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PubMed2004

Visceral hypersensitivity in functional disorders of the upper gastrointestinal tract.

Visceral hypersensitivity is now recognised as a major pathophysiological mechanism in functional gastrointestinal disorders of the upper gastrointestinal tract. In patients with non-cardiac chest pain and functional dyspepsia, a high prevalence of visceral hypersensitivity has been indeed observed. In these patients, luminal physiological stimuli can be perceived as unpleasant or even painful. Although the fine mechanisms underlying such "aberrant perceptions" are yet not fully clarified, it is thought that an altered activation of the gut-wall receptors, an altered conduction of sensory inputs at the level of neural pathways, or an impaired processing of the sensations at the level of brain, may occur along the brain-gut axis. So far, drugs able to reduce hypersensitivity, that target each of the constituents of the stimuli-perception chain, have the therapeutic potential to reduce visceral hypersensitivity and, thus, to improve the symptoms. In this context, the availability of new agonists/antagonists to neurotransmitters offers a new exciting tool for the treatment of functional disorders of the upper gastrointestinal tract.

Chest Pain↗

PubMed2005

Selective loss of NGF-sensitive neurons following experimental colitis.

Nerve growth factor (NGF) enhances neuronal survival during injury to the mature central and peripheral nervous systems, but its potential as a neuroprotective factor in the enteric nervous system (ENS) has not been examined. We used the trinitrobenzene sulfonic acid (TNBS)-induced model of colitis to examine if NGF-sensitive neurons were selectively spared from inflammation-induced cell loss. Immunocytochemistry of whole mounts of the rat colon showed that total myenteric neuronal number decreased by 32.9% +/- 1.4% by 35 days after inflammation. At this time, the proportion of neurons expressing both the p75 and trkA receptor decreased to 38.4% from a control value of 62.0%. The distribution of expression of neural phenotypes among the NGF receptor-expressing population was differentially affected by inflammation, with selective decrease among cholinergic excitatory neurons and calbindin-expressing neurons, and a trend to increase among inhibitory nitrergic neurons. This is evidence of a novel mechanism whereby intestinal inflammation can give rise to a permanent imbalance between excitatory and inhibitory neural pathways, thus tending to compromise intestinal function.

Animals↗

PubMed2005

Transient otoacoustic emissions in the detection of olivocochlear bundle maturation.

OBJECTIVE: The medial olivocochlear bundle, forms a neural pathway connecting the superior olivary complex to the outer hair cells of mainly the contralateral cochlea. Although the biological significance of the bundle remains ambiguous, it is clear that activation of medial olivocochlear fibers alters cochlear output and this can be experimentally evident through a series of changes on otoacoustic emissions, called otoacoustic emission suppression. The aim of this study is to observe the maturation of the medial olivocochlear bundle by measuring the suppression effects on transient otoacoustic emissions. METHODS: The study population consisted of 27 premature babies (53 ears) from the P&A Kyriakou Neonatal Intensive Care Unit (conceptional age: 31-36 weeks) and 43 fullterm babies (61 ears) (conceptional age: 37-42 weeks) from the same unit. The ILO-92 system is used to deliver both the linear clicks to the ear examined (producing the emissions) and the white noise to the contralateral ear. The mode used is based on the alternating on and off presence of the white noise in the contralateral ear. RESULTS: 12/53 (22%) ears of preterm babies presented suppression > or =1 dB. 32/61 (52.4%) ears of fullterm babies presented suppression > or =1 dB. The mean suppression for the ears of premature infants was 0.52 dB, (+/-0.1 S.E.M.). The mean suppression for the ears of fullterm infants was 0.90 dB, (+/-0.09 S.E.M.). At the second half of the time window, suppression of fullterms rises above 1 dB (a pattern similar to that of adults), whereas it remains below 1 dB for preterms. CONCLUSIONS: Suppression of otoacoustic emissions helps us to study the function of the medial olivocochlear bundle in different populations. It appears in premature babies but becomes stronger as the postconceptional age advances.

Acoustic Stimulation↗

PubMed2006

Optokinetic nystagmus as an assessment of visual attention to divided stimuli.

