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The decrease of psychophysical detection thresholds as a function of pulse rate for a fixed-duration electrical pulse train is referred to as multipulse integration (MPI). The MPI slopes correlate with anatomical and physiological indices of cochlear health in guinea pigs with cochlear implants. The aim of the current study was to assess whether the MPI slopes were related to the spatial spread of activation by electrical stimulation. The hypothesis was that MPI is dependent on the total number of excitable neurons at the stimulation site, with broader neural excitation producing a steeper threshold decrease as a function of stimulation rate. MPI functions were measured at all stimulation sites in 22-site electrode arrays in human subjects. Some sites with steep MPI functions and other sites with shallow functions were assessed for spatial spread of excitation at 900 pps using a forward-masking paradigm. The results showed a correlation between the slopes of the forward-masking functions and the steepness of MPI, with broader stimulation predicting greater integration. The results are consistent with the idea that integration of multiple pulses in a pulse train relies on the number of excitable neurons at the stimulation site. [ABSTRACT FROM AUTHOR]

How complex natural sounds are represented by the main converging center of the auditory midbrain, the central inferior colliculus, is an open question. We applied neural discrimination to determine the variation of detailed encoding of individual vocalizations across the best frequency gradient of the central inferior colliculus. The analysis was based on collective responses from several neurons. These multi-unit spike trains were recorded from guinea pigs exposed to a spectrotemporally rich set of eleven species-specific vocalizations. Spike trains of disparate units from the same recording were combined in order to investigate whether groups of multi-unit clusters represent the whole set of vocalizations more reliably than only one unit, and whether temporal response correlations between them facilitate an unambiguous neural representation of the vocalizations. We found a spatial distribution of the capability to accurately encode groups of vocalizations across the best frequency gradient. Different vocalizations are optimally discriminated at different locations of the best frequency gradient. Furthermore, groups of a few multi-unit clusters yield improved discrimination over only one multi-unit cluster between all tested vocalizations. However, temporal response correlations between units do not yield better discrimination. Our study is based on a large set of units of simultaneously recorded responses from several guinea pigs and electrode insertion positions. Our findings suggest a broadly distributed code for behaviorally relevant vocalizations in the mammalian inferior colliculus. Responses from a few non-interacting units are sufficient to faithfully represent the whole set of studied vocalizations with diverse spectrotemporal properties. [ABSTRACT FROM AUTHOR]

Cells expressing doublecortin (DCX+) occur at cortical layer II, predominantly over the paleocortex in mice/rats, but also across the neocortex among larger mammals. Here, we explored the time of origin of these cells in neonatal and 2-month-old guinea pigs following prenatal BrdU pulse-chasing. In the neocortex, BrdU+ cells birth-dated at embryonic day 21 (E21), E28, and E35 laminated over the cortical plate with an inside-out order. In the piriform cortex, cells generated at E21 and E28 occurred with a greater density in layer II than III. Many cells were generated at later time points until birth, occurring in the cortex without a laminar preference. DCX+ cells in the neocortex and piriform cortex partially co-colocalized with BrdU (up to 7.5%) in the newborns after pulse-chasing from E21 to E49 and in the 2 month-old animals after pulse-chasing from E28 to E60/61, with higher rates seen among the E21-E35 groups. Together, layer II DCX+ cells in neonatal and young adult guinea pigs may be produced over a wide prenatal time window, but mainly during the early phases of corticogenesis. Our data also show an earlier establishment of the basic lamination in the piriform relative to neocortical areas in guinea pigs. [ABSTRACT FROM AUTHOR]

Pituitary adenylate cyclase- activating polypeptide (PACAP) is a potent intercellular signaling molecule involved in multiple homeostatic functions. PACAP/ PAC1 receptor signaling increases excitability of neurons within the guinea pig cardiac ganglia, making them a unique system to establish mechanisms underlying PACAP modulation of neuronal function. Calcium influx is required for the PACAP-increased cardiac neuron excitability, although the pathway is unknown. This study tested whether PACAP enhancement of calcium influx through either T-type or R-type channels contributed to the modulation of excitability. Real-time quantitative polymerase chain reaction analyses indicated transcripts for Cav3.1, Cav3.2, and Cav3.3 T-type isoforms and R-type Cav2.3 in cardiac neurons. These neurons often exhibit a hyperpolarization- induced rebound depolarization that remains when cesium is present to block hyperpolarization-activated nonselective cationic currents (Ih). The T-type calcium channel inhibitors, nickel (Ni2+) or mibefradil, suppressed the rebound depolarization, and treatment with both drugs hyperpolarized cardiac neurons by 2-4 mV. Together, these results are consistent with the presence of functional T-type channels, potentially along with R-type channels, in these cardiac neurons. Fifty micromolar Ni2+, a concentration that suppresses currents in both T-type and R-type channels, blunted the PACAPinitiated increase in excitability. Ni2+ also blunted PACAP enhancement of the hyperpolarization-induced rebound depolarization and reversed the PACAP-mediated increase in excitability, after being initiated, in a subset of cells. Lastly, low voltage-activated currents, measured under perforated patch whole cell recording conditions and potentially flowing through T-type or R-type channels, were enhanced by PACAP. Together, our results suggest that a PACAP-enhanced, Ni2+-sensitive current contributes to PACAP-induced modulation of neuronal excitability. [ABSTRACT FROM AUTHOR]

Neurons of the lateral olivocochlear (LOC) system project from the auditory brainstem to the cochlea, where they synapse on radial dendrites of auditory nerve fibers. Selective LOC disruption depresses sound-evoked auditory nerve activity in the guinea pig, but enhances it in the mouse. Here, LOC disruption depressed spontaneous auditory nerve activity in the guinea pig. Recordings from single auditory nerve fibers revealed a significantly reduced proportion of fibers with the highest spontaneous firing rates (SRs) and an increased proportion of neurons with lower SRs. Ensemble activity, estimated using round window noise, also decreased after LOC disruption. Decreased spontaneous activity after LOC disruption may be a consequence of reduced tonic release of excitatory transmitters from the LOC terminals in guinea pigs. [ABSTRACT FROM AUTHOR]

The Hybrid cochlear implant (CI), also known as Electro-Acoustic Stimulation (EAS), is a new type of CI that preserves residual acoustic hearing and enables combined cochlear implant and hearing aid use in the same ear. However, 30–55% of patients experience acoustic hearing loss within days to months after activation, suggesting that both surgical trauma and electrical stimulation may cause hearing loss. The goals of this study were to: 1) determine the contributions of both implantation surgery and EAS to hearing loss in a normal-hearing guinea pig model; 2) determine which cochlear structural changes are associated with hearing loss after surgery and EAS. Two groups of animals were implanted ( n = 6 per group), with one group receiving chronic acoustic and electric stimulation for 10 weeks, and the other group receiving no direct acoustic or electric stimulation during this time frame. A third group ( n = 6) was not implanted, but received chronic acoustic stimulation. Auditory brainstem response thresholds were followed over time at 1, 2, 6, and 16 kHz. At the end of the study, the following cochlear measures were quantified: hair cells, spiral ganglion neuron density, fibrous tissue density, and stria vascularis blood vessel density; the presence or absence of ossification around the electrode entry was also noted. After surgery, implanted animals experienced a range of 0–55 dB of threshold shifts in the vicinity of the electrode at 6 and 16 kHz. The degree of hearing loss was significantly correlated with reduced stria vascularis vessel density and with the presence of ossification, but not with hair cell counts, spiral ganglion neuron density, or fibrosis area. After 10 weeks of stimulation, 67% of implanted, stimulated animals had more than 10 dB of additional threshold shift at 1 kHz, compared to 17% of implanted, non-stimulated animals and 0% of non-implanted animals. This 1-kHz hearing loss was not associated with changes in any of the cochlear measures quantified in this study. The variation in hearing loss after surgery and electrical stimulation in this animal model is consistent with the variation in human patients. Further, these findings illustrate an advantage of a normal-hearing animal model for quantification of hearing loss and damage to cochlear structures without the confounding effects of chemical- or noise-induced hearing loss. Finally, this study is the first to suggest a role of the stria vascularis and damage to the lateral wall in implantation-induced hearing loss. Further work is needed to determine the mechanisms of implantation- and electrical-stimulation-induced hearing loss. [ABSTRACT FROM AUTHOR]

