glutamatergic excitatory neurons. Pattern generation involves neural circuits controlling left-right alternation, which has been described in great detail, and flexor-extensor alternation, which remains poorly understood. Here, we use a mouse model in which glutamatergic neurotransmission has been ablated in the locomotor region of the spinal cord. The isolated invitro spinal cord from these mice produces locomotor-like activity-when stimulated with neuroactive substances-with prominent flexor-extensor alternation. Under these conditions, unlike in control mice, networks of inhibitory interneurons generate the rhythmic activity. In the absence of glutamatergic synaptic transmission, the flexor-extensor alternation appears to be generated by Ia inhibitory interneurons, which mediate reciprocal inhibition from muscle proprioceptors to antagonist motor neurons. Our study defines a minimal inhibitory network that is needed to produce flexor-extensor alternation during locomotion.

Immunohistochemical evaluation of the effect of lead exposure on subcommissural organ innervation and secretion in Shaw's Jird ( Meriones shawi)

The secretory activity of subcommissural organ cells is controlled by various extrinsic and intrinsic factors. Lead has been recognised as a neurotoxic heavy metal, since it induces morphological and functional abnormalities in the brain. In this work, we examined the effect of lead exposure on the subcommissural organ (SCO), a brain gland known by its secretion of Reissner's fiber (RF) in cerebro-spinal fluid. Glycoprotein secretion and serotonin (5HT) innervation of the SCO was examined after acute and chronic lead exposures in the sub-desert rodent Meriones shawi. Lead exposures were achieved by, respectively, intra-peritoneal injection of 25 mg/kg body weight of lead acetate for 3 days and 0.5% of lead acetate in the drinking water over 4 months until adult age. 5HT and RF immunolabeling in the SCO revealed several serotoninergic fibers reaching the SCO and abundant secretory material. An increase in both 5HT innervation and secretory material of the SCO was recorded after both acute and chronic lead exposure. These results show that lead exposure affects the serotonergic innervation of the SCO. Moreover, the enhancement of SCO secretion suggests a role of this gland in neuroprotection and lead detoxification of the brain in Meriones shawi.

A new model to study compensatory mechanisms in MPTP-treated monkeys exhibiting recovery

The cardinal symptoms in Parkinson's disease (PD), akinesia, rigidity and tremor, are only observed when the striatal level of dopamine is decreased by 60-80%. During the preclinical phase of PD, compensatory mechanisms are probably involved in delaying the appearance of motor symptoms. In a MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkey model of PD, a spontaneous recovery has been reported after initial intoxication suggesting that compensatory mechanisms are activated in this model as well. Assuming that mechanisms are similar in these phenomena, the study of recovery in monkeys following MPTP intoxication may enable identification of compensatory mechanisms involved in the preclinical phase of PD. In order to maximize the temporal similarity between PD and the MPTP model, we assessed a new progressive monkey model in which spontaneous recovery is expressed systematically and to characterize it based on (1) its behavioural features, and (2) the presence of compensatory mechanisms revealed by an immunohistological approach comparing dopaminergic and serotoninergic innervation between monkeys either exhibiting behavioural recovery or stable motor symptoms. This immunohistological study focused on the substantia nigra, striatum and pallidum, and their anatomical and functional subdivisions: sensorimotor, associative and limbic. The behavioural analysis revealed that with progressive MPTP intoxication motor symptoms were initially expressed in all monkeys. Observable recovery from these symptoms occurred in all monkeys (7/7) within 3-5 weeks after the last MPTP injection, and most exhibited a full recovery. In contrast, acute intoxication induced stable motor symptoms. Despite this obvious behavioural difference, immunohistological methods revealed that the loss of dopaminergic cell bodies in substantia nigra was substantial and similar in both MPTP-treated groups. However, quantification of fibres revealed that recovered monkeys displayed more dopaminergic and serotoninergic fibres than those with stable motor symptoms in sensorimotor and associative territories of striatum and more dopaminergic fibres in internal pallidum. This study provides a new model of PD where all monkeys expressed functional recovery from motor symptoms despite a large dopaminergic neuronal loss. The immunohistological results suggest that both dopamine and serotonin could be implicated in the compensatory mechanisms.