Attentional resources are finite and decline with age. We measured subjects' abilities to generate optokinetic nystagmus (OKN), to suppress it with fixation and to continue to suppress it when fixating while simultaneously paying covert attention to a feature of the optokinetic (OK) stimulus. During fixation with a red laser spot, OKN was almost fully suppressed. When subjects suppressed the OKN while simultaneously paying covert attention to a feature of the OK stimulus, suppression of the OKN was less well suppressed. The active OKN was vigorous. Age affected only the divided attention task, perhaps reflecting a diminution in resources of attention with age. The neural pathways serving attention and those serving eye movements appear to be closely related. We suggest the test presented here represents an objective measurement of the ability to divide attention, and that it has the potential to be developed for much more widespread, possibly clinical, use.

Adult↗

PubMed2005

Early altered renal sodium handling determined by lithium clearance in spontaneously hypertensive rats (SHR): role of renal nerves.

The mechanism by which blood pressure rises in the SHR strain remains to be elucidated. Since the long-term changes in renal sodium tubule handling associated with genetic hypertension have not been examined in detail, we hypothesized that SHR hypertension development may result from sustained renal sympathetic nerve overactivity and consequently decreased urinary sodium excretion. To test this hypothesis, we assessed renal sodium handling and cumulative sodium balance for 10 consecutive weeks in unanesthetized renal-denervated SHR, performed prior to the start of the entire 10-week metabolic studies, and their age-matched normotensive and hypertensive controls. The present investigation shows that SHR excreted less sodium than Wistar-Kyoto (WKy) rats during the initial 3-week observation period (p <0.05). This tendency was reversed when SHR were 10-wk old. Fractional urinary sodium excretion (FENa+) was significantly lower in 3 and 6-wk-old SHR when compared with the WKy age-matched group, as follows: SHR3-wk-old: 0.33 +/- 0.09% and WKy3-wk-old: 0.75 +/- 0.1% (P <0.05); SHR(6-wk-old): 0.52 +/- 0.12% and WKy6-wk-old: 0.83 +/- 0.11%. The decreased FENa+ in young SHR was accompanied by a significant increase in proximal sodium reabsorption (FEPNa+) compared with the normotensive age-matched control group (P <0.01). This increase occurred despite unchanged creatinine clearance (CCr) and fractional post-proximal sodium excretion (FEPPNa+)in all groups studied. The decreased urinary sodium excretion response in SHR up to the age of 6 weeks was significantly eradicated by bilateral renal denervation of SHR3-wk-old: 0.33 +/- 0.09% and SHR6-wk-old: 0.52 +/- 0.12% to DxSHR 3-wk-old: 1.02 +/- 0.2% and DxSHR 6-wk-old: 0.94 +/- 0.2% (P <0.01), in renal denervated rats. The current data suggest that neural pathways may play an instrumental role on renal sodium reabsorption as result of sustained sympathetic nervous system overexcitability.

Afferent Pathways↗

PubMed2006

Motor control and the management of musculoskeletal dysfunction.

This paper aims to develop understanding of three important motor control issues--feedforward mechanisms, cortical plasticity and task-specificity and assess the implications for musculoskeletal practice. A model of control for the reach-to-grasp movement illustrates how the central nervous system integrates sensorimotor processes to control complex movements. Feedforward mechanisms, an essential element of motor control, are altered in neurologically intact patients with chronic neck pain and low back pain. In healthy subjects, cortical mapping studies using transcranial magnetic stimulation have demonstrated that neural pathways adapt according to what and how much is practised. Neuroplasticity has also been demonstrated in a number of musculoskeletal conditions, where cortical maps are altered compared to normal. Behavioural and neurophysiological studies indicate that environmental and task constraints such as the goal of the task and an object's shape and size, are determinants of the motor schema for reaching and other movements. Consideration of motor control issues as well as signs and symptoms, may facilitate management of musculoskeletal conditions and improve outcome. Practice of entire everyday tasks at an early stage and systematic variation of the task is recommended. Training should be directed with the aim of re-educating feedforward mechanisms where necessary and the amount of practice should be sufficient to cause changes in cortical activity.

Feedback↗

PubMed2005

New ways of looking at memory function: certain traumatic memories function like viruses, replicating themselves.