The degeneration of hair cells in the mammalian cochlea results in permanent sensorineural hearing loss. This study aimed to promote the regeneration of sensory hair cells in the mature cochlea and their reconnection with auditory neurons through the introduction of ATOH1, a transcription factor known to be necessary for hair cell development, and the introduction of neurotrophic factors. Adenoviral vectors containing ATOH1 alone, or with neurotrophin-3 and brain derived neurotrophic factor were injected into the lower basal scala media of guinea pig cochleae four days post ototoxic deafening. Guinea pigs treated with ATOH1 gene therapy, alone, had a significantly greater number of cells expressing hair cell markers compared to the contralateral non-treated cochlea when examined 3 weeks post-treatment. This increase, however, did not result in a commensurate improvement in hearing thresholds, nor was there an increase in synaptic ribbons, as measured by CtBP2 puncta after ATOH1 treatment alone, or when combined with neurotrophins. However, hair cell formation and synaptogenesis after co-treatment with ATOH1 and neurotrophic factors remain inconclusive as viral transduction was reduced due to the halving of viral titres when the samples were combined. Collectively, these data suggest that, whilst ATOH1 alone can drive non-sensory cells towards an immature sensory hair cell phenotype in the mature cochlea, this does not result in functional improvements after aminoglycoside-induced deafness. [ABSTRACT FROM AUTHOR]

Abstract: Neuron counting in the cochlea is a crucial but time-consuming operation for which various methods have been developed. To improve simplicity and efficiency, we tested an imaging method of the cochlea, and based on Confocal Laser Scanning Microscopy (CLSM), we visualised Rosenthal's Canal and quantified the spiral ganglion neurons (SGN) within. Cochleae of 8 normal hearing guinea pigs and one implanted with a silicone filament were fixed in paraformaldehyde (PFA), decalcified, dehydrated and cleared in Spalteholz solution. Using the tissue's autofluorescence, CLSM was performed at 100fold magnification generating z-series stacks of about 20 slices of the modiolus. In 5 midmodiolar slices per cochlea the perimeters of the Rosenthal's Canal were surveyed, representative neuron diameters were measured and the neurons first counted manually and then software-assisted. For comparison, 8 normal hearing guinea pig cochleae were embedded in paraffin and examined similarly. The CLSM method has the advantage that the cochleae remain intact as an organ and keep their geometrical structure. Z-stack creation is nearly fully-automatic and frequently repeatable with various objectives and step sizes and without visible bleaching. The tissue shows minimal or no shrinking artefacts and damage typical of embedding and sectioning. As a result, the cells in the cleared cochleae reach an average diameter of 21 μm and a density of about 18 cells/10,000 μm2 with no significant difference between the manual and the automatical counts. Subsequently we compared the CLSM data with those generated using the established method of paraffin slides, where the SGN reached a mean density of 9.5 cells/10,000 μm2 and a mean soma diameter of 13.6 μm. We were able to prove that the semi-automatic CLSM method is a simple and effective technique for auditory neuron count. It provides a high grade of tissue preservation and the automatic stack-generation as well as the counter software reduces the effort considerably. In addition this visualisation technique offers the potential to detect the position and orientation of cochlear implants (CI) within the cochlea and tissue growing in the scala tympani around the CI and at the position of the cochleostomy due to the fact that the implant does not have to be removed to perform histology as in case of the paraffin method. [Copyright &y& Elsevier]

Abstract: Previous studies have shown that sexual dimorphism in the brain can present two morphological patterns: one in which males present greater morphological measures than females (male>female) and another in which the opposite is true (female>male). These studies have also shown that at least the part of amygdala namely the cortical and medial amygdala, an olfactory region involved in the control of reproductive physiology and behavior, is sexually dimorphic in the rat and other rodents. However, data comparing the basolateral and central amygdala between the sexes is lacking. To my knowledge, the present study is the first morphological work that systematically describes sexual dimorphism throughout the entire amygdala in the guinea pig. The results show that sex differences were found in: (a) the medial amygdala (ME) and its dorsal (MEd) and ventral (MEv) subdivisions, males showing greater values than females in volume and number of neurons, (b) the cortical amygdala (CO) and especially its posterior (COp) subdivision. In the CO, males exhibited a greater number of neurons and in the COp, males showed a greater volume and number of neurons. No differences between the sexes were observed in the basolateral and central amygdala. The results of the present study indicate that in the guinea pig sex differences are present in the large part of the amygdala and they present the male>female pattern, as it was observed in other rodents (rat and hamster), but not in the rabbit. As some previous neurochemical and functional studies have indicated that all parts of the amygdala may be sexually dimorphic, further studies are required to elucidate how much this brain region differs in both sexes. [Copyright &y& Elsevier]

Highlights: [•] Intrinsic primary afferent neurons of the ileum are hyperexcitable during colitis. [•] Excitability of ileum myenteric AH neurons persists after colitis has resolved. [•] There are no changes in fast synaptic transmission in the ileum during colitis. [•] An early transient reduction in small bowel transit is restored during colitis. [•] Neither reduced transit nor restoration coincide with changes in AH excitability. [ABSTRACT FROM AUTHOR]

Abstract: The time of onset of hyperactivity (increased spontaneous firing rates) was investigated by single neuron recording in the inferior colliculus (IC) of guinea pigs subjected to unilateral acoustic trauma (exposure to a loud 10 kHz tone). Hyperactivity was present by 12 h post acoustic trauma whereas data obtained within approximately 4 h of the cessation of acoustic trauma found no evidence of hyperactivity. These data suggest that hyperactivity in the IC begins at some time between 4 and 12 h post trauma and is a relatively rapid plastic event beginning within hours rather than days post cochlear trauma. This is consistent with results reported in the cat auditory cortex (Norena and Eggermont, 2003). Hyperactivity did not show any further systematic increase between 12 h and up to 2 weeks post acoustic trauma. At recovery times of 12 and 24 h hyperactivity was widespread across most regions of the IC but at longer recovery times, it became progressively more restricted to ventral regions corresponding to the regions of the cochlea where there was persistent damage. [Copyright &y& Elsevier]

Abstract: The discrete functional classes of enteric neurons in the mammalian gastrointestinal tract have been successfully distinguished on the basis of the unique combination of molecules and enzymes in their cell bodies (“chemical coding”). Whether the same chemical coding exists in varicose axons of different functional classes has not been systematically tested. In this study, we quantified the coexistence of markers that define classes of nerve cell bodies in the myenteric plexus of the guinea-pig ileum, in varicose axons of the same neurons. Profound differences between the combinations of immunohistochemical markers in myenteric nerve cell bodies and in their varicosities were identified. These discrepancies were particularly notable for classes of neurons that had previously been classified as cholinergic, based on immunoreactivity for choline acetyltransferase (ChAT) in their cell bodies. To detect cholinergic varicose axons of enteric neurons in this study, we used antiserum against the vesicular acetylcholine transporter (VAChT). ChAT-immunoreactivity has been reported to be consistently co-localized with 5-hydroxytryptamine (5-HT) in interneuronal cell bodies, yet only 29±5% (n =4) of 5-HT-immunoreactive varicosities contained vesicular acetylcholine transporter (VAChT). Somatostatin coexists with ChAT-immunoreactivity in a class of descending interneuron but only 21±1% (n =4) of somatostatin-immunoreactive varicosities were VAChT-immunoreactive. Comparable discrepancies were also noted for non-cholinergic markers. The results suggest that chemical coding of cell bodies does not necessarily reflect chemical coding of varicose axon terminals and that the assumption that nerve cell bodies that contain ChAT are functionally cholinergic may be questionable. [Copyright &y& Elsevier]

Abstract: The modern-day population is overexposed to visual stimuli accompanied by contrast and strength changes, such as the television or videogames, beginning early in life. These light stimuli may have an influence on the development of the visual system. The purpose of this study was to examine the effects of light stimuli on retinal development. We reared guinea pigs under a daily 12-h strobe light (2Hz)/dark cycle from birth, while control animals were reared under a 12-h light/dark cycle. The animals were sacrificed 1, 2, and 4 weeks after birth. The thickness of the outer nuclear layer (ONL) thickness decreased by 14.8% in the strobe-reared animals compared to the control group at 4 weeks, but not at 1 and 2 weeks. The Müller cells of the strobe-reared animals showed a stouter branch compared to that of the control animals at 2 and 4 weeks. In the strobe-reared model, axon-like processes emerging from the rod bipolar cell bodies were observed in the outer plexiform layer (OPL). These findings show that strobe-light stimuli induce morphological changes in retinal neurons, which may lead to the disturbance of normal visual processing during development. [Copyright &y& Elsevier]

Background Enteric viscerofugal neurons provide cholinergic synaptic inputs to prevertebral sympathetic neurons, forming reflex circuits that control motility and secretion. Extracellular recordings of identified viscerofugal neurons have not been reported. Methods Preparations of guinea pig distal colon were maintained in organotypic culture for 4-6 days ( n = 12), before biotinamide tracing, immunohistochemistry, or extracellular electrophysiological recordings from colonic nerves. Key Results After 4-6 days in organ culture, calcitonin gene-related peptide and tyrosine hydroxylase immunoreactivity in enteric ganglia was depleted, and capsaicin-induced firing (0.4 μmol L−1) was not detected, indicating that extrinsic sympathetic and sensory axons degenerate in organ culture. Neuroanatomical tracing of colonic nerves revealed that viscerofugal neurons persist and increase as a proportion of surviving axons. Extracellular recordings of colonic nerves revealed ongoing action potentials. Interestingly, synchronous bursts of action potentials were seen in 10 of 12 preparations; bursts were abolished by hexamethonium, which also reduced firing rate (400 μmol L−1, P < 0.01, n = 7). DMPP (1,1-dimethyl-4-phenylpiperazinium; 10−4 mol L−1) evoked prolonged action potential discharge. Increased firing preceded both spontaneous and stretch-evoked contractions (χ2 = 11.8, df = 1, P < 0.001). Firing was also modestly increased during distensions that did not evoke reflex contractions. All single units (11/11) responded to von Frey hairs (100-300 mg) in hexamethonium or Ca2+-free solution. Conclusions & Inferences Action potentials recorded from colonic nerves in organ cultured preparations originated from viscerofugal neurons. They receive nicotinic input, which coordinates ongoing burst firing. Large bursts preceded spontaneous and reflex-evoked contractions, suggesting their synaptic inputs may arise from enteric circuitry that also drives motility. Viscerofugal neurons were directly mechanosensitive to focal compression by von Frey hairs. [ABSTRACT FROM AUTHOR]

Decreasing body size has been suggested as the third universal biological response to global warming after latitudinal/altitudinal range shifts and shifts in phenology. Size shifts in a community can be the composite result of intraspecific size shifts and of shifts between differently sized species. Metabolic explanations for the size shifts dominate in the literature but top down effects, i.e. intensified size-selective consumption at higher temperatures, have been proposed as alternative explanation. Therefore, we performed phytoplankton experiments with a factorial combination of warming and consumer type (protist feeding mainly on small algae vs. copepods mainly feeding on large algae). Natural phytoplankton was exposed to 3 (1st experiment) or 4 (2nd experiment) temperature levels and 3 (1st experiment: nano-, microzooplankton, copepods) or 2 (2nd experiment: microzooplankton, copepods) types of consumers. Size shifts of individual phytoplankton species and community mean size were analyzed. Both, mean cell size of most of the individual species and mean community cell size decreased with temperature under all grazing regimes. Grazing by copepods caused an additional reduction in cell size. Our results reject the hypothesis, that intensified size selective consumption at higher temperature would be the dominant explanation of decreasing body size. In this case, the size reduction would have taken place only in the copepod treatments but not in the treatments with protist grazing (nano- and microzooplankton). [ABSTRACT FROM AUTHOR]

While having the highest vitamin C (VitC) concentrations in the body, specific functions of VitC in the brain have only recently been acknowledged. We have shown that postnatal VitC deficiency in guinea pigs causes impairment of hippocampal memory function and leads to 30% less neurons. This study investigates how prenatal VitC deficiency affects postnatal hippocampal development and if any such effect can be reversed by postnatal VitC repletion. Eighty pregnant Dunkin Hartley guinea pig dams were randomized into weight stratified groups receiving High (900 mg) or Low (100 mg) VitC per kg diet. Newborn pups (n = 157) were randomized into a total of four postnatal feeding regimens: High/High (Control); High/Low (Depleted), Low/Low (Deficient); and Low/High (Repleted). Proliferation and migration of newborn cells in the dentate gyrus was assessed by BrdU labeling and hippocampal volumes were determined by stereology. Prenatal VitC deficiency resulted in a significant reduction in postnatal hippocampal volume (P<0.001) which was not reversed by postnatal repletion. There was no difference in postnatal cellular proliferation and survival rates in the hippocampus between dietary groups, however, migration of newborn cells into the granular layer of the hippocampus dentate gyrus was significantly reduced in prenatally deficient animals (P<0.01). We conclude that a prenatal VitC deficiency in guinea pigs leads to persistent impairment of postnatal hippocampal development which is not alleviated by postnatal repletion. Our findings place attention on a yet unrecognized consequence of marginal VitC deficiency during pregnancy. [ABSTRACT FROM AUTHOR]

Key points Acute changes in glycaemia can have substantial effects on gastro-intestinal motor function., A feeding state-related bistable memory system has been previously described in neurons of the hypothalamus., We found that peristaltic bowel movements are more pronounced in intestinal segments from re-fed compared to fasted animals and neuronal responses in the myenteric plexus are tuned to the feeding state, which illustrates that the feeding status remains imprinted ex vivo., This feeding state-related memory can be reproduced in vitro and humoral factors as well as glucose-dependent pathways are involved., Pharmacological manipulation of feeding state-specific signalling in enteric neurons can be of therapeutic importance in the treatment of motility-related feeding disorders., Abstract Although hunger and satiety are mainly centrally regulated, there is convincing evidence that also gastrointestinal motor activity and hormone fluctuations significantly contribute to appetite signalling. In this study, we investigated how motility and enteric nerve activity are set by fasting and feeding. By means of video-imaging, we tested whether peristaltic activity differs in ex vivo preparations from fasted and re-fed guinea pigs. Ca2+ imaging was used to investigate whether the feeding state directly alters neuronal activity, either occurring spontaneously or evoked by (an)orexigenic signalling molecules. We found that pressure-induced (2 cmH2O) peristaltic activity occurs at a higher frequency in ileal segments from re-fed animals (re-fed versus fasted, 6.12 ± 0.22 vs. 4.84 ± 0.52 waves min−1, P= 0.028), even in vitro hours after death. Myenteric neuronal responses were tuned to the feeding status, since neurons in tissues from re-fed animals remained hyper-responsive to high K+-evoked depolarization ( P < 0.001) and anorexigenic molecules ( P < 0.001), while being less responsive to orexigenic ghrelin ( P= 0.013). This illustrates that the feeding status remains 'imprinted' ex vivo. We were able to reproduce this feeding state-related memory in vitro and found humoral feeding state-related factors to be implicated. Although the molecular link with hyperactivity is not entirely elucidated yet, glucose-dependent pathways are clearly involved in tuning neuronal excitability. We conclude that a bistable memory system that tunes neuronal responses to fasting and re-feeding is present in the enteric nervous system, increasing responses to depolarization and anorexigenic molecules in the re-fed state, while decreasing responses to orexigenic ghrelin. Unlike the hypothalamus, where specific cell populations sensitive to either orexigenic or anorexigenic molecules exist, the enteric feeding state-related memory system is present at the functional level of receptor signalling rather than confined to specific neuron subtypes. [ABSTRACT FROM AUTHOR]

Aim:To determine whether electrical stimulation of caudal medial prefrontal cortex (mPFC) as conditioned stimulus (CS) paired with airpuff unconditioned stimulus (US) was sufficient for establishing eyeblink conditioning in guinea pigs, and whether it was dependent on cerebellar interpositus nucleus.Methods:Thirty adult guinea pigs were divided into 3 conditioned groups, and trained on the delay eyeblink conditioning, short-trace eyeblink conditioning, and long-trace eyeblink conditioning paradigms, respectively, in which electrical stimulation of the right caudal mPFC was used as CS and paired with corneal airpuff US. A pseudo conditioned group of another 10 adult guinea pigs was given unpaired caudal mPFC electrical stimulation and the US. Muscimol (1 μg in 1 μL saline) and saline (1 μL) were infused into the cerebellar interpositus nucleus of the animals through the infusion cannula on d 11 and 12, respectively.Results:The 3 eyeblink conditioning paradigms have been successfully established in guinea pigs. The animals acquired the delay and short-trace conditioned responses more rapidly than long-trace conditioned responses. Muscimol infusion into the cerebellar interpositus nucleus markedly impaired the expression of the 3 eyeblink conditioned responses.Conclusion:Electrical stimulation of caudal mPFC is effective CS for establishing eyeblink conditioning in guinea pigs, and it is dependent on the cerebellar interpositus nucleus. [ABSTRACT FROM AUTHOR]