By the process of natural selection, life on earth spreads in all directions, finding niches favorable for survival. Some niches are harmful to another plant or animal (parasitism). This universal survival strategy applies to all living things, and apparently even non-living things such as viruses and prions. The same pattern may occur with immaterial entities such as memories. Traumatic memories mimic virus behavior in many ways such as infecting, spreading, occasionally becoming latent, and even reproducing themselves. Patients with past traumatic experiences are still "infected" with pathogenic memories. The experience remains ever-present in the patient's neural pathways and may even grow via a feedback loop in which each episode of remembering produces a stress hormone response. Under this model, doctors might view and treat patients with a history of trauma as persons infected with latent memories which periodically break out and cause new damage.

Biomimetics↗

PubMed2006

Down-regulation of microglial activation may represent a practical strategy for combating neurodegenerative disorders.

Chronic neurodegenerative disorders are characterized by activation of microglia in the affected neural pathways. Peroxynitrite, prostanoids, and cytokines generated by these microglia can potentiate the excitotoxicity that contributes to neuronal death and dysfunction in these disorders--both by direct effects on neurons, and by impairing the capacity of astrocytes to sequester and metabolize glutamate. This suggests a vicious cycle in which the death of neurons leads to microglial activation, which in turn potentiates neuronal damage. If this model is correct, measures which down-regulate microglial activation may have a favorable effect on the induction and progression of neurodegenerative disease, independent of the particular trigger or target involved in a given disorder. Consistent with this possibility, the antibiotic minocycline, which inhibits microglial activation, shows broad utility in rodent models of neurodegeneration. Other agents which may have potential in this regard include PPARgamma agonists, genistein, vitamin D, COX-2 inhibitors, statins (and possibly policosanol), caffeine, cannabinoids, and sesamin; some of these agents could also be expected to be directly protective to neurons threatened with excitotoxicity. To achieve optimal clinical outcomes, regimens which down-regulate microglial activation could be used in conjunction with complementary measures which address other aspects of excitotoxicity.

Animals↗

PubMed2004

Modulation of synaptic function by cGMP and cGMP-gated cation channels.

Cyclic nucleotide-gated cation channels have been studied intensively in the primary sensory neurons of the visual and olfactory systems. Using both anatomical and physiological methods we have shown that they have a much more widespread distribution in the nervous system. In many retinal ganglion cells cGMP, but not cAMP, activates a non-selective conductance that has many of the properties of CNG channels. As many neurons also contain cGMP-dependent protein kinases (PKGs), we have used a variety of cGMP analogues to distinguish the actions of cGMP. Sp-8-Br-PET-cGMPS is a potent non-hydrolyzable cGMP analogue that is an agonist of PKG. We found that Sp-8-Br-PET-cGMPS acts as a competitive inhibitor of at least the rod CNG channel. Rp-8-Br-cGMPS has shown the opposite effects, namely as an agonist of the rod CNG channel and an inhibitor of PKG. In dissociated cell cultures and slices of rodent visual cortex cGMP had multiple rapid and reversible effects on transmission at glutamatergic synapses. Extracellular application of 8-Br-cGMP or Sp-8-Br-PET-cGMPS reduced stimulus evoked EPSPs in cortical slices. In cortical cultures both analogs reduced the frequency of spontaneous EPSCs, but not their amplitude. The effects on both EPSPs and EPSCs were presynaptic. The effects on evoked EPSPs may be due, in part, to reduced calcium influx through voltage-gated calcium channels. The effects on spontaneous EPSCs may be due, in part, to modulation of calcium fluxes through internal stores. Similar modulations of synaptic transmission have been found at gabaergic synapses. On postsynaptic cells, PKG activation produced a dramatic enhancement of the responses to applied NMDA. No effects were detected on applied AMPA/kainate or GABA. Together the results suggest that cGMP may use multiple mechanisms to modulate synaptic efficacy and that its actions may include regulating synaptic plasticity and the relative strength of excitatory and inhibitory drive through neural pathways.

Animals↗

PubMed2006

Central but not peripheral glucoprivation is impaired in monosodium glutamate-treated rats.