Abstract: Tonic immobility (TI) is an innate defensive behavior that can be elicited by physical restriction and postural inversion and is characterized by a profound and temporary state of akinesis. Our previous studies demonstrated that the stimulation of serotonin receptors in the dorsal raphe nucleus (DRN) appears to be biphasic during TI responses in guinea pigs (Cavia porcellus). Serotonin released by the DRN modulates behavioral responses and its release can occur through the action of different neurotransmitter systems, including the opioidergic and GABAergic systems. This study examines the role of opioidergic, GABAergic and serotonergic signaling in the DRN in TI defensive behavioral responses in guinea pigs. Microinjection of morphine (1.1nmol) or bicuculline (0.5nmol) into the DRN increased the duration of TI. The effect of morphine (1.1nmol) was antagonized by pretreatment with naloxone (0.7nmol), suggesting that the activation of μ opioid receptors in the DRN facilitates the TI response. By contrast, microinjection of muscimol (0.5nmol) into the DRN decreased the duration of TI. However, a dose of muscimol (0.26nmol) that alone did not affect TI, was sufficient to inhibit the effect of morphine (1.1nmol) on TI, indicating that GABAergic and enkephalinergic neurons interact in the DRN. Microinjection of alpha-methyl-5-HT (1.6nmol), a 5-HT2 agonist, into the DRN also increased TI. This effect was inhibited by the prior administration of naloxone (0.7nmol). Microinjection of 8-OH-DPAT (1.3nmol) also blocked the increase of TI promoted by morphine (1.1nmol). Our results indicate that the opioidergic, GABAergic and serotonergic systems in the DRN are important for modulation of defensive behavioral responses of TI. Therefore, we suggest that opioid inhibition of GABAergic neurons results in disinhibition of serotonergic neurons and this is the mechanism by which opioids could enhance TI. Conversely, a decrease in TI could occur through the activation of GABAergic interneurons. [Copyright &y& Elsevier]

Irregular vestibular afferents exhibit significant phase leads with respect to angular velocity of the head in space. This characteristic and their connectivity with vestibulospinal neurons suggest a functionally important role for these afferents in producing the vestibulo-collic reflex (VCR). A goal of these experiments was to test this hypothesis with the use of weak galvanic stimulation of the vestibular periphery (GVS) to selectively activate or suppress irregular afferents during passive whole body rotation of guinea pigs that could freely move their heads. Both inhibitory and excitatory GVS had significant effects on compensatory head movements during sinusoidal and transient whole body rotations. Unexpectedly, GVS also strongly affected the vestibulo-ocular reflex (VOR) during passive whole body rotation. The effect of GVS on the VOR was comparable in light and darkness and whether the head was restrained or unrestrained. Significantly, there was no effect of GVS on compensatory eye and head movements during volitional head motion, a confirmation of our previous study that demonstrated the extravestibular nature of anticipatory eye movements that compensate for voluntary head movements. [ABSTRACT FROM AUTHOR]

Abstract: Transtympanic administration of gentamicin is a widely accepted and effective approach for treating patients with intractable vertigo. Previous studies have demonstrated the uptake, distribution and effects of gentamicin in peripheral vestibular and cochlear structures after transtympanic injection. However, little is known about whether transtympanically administered gentamicin is trafficked into more central auditory and vestibular structures and its effect on these structures. In this study, we used immunofluorescence to determine the distribution of gentamicin within the auditory and vestibular brainstem. We observed gentamicin immunolabeling bilaterally in the vestibular efferent neurons, and in the superior olivary complex, and ipsilaterally in the cochlear nucleus 24h after transtympanic administration of gentamicin, and that the drug could still be detected in these locations 30 days after injection. In contrast, no gentamicin labeling was detected in the vestibular nuclear complex. In the vestibular efferent neurons and superior olivary complex, gentamicin labeling was detected in the cytoplasm and cell processes, while in the cochlear nucleus gentamicin is mainly localized outside and adjacent to the cell bodies of neurons. Nerve fibers in cochlear nucleus, root of eighth nerve, as well as descending pathways from the superior olivary complex, are also immunolabeled with gentamicin continuously. Based on these data, we hypothesize that retrograde axonal transport of gentamicin is responsible for the distribution of gentamicin in these efferent nuclei including vestibular efferent neurons and superior olivary complex and anterograde axonal transport into the ipsilateral cochlear nucleus. [Copyright &y& Elsevier]

The intrinsic cardiac plexus represents a major peripheral integration site for neuronal, hormonal, and locally produced neuromodulators controlling efferent neuronal output to the heart. This study examined the interdependence of norepinephrine, muscarinic agonists, and ANG II, to modulate intrinsic cardiac neuronal activity. Intracellular voltage recordings from whole-mount preparations of the guinea pig cardiac plexus were used to determine changes in active and passive electrical properties of individual intrinsic cardiac neurons. Application of either adrenergic or muscarinic agonists induced changes in neuronal resting membrane potentials, decreased afterhyperpolarization duration of single action potentials, and increased neuronal excitability. Adrenergic responses were inhibited by removal of extracellular calcium ions, while muscarinic responses were inhibited by application of TEA. The adrenergic responses were heterogeneous, responding to a variety of receptor-specific agonists (phenylephrine, clonidine, dobutamine, and terbutaline), although α-receptor agonists produced the most frequent responses. Application of ANG II alone produced a significant increase in excitability, while application of ANG II in combination with either adrenergic or muscarinic agonists produced a much larger potentiation of excitability. The ANG II-induced modulation of firing was blocked by the angiotensin type 2 (AT2) receptor inhibitor PD 123319 and was mimicked by the AT2 receptor agonist CGP-42112A. AT1 receptor blockade with telmasartin did not alter neuronal responses to ANG II. These data demonstrate that ANG II potentiates both muscarinically and adrenergically mediated activation of intrinsic cardiac neurons, doing so primarily via AT2 receptor-dependent mechanisms. These neurohumoral interactions may be fundamental to regulation of neuronal excitability within the intrinsic cardiac nervous system. [ABSTRACT FROM AUTHOR]

Abstract: Many communication calls contain information about the physical characteristics of the calling animal. During maturation of the guinea pig purr call the pitch becomes lower as the fundamental frequency progressively decreases from 476 to 261 Hz on average. Neurons in the primary auditory cortex (AI) often respond strongly to the purr and we postulated that some of them are capable of distinguishing between purr calls of different pitch. Consequently four pitch-shifted versions of a single call were used as stimuli. Many units in AI (79/182) responded to the purr call either with an onset response or with multiple bursts of firing that were time-locked to the phrases of the call. All had a characteristic frequency ≤5 kHz. Both types of unit altered their firing rate in response to pitch-shifted versions of the call. Of the responsive units, 41% (32/79) had a firing rate locked to the stimulus envelope that was at least 50% higher for one version of the call than any other. Some (14/32) had a preference that could be predicted from their frequency response area while others (18/32) were not predictable. We conclude that about 18% of stimulus-driven cells at the low-frequency end of AI are very sensitive to age-related changes in the purr call. [Copyright &y& Elsevier]

Abstract: Earlier studies using the guinea pig longitudinal muscle/myenteric plexus (LM/MP) demonstrated that chronic morphine treatment in vivo leads to the development of heterologous tolerance while chronic treatment with WIN 55,212-2 induces homologous tolerance. Few studies have evaluated whether a similar difference in tolerance development exists to the analgesic or hypothermic effects of these agents. Tolerance produced following chronic morphine (7days) or WIN-55,212-2 (5days) injection was assessed by determining the alteration in hypothermic response (using a rectal thermometer) or mechanical (paw pressure) or thermal (hot plate) analgesic threshold to challenge doses of WIN-55,212-2 and morphine. The tolerance observed in the hot plate test corresponded closely to that observed in the LM/MP studies where morphine pretreatment produced heterologous tolerance and WIN-55,212-2 pretreatment induced homologous tolerance. In contrast, chronic WIN-55,212-2 pretreatment precipitated tolerance to the analgesic effect of morphine in the paw pressure model despite the absence of an analgesic effect to this agent. Unlike chronic treatment with WIN-55,212-2, no tolerance to the hypothermic effect of WIN-55,212-2 was observed following morphine treatment. However, the hypothermic response observed to morphine challenge was modest suggesting that tolerance to this effect may be difficult to assess or not biologically relevant. The non-uniform character of tolerance observed in different models further suggests that the analysis of tolerance using in vivo test systems involves complex neuronal interactions in which altered responsiveness at one site may produce cascading cellular effects within a neuronal circuit that may differentially impact on tolerance expression. [Copyright &y& Elsevier]

Single- and double-immunostaining techniques were used systematically to study the distribution pattern and neurochemical density of oxytocin-immunoreactive (-ir) neurons in the digestive tract of the guinea pig. Oxytocin immunoreactivity was distributed widely in the guinea pig gastrointestinal tract; 3%, 13%, 17%, 15%, and 10% of ganglion neurons were immunoreactive for oxytocin in the myenteric plexuses of the gastric corpus, jejunum, ileum, proximal colon, and distal colon, respectively, and 36%, 40%, 52%, and 56% of ganglion neurons were immunoreactive for oxytocin in the submucosal plexuses of the jejunum, ileum, proximal colon, and distal colon, respectively. In the myenteric plexus, oxytocin was expressed exclusively in the intrinsic enteric afferent neurons, as identified by calbindin 28 K. In the submucosal plexuses, oxytocin was expressed in non-cholinergic secretomotor neurons, as identified by vasoactive intestinal polypeptide. Oxytocin-ir nerve fibers in the inner circular muscle layer possibly arose from the myenteric oxytocin-ir neurons, and oxytocin-ir nerve fibers in the mucosa possibly arose from both the myenteric and submucosal oxytocin-ir neurons. Thus, oxytocin in the digestive tract might be involved in gastrointestinal tract motility mainly via the regulation of the inner circular muscle and the balance of the absorption and secretion of water and electrolytes. [ABSTRACT FROM AUTHOR]

Abstract: Phase-locked responses to pure tones have previously been described in the primary auditory cortex (AI) of the guinea pig. They are interesting because they show that some cells may use a temporal code for representing sounds of 60–300 Hz rather than the rate or place mechanisms used over most of AI. Our previous study had shown that the phase-locked responses were grouped together, but it was not clear whether they were in separate minicolumns or a larger macrocolumn. We now show that the phase-locked cells are arranged in a macrocolumn within AI that forms a subdivision of the isofrequency bands. Phase-locked responses were recorded from 158 multiunits using silicon based multiprobes with four shanks. The phase-locked units gave the strongest response in layers III/IV but phase-locked units were also recorded in layers II, V and VI. The column included cells with characteristic frequencies of 80 Hz–1.3 kHz (0.5–0.8 mm long) and was about 0.5 mm wide. It was located at a constant position at the intersection of the coronal plane 1 mm caudal to bregma and the suture that forms the lateral edge of the parietal bone. [Copyright &y& Elsevier]

We investigated how physiologically observed forward suppression interacts with stimulus frequency in neuronal responses in the guinea pig auditory cortex. The temporal order and frequency proximity of sounds influence both their perception and neuronal responses. Psychophysically, preceding sounds (conditioners) can make successive sounds (probes) harder to hear. These effects are larger when the two sounds are spectrally similar. Physiological forward suppression is usually maximal for conditioner tones near to a unit's characteristic frequency (CF), the frequency to which a neuron is most sensitive. However, in most physiological studies, the frequency of the probe tone and CF are identical, so the role of unit CF and probe frequency cannot be distinguished. Here, we systemically varied the frequency of the probe tone, and found that the tuning of suppression was often more closely related to the frequency of the probe tone than to the unit's CF, i.e. suppressed tuning was specific to probe frequency. This relationship was maintained for all measured gaps between the conditioner and the probe tones. However, when the probe frequency and CF were similar, CF tended to determine suppressed tuning. In addition, the bandwidth of suppression was slightly wider for off-CF probes. Changes in tuning were also reflected in the firing rate in response to probe tones, which was maximally reduced when probe and conditioner tones were matched in frequency. These data are consistent with the idea that cortical neurons receive convergent inputs with a wide range of tuning properties that can adapt independently. [ABSTRACT FROM AUTHOR]

Exogenous neurotrophin delivery to the deaf cochlea can prevent deafness-induced auditory neuron degeneration, however, we have previously reported that these survival effects are rapidly lost if the treatment stops. In addition, there are concerns that current experimental techniques are not safe enough to be used clinically. Therefore, for such treatments to be clinically transferable, methods of neurotrophin treatment that are safe, biocompatible and can support long-term auditory neuron survival are necessary. Cell transplantation and gene transfer, combined with encapsulation technologies, have the potential to address these issues. This study investigated the survival-promoting effects of encapsulated BDNF over-expressing Schwann cells on auditory neurons in the deaf guinea pig. In comparison to control (empty) capsules, there was significantly greater auditory neuron survival following the cell-based BDNF treatment. Concurrent use of a cochlear implant is expected to result in even greater auditory neuron survival, and provide a clinically relevant method to support auditory neuron survival that may lead to improved speech perception and language outcomes for cochlear implant patients. [ABSTRACT FROM AUTHOR]

Background/Aims: Morphine is known to inhibit cholinergic contractions of the guinea pig small intestine. This has been compared to the human small intestinal innervated longitudinal muscle in the current study. Methods: Cholinergic primary contractions of human small intestinal longitudinal strips were evoked by electrical field stimulation (EFS; 0.5– 5 Hz in the presence of purinergic and nitrergic blockers or 5 Hz without pretreatment) and recorded isotonically in organ bath experiments. Guinea pig small intestinal segments were also studied. Results and Conclusion: Neurogenic cholinergic contractions of human preparations were unaffected by morphine (1, 2 or 10 μmol/l). Longitudinal contractions of the guinea pig ileum were concentration-dependently suppressed by morphine (0.1–10 μmol/l). It is concluded that myenteric neurons supplying the longitudinal muscle of the human small intestine are much less sensitive to morphine than those of the guinea pig. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: The present study was designed to investigate the effects of recurrent periods of apnea/hypoxia on the morphology of neurons in sites that control NREM and REM sleep. In addition, we determined whether the administration of a GABA agonist, eszopiclone, was capable of preventing the degenerative, i.e., apoptotic, sequelae of hypoxia in these sleep-promoting neurons. Adult guinea pigs were divided into control (normoxic) and hypoxic groups; a separate group of hypoxic animals was administered eszopiclone. Recurrent periods of hypoxia and normoxia lasted for a duration of 3h. Subsequently, the brains were sectioned, and areas in the CNS that control NREM sleep as well as REM sleep were examined after staining with an antibody raised against single-stranded DNA, which labels apoptotic neurons. In the group of control (normoxic) animals, apoptotic neurons were not observed in CNS regions that control NREM or REM sleep. In hypoxic animals, a large number of apoptotic neurons were found in the preceding regions. In the hypoxic animals that were administered eszopiclone, there were almost no apoptotic neurons in the brain regions that control NREM or REM sleep. These results demonstrate that recurrent periods of apnea induce extensive apoptosis in CNS nuclei that control NREM and REM sleep and that eszopiclone is capable of preventing neuronal degeneration in these sites. We suggest that the degeneration of neurons in sites that control the states of sleep is responsible for those sleep disturbances that arise as a consequence of hypoxia in individuals with sleep-related breathing disorders. [Copyright &y& Elsevier]

Background and Purpose: Urocortins (Ucns) 1, 2 and 3 are corticotropin-releasing factor (CRF)-related neuropeptides and may be involved in neural regulation of colonic motor functions. Nevertheless, details of the neural mechanism of action for Ucns have been unclear. We have, here, tested the hypothesis that Ucns act in the enteric nervous system (ENS) to influence colonic motor behaviour.Experimental Approach: We used intracellular recording with 'sharp' microelectrodes, followed by intraneuronal injection of biocytin, and immunohistochemical localization of CRF(1) and CRF(2) receptors in guinea pig colonic tissue.Key Results: Application of Ucn1 depolarized membrane potentials and elevated excitability in 58% of AH-type and 60% of S-type colonic myenteric neurons. In most of the neurons tested, depolarizing responses evoked by Ucn-1 were suppressed by the CRF(1) receptor antagonist NBI 27914, but were unaffected by the CRF(2) receptor antagonist antisauvagine-30. The selective CRF(2) receptor agonists, Ucn2 and Ucn3, evoked depolarizing responses in 12 and 8% of the AH-type myenteric neurons, respectively, and had no effect on S-type neurons. Antisauvagine-30, but not NBI 27914, suppressed these Ucn2- and Ucn3-evoked responses. Immunohistochemical staining identified CRF(1) as the predominant CRF receptor subtype expressed by ganglion cell somas, while CRF(2)-immunoreactive neuronal somas were sparse. Ucns did not affect excitatory synaptic transmission in the ENS.Conclusions and Implications: The results suggest that Ucns act as neuromodulators to influence myenteric neuronal excitability. The excitatory action of Ucn1 in myenteric neurons was primarily at CRF(1) receptors, and the excitatory action of Ucn2 and Ucn3 was at CRF(2) receptors. [ABSTRACT FROM AUTHOR]