In the present study, newborn male Wistar rats were injected, subcutaneously, five times, every other day, with monosodium glutamate (MSG, 4 g/kg bw) or saline (as control, C), during the neonatal period. MSG animals developed destruction of the arcuate nuclei (ARC) with absence of NPY-immunoreactive cell bodies, which impaired both the food intake (baseline) and the 2-deoxy-D-glucose (2DG) glucoprivic feeding response. Increases in the immunoreactivity of corticotropin-releasing hormone-cell bodies in the paraventricular nuclei might have developed to compensate for the atrophy of the pituitary in MSG-treated rats. After systemic 2DG injection, neither the C nor the MSG rats increased their food intake, but they showed similar hyperglycemic responses, whereas plasma free fatty acids (FFA) increased only in the C group. In other groups, 2DG, norepinephrine (NE), neostigmine (NEO) and saline were intracerebroventricularly (i.c.v.) administered. In this condition, impairment of the hyperglycemic and food intake responses, associated to a lower increase in plasma FFA levels, were observed. As opposed to this, the MSG treatment gives support to NE effects, enhancing food intake, as well as plasma glucose and FFA levels. After NEO, plasma glucose increased only in the MSG group, while plasma FFA levels were elevated in the C rats. Taken together, the results obtained after MSG treatment point to a separate neural control of the hyperglycemic response and of the lipid mobilization when stimulated by central 2DG, NE or NEO administration. It seems likely that the excitatory neural pathway that controls lipid metabolism and is present in C rats was destroyed by the MSG treatment.

Animals↗

PubMed2006

Pharmacological MRI in awake rats reveals neural activity in area postrema and nucleus tractus solitarius: relevance as a potential biomarker for detecting drug-induced emesis.

Drug-induced vomiting (emesis) is a major concern in patient care and a significant hurdle in the development of novel therapeutics. With respect to the latter, rodents, such as the rat and mouse, are typically used in efficacy and safety studies; however, drug-induced emesis cannot be readily observed in these species due to the lack of an emetic reflex. It is known that emesis can be triggered by neural activity in brain regions including area postrema (AP) and nucleus tractus solitarius (NTS). In this study, using pharmacological magnetic resonance imaging (phMRI) and a blood-pool contrast agent, we imaged the hemodynamic consequences of brain activity in awake rats initiated by the administration of compounds (apomorphine 0.1, 0.3 micromol/kg i.v. and ABT-594 0.03, 0.1, 0.3 micromol/kg i.v.) that elicit emesis in other species. Regional drug-induced relative cerebral blood volume (rCBV) changes and percent activated area within the AP and NTS were calculated, in which a dose-dependent relationship was evident for both apomorphine and ABT-594. Additionally, to correlate with behavioral readouts, it was found that the activation of AP and NTS was observed at plasma concentrations consistent with those that induced emesis in ferrets for both drugs. Our data thus suggest that phMRI in awake rats may be a useful tool for predicting emetic liability of CNS-acting drugs and may provide insights into depicting the underlying emetic neural pathways in vivo.

Animals↗

PubMed2005

Adaptation of oriented and unoriented color-selective neurons in human visual areas.

Primary visual cortex contains at least two distinct populations of color-selective cells: neurons in one have circularly symmetric receptive fields and respond best to reddish and greenish light, while neurons in another have oriented receptive fields and a variety of color preferences. The relative prevalence and perceptual roles of the two kinds of neurons remain controversial, however. We used fMRI and a selective adaptation technique to measure responses attributable to these two populations. The technique revealed evidence of adaptation in both populations and indicated that they each produced strong signals in V1 and other human visual areas. The activity of both sets of neurons was also reflected in color appearance measurements made with the same stimuli. Thus, both oriented and unoriented color-selective cells in V1 are important components of the neural pathways that underlie perception of color.

Adaptation, Physiological↗

PubMed2006

Serotonin reciprocally regulates melanocortin neurons to modulate food intake.

The neural pathways through which central serotonergic systems regulate food intake and body weight remain to be fully elucidated. We report that serotonin, via action at serotonin1B receptors (5-HT1BRs), modulates the endogenous release of both agonists and antagonists of the melanocortin receptors, which are a core component of the central circuitry controlling body weight homeostasis. We also show that serotonin-induced hypophagia requires downstream activation of melanocortin 4, but not melanocortin 3, receptors. These results identify a primary mechanism underlying the serotonergic regulation of energy balance and provide an example of a centrally derived signal that reciprocally regulates melanocortin receptor agonists and antagonists in a similar manner to peripheral adiposity signals.