Conclusion. High-frequency overstimulation can cause the loss of duration selectivity in low-frequency inferior colliculus neurons in guinea pigs. Objective. To investigate the effect of high-frequency overstimulation on duration tuning in low-frequency inferior colliculus neurons in guinea pigs. Materials and methods. Duration tuning pattern was recorded by measuring the spikes of single neurons in response to the best frequency (BF) of different durations. The effect of high-frequency overstimulation was verified by comparing the responses before and after the tone exposure. Results. In total, 40 duration-tuned neurons were successfully recorded before and after the tone exposure. After the high-frequency tone trauma, a total of 29 neurons (72.5%) became non-duration-tuned. [ABSTRACT FROM AUTHOR]

We investigated the effect of inflammation on slow synaptic transmission in myenteric neurons in the guinea pig ileum. Inflammation was induced by the intraluminal injection of trinitrobenzene sulfonate, and tissues were taken for in vitro investigation 6-7 days later. Brief tetanic stimulation of synaptic inputs (20 Hz, 1 s) induced slow excitatory postsynaptic potentials (EPSPs) in 49% and maintained postsynaptic excitation that lasted from 27 mm to 3 h in 13% of neurons from the inflamed ileum. These neurons were classified electrophysiologically as AH neurons; 10 were morphological type II neurons, and one was type 1. Such long-term hyperexcitability after a brief stimulus is not encountered in enteric neurons of normal intestine. Electrophysiological properties of neurons with maintained postsynaptic excitation were similar to those of neurons with slow EPSPs. Another form of prolonged excitation, sustained slow postsynaptic excitation (SSPE), induced by 1-Hz, 4-mm stimulation, in type II neurons from the inflamed ileum reached its peak earlier but had lower amplitude than that in control. Unlike slow EPSPs and similar to SSPEs, maintained excitation was not inhibited by neurokinin-1 or neurokinin-3 receptor antagonists. Maintained postsynaptic excitation was not influenced by PKC inhibitors, but the PKA inhibitor, H-89, caused further increase in neuronal excitability. In conclusion, maintained excitation, observed only in neurons from the inflamed ileum, may contribute to the dysmotility, pain, and discomfort associated with intestinal inflammation. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the neurochemical characteristics of olfactory ensheathing cells (OECs) in adult cats and in adult guinea pigs. Three conventional biomarkers for OECs, p75 neurotrophin receptor (p75NTR), S100, and glial fibrillary acidic protein (GFAP), as well as two recently identified biomarkers, smooth muscle α-actin (SMA) and calponin, were used. We found that 1) antibodies against SMA and S100 yielded positive immunostaining of mucosal and bulbar OECs in cats and guinea pigs; 2) antibodies against GFAP gave positive immunostaining of mucosal and bulbar OECs in cats; and 3) antibodies against calponin yielded positive immunostaining of bulbar OECs in adult cats. Unexpectedly, antibodies against p75NTR failed to positively stain mucosal and bulbar OECs in cats and guinea pigs, and antibodies against GFAP and calponin failed to positively stain mucosal and bulbar OECs in guinea pigs. These findings show the importance for empirical testing of all biomarkers for OECs among different mammalian species when attempting to identify these cells in vivo, in vitro, and following intraspinal implantation. [Copyright &y& Elsevier]

Slow oscillations at frequencies <1 Hz manifest in many brain regions as discrete transitions between a depolarized up state and a hyperpolarized down state of the neuronal membrane potential. Although up and down states are known to differentially affect sensoryevoked responses, whether and how they are modulated by sensory stimuli are not well understood. In the present study, intracellular recording in anesthetized guinea pigs showed that membrane potentials of nonlemniscal auditory thalamic neurons exhibited spontaneous up/down transitions at random intervals in the range of 2-30 s, which could be entrained to a regular interval by repetitive sound stimuli. After termination of the entraining stimulation (ES), regular up/down transitions persisted for several cycles at the ES interval. Furthermore, the efficacy of weak sound stimuli in triggering the up-to-down transition was potentiated specifically at the ES interval for at least 10 min. Extracellular recordings in the auditory thalamus of unanesthetized guinea pigs also showed entrainment of slow oscillations by rhythmic sound stimuli during slow wave sleep. These results demonstrate a novel form of network plasticity, which could help to retain the information of stimulus interval on the order of seconds. [ABSTRACT FROM AUTHOR]

Comparative studies of the activity of extracellularly recorded neurons in living slices of the medial septal area of healthy guinea pigs and animals with a model of chronic temporal epilepsy demonstrated differences between them in terms of the frequency and pattern of cell discharges. The brains of animals with experimental epilepsy showed a doubling of the total level of activity as compared with controls, due to increases in the discharge frequencies of irregular and regular non-volleying neurons. There was a sharp (three-fold) increase in the number of cells with rhythmic discharge volleys, along with changes in the parameters of volley activity — both in neurons with the endogenous (pacemaker) pattern and in cells with secondary involvement in rhythmic activity. The possible mechanisms for these changes are discussed. These data widen our understanding of the processes forming pathological synchronization in epilepsy and may assist in the creation of new approaches to the treatment of this disease. [ABSTRACT FROM AUTHOR]

Conclusion. GABA-mediated inhibition is responsible for the duration tuning in the inferior colliculus (IC) of guinea pigs, a non-echo-locating mammal. Duration tuning in this species is better demonstrated in an appropriate short time window. Objectives. To investigate the role of GABA-mediated inhibition in duration tuning of neurons in the IC of guinea pigs. Materials and methods. Duration tuning pattern was recorded by measuring the spikes of single neurons in response to broadband noise of different durations. The effect of GABA-mediated inhibition was verified by comparing the responses with and without the use of the GABA-A receptor blocker bicuculline (BIC), which was applied using micro-iontophoresis. Results. In addition to overall increase in responsiveness, the application of BIC was found to significantly reduce or eliminate the duration selectivity in 44 of the 67 neurons that showed clear duration tuning from a sample of total 340 neurons. [ABSTRACT FROM AUTHOR]

Cochlear implant speech processors transmit temporal features of sound as amplitude modulation of constant-rate electrical pulse trains. This study evaluated the central representation of amplitude modulation in the form of phase-locked firing of neurons in the auditory cortex. Anesthetized pigmented guinea pigs were implanted with cochlear electrode arrays. Stimuli were 254 pulse/s (pps) trains of biphasic electrical pulses, sinusoidally modulated with frequencies of 10–64 Hz and modulation depths of –40 to –5 dB re 100% (i.e., 1–56.2% modulation). Single- and multiunit activity was recorded from multi-site silicon-substrate probes. The maximum frequency for significant phase locking (limiting modulation frequency) was ≥60 Hz for 42% of recording sites, whereas phase locking to pulses of unmodulated pulse trains rarely exceeded 30 pps. The strength of phase locking to frequencies ≥40 Hz often varied nonmonotonically with modulation depth, commonly peaking at modulation depths around –15 to –10 dB. Cortical phase locking coded modulation frequency reliably, whereas a putative rate code for frequency was confounded by rate changes with modulation depth. Group delay computed from the slope of mean phase versus modulation frequency tended to increase with decreasing limiting modulation frequency. Neurons in cortical extragranular layers had lower limiting modulation frequencies than did neurons in thalamic afferent layers. Those observations suggest that the low-pass characteristic of cortical phase locking results from intracortical filtering mechanisms. The results show that cortical neurons can phase lock to modulated electrical pulse trains across the range of modulation frequencies and depths presented by cochlear implant speech processors. [ABSTRACT FROM AUTHOR]

5-HT4 receptor agonists facilitate synaptic transmission in the enteric nervous system, and these drugs are used to treat constipation. In the present study, we investigated the effects of the 5-HT4 receptor agonist, renzapride, on rundown and recovery of fast excitatory postsynaptic potentials (fEPSPs) during and after trains of stimulation and on transmitter release from individual myenteric neuronal varicosities. Intracellular electro-physiological methods were used to record fEPSPs from neurons in longitudinal muscle myenteric plexus preparations of guinea pig ileum in vitro. During trains of supramaxirnal electrical stimulation (10 Hz, 2 s), fEPSP amplitude declined (time constant 0.6 ± 0.1 s) from 17 ± 2 mV to 0.7 ± 0.3 mV. Renzapride (0.1 µM) did not change the time constant for fEPSP rundown, but it decreased the time constant for recovery of fEPSP amplitude after the stimulus train from 7 ± 2 s to 1.6 ± 0.2 s (P < 0.05). 5-HT (0.1 µM) also increased fEPSPs and facilitated recovery from rundown. The adenylate cyclase activator, forskolin (1 µM), mimicked the actions of renzapride and 5-HT, whereas H-89, a protein kinase A (PKA) inhibitor, blocked the effects of renzapride. We used nicotinic acetylcholine receptor containing outside-out patches obtained from myenteric neurons maintained in primary culture to detect acetylcholine release from single varicosities. Renzapride (0.1 µM) increased release probability two-fold. We conclude that 5-HT4 receptors activate the adenylyl cyclase-PKA pathway to increase acetylcholine release from single varicosities and to accelerate recovery from synaptic rundown. These responses may contribute to the prokinetic actions of 5-HT4 receptor agonists. [ABSTRACT FROM AUTHOR]

Abstract: The minimal change in a stimulus property that is detectable by neurons has been often quantified using the receiver operating characteristic (ROC) curve, but recent studies introduced the use of the related Fisher information (FI). Whereas ROC analysis and FI quantify the information available for discriminating between two stimuli, global aspects of the information carried by a neuron are quantified by the mutual information (MI) between stimuli and responses. FI and MI have been shown to be related to each other when FI is large. Here the responses of neurons recorded in the inferior colliculus of anesthetized guinea pigs in response to ensembles of sounds differing in their interaural time differences (ITDs) or binaural correlation (BC) were analyzed. Although the FI is not uniformly large, there are strong relationships between MI and FI. Information-theoretic measures are used to demonstrate the importance of the non-Poisson statistics of these responses. These neurons may reflect the maximization of the MI between stimuli and responses under constraints on the coded stimulus range and the range of firing rates. Remarkably, whereas the maximization of MI, in conjunction with the non-Poisson statistics of the spike trains, is enough to create neurons whose ITD discrimination capabilities are close to the behavioral limits, the same rule does not achieve single-neuron BC discrimination that is as close to behavioral performance. [Copyright &y& Elsevier]

Exposure of the immature brain to general anesthesia is common. The safety of this practice has recently been challenged in view of evidence that general anesthetics can damage developing mammalian neurons. Initial reports on immature rats raised criticism regarding the possibly unique vulnerability of this species, short duration of their brain development and a lack of close monitoring of nutritional and cardiopulmonary homeostasis during anesthesia. Therefore, we studied the neurotoxic effects of anesthesia in guinea pigs, whose brain development is longer and is mostly a prenatal phenomenon, so that anesthesia-induced neurotoxicity studies of the fetal brain can be performed by anesthetizing pregnant female pigs. Because of their large size, these animals made invasive monitoring of maternal and, indirectly, fetal well-being technically feasible. Despite adequate maintenance of maternal homeostasis, a single short maternal exposure to isoflurane, whether alone or with nitrous oxide and/or midazolam at the peak of fetal synaptogenesis, induced severe neuroapoptosis in the fetal guinea pig brain. As detected early in post-natal life, this resulted in the loss of many neurons from vulnerable brain regions, demonstrating that anesthesia-induced neuroapoptosis can cause permanent brain damage. [ABSTRACT FROM AUTHOR]

Abstract: The mammalian parasympathetic cardiac ganglia form a complex intrinsic cardiac nervous system presumed to contain multiple neuron types and are innervated by extrinsic fibers from multiple sources, each containing specific neurotransmitters and neuropeptides. In the guinea pig, the preganglionic parasympathetic cholinergic fibers contain the neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), and essentially all cardiac neurons express the PACAP selective PAC1 receptor. Application of exogenous PACAP depolarizes and enhances the excitability of guinea pig cardiac neurons. The mechanism by which PACAP enhances excitability is not established. However, Ca2+ influx through PACAP-activated nonselective cation channels is required for the PACAP-induced increase in excitability of guinea pig cardiac neurons. In addition, a PACAP-induced shift in the voltage dependence of activation of the cyclic nucleotidegated, hyperpolarization-activated current, Ih, most likely participates in the peptide-induced increase in neuronal excitability. The release of endogenous PACAP by repetitive stimulation of preganglionic fibers in vitro contributes to the generation of a slow excitatory postsynaptic potential and also can enhance cardiac neuron excitability. We hypothesize that PACAP released during ongoing vagal activity may regulate cardiac neuron excitability in vivo. [Tzu Chi Med J 2008;20(1):11–18] [Copyright &y& Elsevier]

Abstract: The study investigated the time course of the effects of acoustic and electric stimulation on the electrically evoked compound action potential (ECAP). Adult guinea pigs were used in acute experimental sessions. Bursts of acoustic noise and high-rate (5000pulses/s) electric pulse trains were used as maskers. Biphasic electric pulses were used as probes. ECAPs were recorded from the auditory nerve trunk. Simultaneous masking of the ECAP with acoustic noise featured an onset effect and a decrease in the amount of masking to a steady state. It was characterized by a two-component exponential function. The amount of masking increased with masker level and decreased with probe level. Post-stimulatory ECAP recovery often featured a non-monotonic time course, described by a three-component exponent. Electric maskers produced similar post-stimulatory effects in hearing and acutely deafened subjects. Acoustic stimulation affects the ECAP in a level- and time-dependent manner. Simultaneous masking follows a time course comparable to that of adaptation to an acoustic stimulus. Refractoriness, spontaneous activity, and adaptation are suggested to play a role in ECAP recovery. Post-stimulatory changes in synchrony, possibly due to recovery of spontaneous activity and an additional hair-cell independent mechanism, are hypothesized to contribute to the observed non-monotonicity of recovery. [Copyright &y& Elsevier]

Extracellular recordings were obtained from single cochlear nucleus neurons in guinea pigs anesthetized with Nembutal and Hypnorm. Neurons were classified by their spontaneous firing rates and responses to acoustic stimuli. In addition, electrical shocks were applied to the midline at the level of the IVth ventricle and spike responses were recorded. Spikes were evoked by shocks only in neurons that were classified as onset choppers (O(c)). The shock-evoked spikes could be extinguished by acoustically evoked action potentials in the same neurons. In roughly 30% of the sample of O(c) neurons, quantitative aspects of the timing of this extinction were not compatible with the shock-evoked spike being antidromically conducted from O(c) output axons. Together with the presence of temporal jitter at high shock rates, the data suggest the possibility that at least some of the shock-evoked spikes may be generated by excitatory synaptic input to the O(c) neurons, most likely from the collaterals of the medial olivocochlear system (MOCS), whose axons pass close to the floor of the IVth ventricle. This excitatory synaptic input may operate to modulate the activity of O(c) neurons in addition to MOCS actions in the auditory periphery. [ABSTRACT FROM AUTHOR]

Abstract: The study of the early events that characterize cerebral ischemia is limited in available experimental models. The study of neurophysiological network changes that occur in brain tissue during the early minutes that follow focal ischemia induction is restricted in the in vivo condition. Very simplified systems, such as in vitro brain slices and in isolated neurons, have been utilized for this type of studies. We describe here a new model of transient focal ischemia and reperfusion developed in the isolated guinea pig brain, maintained in vitro by arterial perfusion with a complex saline solution without blood cells. In this preparation, that combines the advantage of an in vitro preparation with the functional preservation of both vascular and neuronal compartments, the arteries of the Willis circle are directly accessible by visual control. To induce transitory focal ischemia, one medial cerebral artery (MCA) was transiently tied for 30 min, while brain activity was recorded with multiple electrodes positioned in brain areas within and outside MCA territory. Anoxic depression in ischemic areas propagated to the surrounding tissue and was associated with the abolition of evoked responses due to both functional impairment of afferent olfactory input and tissue depression. Recovery of evoked responses was obtained after MCA reperfusion. The spatial distribution of hypoxic depressions was characterized and was correlated with the extension of brain damage, defined by immunohistochemical analysis with antibodies against microtubule-associated protein (MAP-2). We propose that the present model can be utilized to analyze brain activity changes that occur in early stages of focal brain ischemia and reperfusion. [Copyright &y& Elsevier]