Animals↗

PubMed2006

Stimulation of dopamine receptors in the paraventricular nucleus of the hypothalamus of male rats induces penile erection and increases extra-cellular dopamine in the nucleus accumbens: Involvement of central oxytocin.

The effect of a pro-erectile dose of apomorphine, a mixed dopamine receptor agonist, and of PD-168077 (N-[4-(2-cyanophenyl)piperazin-1-ylmethyl]-3-methylbenzamide maleate), a selective dopamine D4 receptor agonist, injected into the paraventricular nucleus of the hypothalamus on the concentration of extra-cellular dopamine and its main metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the dialysate from the nucleus accumbens was studied in male rats. As expected, apomorphine (0.1microg) and PD-168077 (0.1microg) induced penile erection episodes, which occurred concomitantly to an increase in extra-cellular dopamine and DOPAC concentration in the dialysate from the shell of the nucleus accumbens, as measured by intracerebral microdialysis. When induced by apomorphine, these effects were reduced by 80% by raclopride, a selective D2/D3 receptor antagonist (1microg) and only by 40-45% by L-745,870 (1microg), a selective dopamine D4 receptor antagonist. When induced by PD-168077, these effects were reduced by more than 80% by L-745,870 (1microg), but only by 35-40% by raclopride. Irrespective of the dopamine agonist used to induce penile erection, the pro-erectile effect and the concomitant increase in dopamine and DOPAC concentration in the nucleus accumbens dialysate were almost completely abolished by d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin(1microg), a potent oxytocin receptor antagonist, given into the lateral ventricles. The present results suggest that stimulation of dopamine receptors (mainly of the D2 to D4 subtype) in the paraventricular nucleus induces the release of oxytocin in brain areas that influence the activity of mesolimbic dopaminergic neurons mediating the appetitive and reinforcing effects of sexual activity. This provides evidence for a role of oxytocin in neural circuits that integrate the activity of neural pathways controlling the consummatory aspects of sexual behaviour (e.g., penile erection) with those controlling sexual motivation and sexual arousal.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2006

Temporo-prefrontal coordination increases when semantic associations are strongly encoded.

Relational association of disparate semantic concepts can strengthen encoding of episodes. Previous research has shown that the left medial temporal lobe (MTL) and the left prefrontal cortex (PFC) are the primary brain regions activated during both verbal encoding and the association of disparate semantic concepts. In the current functional magnetic resonance imaging (fMRI) study, our goal was to compare the coordinated response of the left MTL and left PFC when disparate semantic associations are strongly encoded compared to when they are weakly encoded. To achieve this goal, subjects were scanned while creating sentences based on a presented pair of words, and were asked to free-recall these sentences at a later time. Half the word pairs were semantically unrelated, and half were semantically related. Analysis of relatedness activations (unrelated-related contrast) suggested that the PFC was active whether or not the items were free-recalled, and increased activation of the MTL was required to promote encoding. Analyses of coordination of relatedness activations comparing free-recalled items to not free-recalled items showed an increase in left MTL-left PFC coordination for relatedness activations on free-recalled items. These results suggest that formation of relational semantic associations that lead to strongly encoded episodes requires increased coordination of the left MTL-left PFC neural pathway.

Adolescent↗

PubMed2005

Slow excitatory post-synaptic potentials in myenteric AH neurons of the guinea-pig ileum are reduced by the 5-hydroxytryptamine7 receptor antagonist SB 269970.

Serotonin (5-HT) is a key modulator of neuronal excitability in the central and peripheral nervous system. In the enteric nervous system, 5-HT causes a slow depolarization in the intrinsic sensory neurons, but the receptor responsible for this has not been correlated with known gene products. The aim of this study was to determine whether the newly characterized 5-HT7 receptor may participate in the 5-HT-mediated depolarization of, and synaptic transmission to, the intrinsic sensory neurons of the guinea-pig ileum. Intracellular electrophysiological recordings were made from intrinsic sensory neurons identified as myenteric AH neurons from guinea-pig ileum. 5-HT (5 microM) applied to the cell body evoked both a fast depolarization (5-HT3 mediated) and/or a slow depolarization (5-HT1P-like). The 5-HT1/5/7 receptor agonist 5-carboxamidotryptamine (5-CT) (5 microM) evoked only a slow depolarization. When the fast depolarization evoked by 5-HT was blocked with granisetron (1 microM, 5-HT3 receptor antagonist), only a slow depolarization remained; this was abolished by the 5-HT7 receptor antagonist SB 269970 (1 microM, control: 14+/-2 mV, granisetron+SB 269970: -1+/-2 mV). The slow depolarization evoked by 5-CT was also significantly reduced by SB 269970 (control: 14+/-1 mV, SB 269970: 5+/-2 mV) suggesting a 5-HT7 receptor was activated by exogenous application of 5-CT and 5-HT. Slow excitatory postsynaptic potentials evoked by stimulating descending neural pathways (containing serotonergic fibers) were reduced by SB 269970 (control: 8+/-3 mV, SB 269970: 3+/-1 mV). However, SB 269970 had no effect on slow excitatory postsynaptic potentials evoked by stimulation of circumferential (tachykinergic) pathways (control: 7+/-1 mV, SB 269970: 6+/-1 mV). These data are consistent with the presence on enteric AH neurons of functional 5-HT7 receptors that participate in slow synaptic transmission.

Animals↗

PubMed2005

Melanotan-II: Investigation of the inducer and facilitator effects on penile erection in anaesthetized rat.

The effects of melanotan-II, a non-specific agonist of melanocortin receptors, on erection and its possible sites of action were investigated in anesthetized rats. Delivered i.v. (0.1, 0.3 and 1 mg/kg) or within the paraventricular nucleus of the hypothalamus (0.1 and 1 microg), melanotan-II exerted a dose-dependent inducer activity on erection by eliciting erectile events and shortening latency of the first erectile event to occur. Erectile events were of higher amplitude in rats treated with melanotan-II i.t. (0.2 microg) delivered at the L6-S1 level than in animals treated with the vehicle i.t. delivered. Erectile responses elicited by cavernous nerve stimulation were increased after i.v. melanotan-II (1 mg/kg), thereby exerting facilitator effect on erection. In contrast, melanotan-II injected within the corpus cavernosum (1 microg) did not display any facilitator activity. To investigate the neural pathways involved in the facilitator effect of melanotan-II, we performed acute spinalization (T8 level) and differential selective nerve transections. Neither spinalization nor bilateral transection of pelvic nerves or dorsal penile nerves impaired facilitator activity of i.v. melanotan-II (1 mg/kg). Conversely, the facilitator effect of melanotan-II was abolished after acute removal of the lumbar paravertebral sympathetic chain. These results lead to the conclusion that central and peripheral melanocortin pathways are recruited by melanotan-II, depending on its route of delivery, to exert both inducer and facilitator activities on erection.

Anesthesia↗

PubMed2006

Cholinergic modulation of trace conditioning trained in serial compound: A developmental analysis.

In four experiments the effects of serial compound conditioning on responding to a trace-conditioned CS were evaluated using a fear conditioning paradigm. The subjects were 18- and 25-day-old Sprague-Dawley rats, previously shown to exhibit little or no trace fear conditioning. Here, animals as young as 18 days of age were shown to be capable of trace conditioning between a visual CS1 and a shock US, provided the trace interval was filled with a non-target CS2 during serial conditioning trials (CS1-->CS2-->US). To explore cholinergic mechanisms involved in trace and serial conditioning, additional experiments assessed conditioned responding following pre-training administration of the muscarinic receptor antagonist scopolamine. Scopolamine produced a dose-dependent reduction in responding to the trace CS1, regardless of whether subjects were trained with standard trace (CS1-->trace interval-->US) or serial (CS1-->CS2-->US) trials. Responding to CS2 was unaffected by scopolamine. These data suggest that central cholinergic systems are functional in the young animals, but are not normally sufficiently activated by standard trace conditioning procedures. The results suggest that serial compound conditioning can promote trace conditioning in young rats, as it does in adults, perhaps by enhancing cholinergic activity during training. Implications for the late ontogenetic emergence of trace conditioning as it relates to maturation of neural pathways and their role in the potentiating effects of a gap filler are discussed.

Age Factors↗