This study examined whether mucosal stimulation activates long secretomotor neural reflexes and, if so, how they are organized. The submucosa of in vitro full thickness guinea pig ileal preparations was exposed in the distal portion and intracellular recordings were obtained from electrophysiologically identified secretomotor neurons. Axons in the intact mucosa of the oral segment were stimulated by a large bipolar stimulating electrode. In control preparations, a single stimulus pulse evoked a fast excitatory postsynaptic potential (EPSP) in 86% of neurons located 0.7-1.0 cm anal to the stimulus site. A stimulus train evoked multiple fast EPSPs, but slow EPSPs were not observed. To examine whether mucosal stimulation specifically activated mucosal sensory nerve terminals, the mucosa/submucosa was severed from the underlying layers and repositioned. In these preparations, fast EPSPs could not be elicited in 89% of cells. Superfusion with phorbol dibutyrate enhanced excitability of sensory neurons and pressure-pulse application of serotonin to the mucosa increased the fast EPSPs evoked by mucosal stimulation, providing further evidence that sensory neurons were involved. To determine whether these reflexes projected through the myenteric plexus, this plexus was surgically lesioned between the stimulus site and the impaled neuron. No fast EPSPs were recorded in these preparations following mucosal stimulation whereas lesioning the submucosal plexus had no effect. These results demonstrate that mucosal stimulation triggers a long myenteric pathway that activates submucosal secretomotor neurons. This pathway projects in parallel with motor and vasodilator reflexes, and this common pathway may enable coordination of intestinal secretion, blood flow, and motility. [ABSTRACT FROM AUTHOR]

Functional changes induced by inflammation persist following recovery from the inflammatory response, but the mechanisms underlying these changes are not well understood. Our aim was to investigate whether the excitability and synaptic properties of submucosal neurons remained altered 8 wk post-trinitrobenzene sulfonic acid (TNBS) treatment and to determine whether these changes were accompanied by alterations in secretory function in submucosal preparations voltage clamped in Ussing chambers. Mucosal serotonin (5-HT) release measurements and 5-HT reuptake transporter (SERT) immunohistochemistry were also performed. Eight weeks after TNBS treatment, colonic inflammation resolved, as assessed macroscopically and by myeloperoxidase assay. However, fast excitatory postsynaptic potential (fEPSP) amplitude was significantly increased in submucosal S neurons from previously inflamed colons relative to those in control tissue. In addition, fEPSPs from previously inflamed colons had a hexamethonium-insensitive component that was not evident in age-matched controls. AH neurons were hyperexcitable, had shorter action potential durations, and decreased afterhyperpolarization 8 wk following TNBS administration. Neuronally mediated colonic secretory function was significantly reduced after TNBS treatment, although epithelial cell signaling, as measured by responsiveness to both forskolin and bethanecol in the presence of tetrodotoxin, was comparable with control tissue. 5-HT levels and SERT immunoreactivity were comparable to controls 8 wk after the induction of inflammation, but there was an increase in glucagon-like peptide 2-immunoreactive L cells. In conclusion, sustained alterations in enteric neural signaling occur following the resolution of colitis, which are accompanied by functional changes in the absence of active inflammation. [ABSTRACT FROM AUTHOR]

The aim of this study was to perform an immunohistochemical characterization of two different myenteric neuron types of the pig displaying opposite axonal projections. These were type I neurons equipped with lamellar dendrites that projected mainly orally, and type VI neurons that displayed typical axonal dendrites and projected anally. Double immunostainings of longitudinal muscle/myenteric plexus wholemounts from ileal segments of four pigs were performed to visualize neurofilaments (NF) in combination with calcitonin gene-related peptide (CGRP), leu-enkephalin (ENK) and substance P (SP), respectively. Triple immunostainings of wholemounts, using antibodies against neuronal nitric oxide synthase (nNOS) and vasoactive intestinal peptide (VIP) as well as against VIP and galanin (GAL), were performed. We found that 78% of type I neurons immunoreacted to ENK, 21% to CGRP and 24% to SP. The NF-positive type I neurons co-reactive for one of the three above markers displayed mostly frayed outlines of both their somal contours and their broadened dendritic endings. By contrast, most of the non-coreactive type I neurons displayed rather sharply outlined somata and dendrites. No type I neuron immunoreacted to nNOS, VIP or GAL and none of the type VI NF-reactive neurons reacted to CGRP, ENK or SP. All type VI neurons investigated displayed immunoreactivity for nNOS, 92% of which were co-reactive for VIP. Co-reactivity for VIP and GAL was found in 69% of type VI neurons, 21% were positive for VIP but negative for GAL, 9% were negative for both GAL and VIP, and 1% were positive for GAL but negative for VIP. We conclude that there are two subpopulations of morphological type I neurons. One of these displays mainly oral projections and could not be further characterized in this study. The other, which may correspond to neurons innervating the longitudinal and circular muscle layers, were partly immunoreactive for ENK, CGRP and/or SP. Type VI neurons are immunoreactive for nNOS frequently co-localized with VIP and, partly, also GAL. These may be inhibitory motor neurons and are different from VIP/GAL-coreactive minineurons described earlier. [ABSTRACT FROM AUTHOR]

Low voltage-activated (T-type) Ca2+ channels are responsible for generating low-threshold spikes (LTS) that facilitate burst firing and transmitter release in neurons. The T-type Ca2+ channels contain a regulatory α1 subunit, and several isoforms of the α1 subunit (Cav3.1, 3.2, 3.3) have been cloned. The Cav 3.1 α1 subunit is abundantly expressed in the hypothalamus. Previously, we found that 17 β-estradiol (E2) increased the number of arcuate neurons expressing LTS. Therefore, we used an ovariectomized female guinea pig model to measure the distribution and regulation of Cav3.1mRNAexpression by E2. Guinea pig Cav3.1 α1 subunit sequences, which were cloned by PCR, were used in ribonuclease protection (RPA) and in situ hybridization assays to evaluate mRNA expression. Based on a RPA, E2 significantly increased the mRNA expression of Cav3.1 α1 subunit in the mediobasal hypothalamus and the pituitary. In situ hybridization analysis revealed that E2 significantly increased Cav 3.1mRNAexpression in medial preoptic nuclei, bed nuclei stria terminalis, and the arcuate nucleus. Whole-cell patch recordings in arcuate neurons revealed that E2 treatment significantly increased the peak T-type Ca2+ current density by twofold without affecting the activation/inactivation characteristics and augmented the rebound excitation by threefold to fourfold. These results suggest that estrogen regulates the mRNA expression of T-type calcium channels, which leads to increased functional expression of the channel. Increased expression of T-type channels could be one mechanism by which estrogen augments burst firing and transmitter release in hypothalamic neurons. [ABSTRACT FROM AUTHOR]

Numerous models of the oculomotor neuronal integrator located in the prepositus hypoglossi nucleus (PHN) involve both highly tuned recurrent networks and intrinsic neuronal properties; however, there is little experimental evidence for the relative role of these two mechanisms. The experiments reported here show that all PHN neurons (PHNn) show marked phasic behavior, which is highly oscillatory in approximately 25% of the population. The behavior of this subset of PHNn, referred to as type D PHNn, is clearly different from that of the medial vestibular nucleus neurons, which transmit the bulk of head velocity-related sensory vestibular inputs without integrating them. We have investigated the firing and biophysical properties of PHNn and developed data-based realistic neuronal models to quantitatively illustrate that their active conductances can produce the oscillatory behavior. Although some individual type D PHNn are able to show some features of mathematical integration, the lack of robustness of this behavior strongly suggests that additional network interactions, likely involving all types of PHNn, are essential for the neuronal integrator. Furthermore, the relationship between the impulse activity and membrane potential of type D PHNn is highly nonlinear and frequency-dependent, even for relatively small-amplitude responses. These results suggest that some of the synaptic input to type D PHNn is likely to evoke oscillatory responses that will be nonlinearly amplified as the spike discharge rate increases. It would appear that the PHNn have specific intrinsic properties that, in conjunction with network interconnections, enhance the persistent neural activity needed for their function. [ABSTRACT FROM AUTHOR]