RESUMEN
Prior research [Caine et al., 1981] suggested that scopolamine, a central cholinergic antagonist, may increase gap thresholds in young human listeners. If confirmed, an effect of scopolamine on gap detection might help to explain why both aged humans and aged laboratory animals have less sensitive temporal acuity on gap detection tests, as they may be presumed to have less effective cholinergic mechanisms. Here we measured the effect of scopolamine on gap detection in rats (n=8) using reflex modification audiometry, which depends on the fact that brief gaps in noise presented immediately prior to a loud noise inhibit the acoustic startle reflex. Scopolamine increased the gap threshold and reduced reflex inhibition produced by gaps that were presented at and beyond about 40 ms prior to the startle reflex, but not at shorter lead times. A peripheral antagonist had no effect at long lead times. These data indicate that central cholinergic mechanisms are involved in relatively high level perceptual processing of gaps. This conclusion is consistent with the hypothesis that temporal acuity may be compromised in the aged listener because of deficits in the efficacy of these central mechanisms.
Asunto(s)
Fibras Colinérgicas/fisiología , Audición/efectos de los fármacos , Antagonistas Muscarínicos/farmacología , Escopolamina/farmacología , Percepción del Tiempo/fisiología , Estimulación Acústica/métodos , Animales , Audiometría , Femenino , Masculino , Antagonistas Muscarínicos/metabolismo , Ruido , Enmascaramiento Perceptual , Ratas , Ratas Long-Evans , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Escopolamina/metabolismoRESUMEN
The use of adenovirus vectors for gene therapy has been limited by well-defined cellular and humoral immune responses. We have previously shown that adenovirus vectors rapidly induce the expression of the C-X-C chemokine, interferon-inducible protein 10 (IP-10), in vivo. Various first-generation, type 5 adenovirus vectors, including adCMVbetagal and UV-psoralen-inactivated adenovirus, equally induced the expression of IP-10 mRNA as early as 3 h following infection in mouse renal epithelial cells (REC). Luciferase reporter experiments using deletional mutants of the murine IP-10 5'-flanking region revealed that transcriptional activation of the IP-10 promoter by adCMVbetagal was dependent on the -161- to -96-bp region upstream of the transcription start site. In electrophoretic mobility shift assays, adCMVbetagal, adCMV-GFP, FG140, and transcription-defective adenovirus induced protein binding to oligonucleotides containing a consensus sequence for NF-kappaB at position -113 of the IP-10 promoter. Supershift assays confirmed an increase in binding activity of NF-kappaB p65 but not p50 or cRel in REC cells infected with various replication-deficient adenoviruses. Coinfection of REC cells with adCMVbetagal and an adenoviral vector expressing IkappaBalpha resulted in suppression of adCMVbetagal-induced expression of IP-10 at 6 and 16 h, further strengthening the conclusion that adenovirus-induced activation of IP-10 is dependent on NF-kappaB. The induction of IP-10 appeared to be direct because infection with adenovirus vectors failed to induce the expression of the potent IP-10 stimulators, interferon gamma and tumor necrosis factor alpha. Together, these findings demonstrate that adenovirus vectors directly induce the expression of IP-10 through capsid dependent activation of NF-kappaB.
Asunto(s)
Adenovirus Humanos/fisiología , Quimiocinas CXC/genética , Productos del Gen gag/metabolismo , Vectores Genéticos/fisiología , Interferón gamma/genética , FN-kappa B/metabolismo , Adenovirus Humanos/genética , Animales , Células Cultivadas , Quimiocina CXCL10 , Regulación de la Expresión Génica , Productos del Gen gag/genética , Vectores Genéticos/genética , Ratones , Ratones Endogámicos DBA , Subunidad p50 de NF-kappa B , Regiones Promotoras Genéticas , Factor de Transcripción ReIA , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Young rats were presented with light flash prepulses varying in duration from 1 to 128 ms, with light offset or light onset fixed at 70 ms prior to an acoustic startle stimulus (Experiment 1A), and, with single or paired 1-ms flashes, the 2nd (or only) flash given 100 to 500 ms before the startle, and 1 ms to 400 ms interflash intervals (Experiment 1B). Older rats (10 and 20 months old) received the same single and double flashes but with the maximum interflash interval extended to 1,500 ms (Experiment 2). Reflex inhibition increased with increased duration from 1 to 8 ms and decreased as light onset progressively exceeded 100 ms. Inhibition for both single and double flashes also declined for onset lead times beyond 100 ms, then increased for a double flash once the interflash interval exceeded 100 ms in young and middle-aged rats and 1,500 ms in the oldest rats. Peak inhibition was much reduced in the oldest rats at short lead times but was greater than that of younger rats at long lead times. These data suggest that aged rats process visual stimuli more slowly than younger rats and show poorer temporal acuity coupled with greater visual persistence.
Asunto(s)
Envejecimiento/fisiología , Conducta Animal/fisiología , Condicionamiento Clásico/fisiología , Potenciales Evocados Visuales/fisiología , Reflejo de Sobresalto/fisiología , Percepción Visual/fisiología , Estimulación Acústica/métodos , Análisis de Varianza , Animales , Inhibición Psicológica , Estimulación Luminosa/métodos , Ratas , Ratas Long-Evans , Tiempo de ReacciónRESUMEN
Small increments in background noise were shown to increase the amplitude of a subsequently elicited acoustic startle reflex (ASR) in rats by as much as 100% under optimal conditions. Increment lead time (5-160 ms) and level (1.5-15 dB), initial noise level (30-70 dB), startle level (95-125 dB), number of test days (1-5), and drug condition (diazepam or saline ip) were varied in 6 experiments. Prepulse facilitation (PPF), measured by difference scores, was greatest for intermediate increments (3 dB) and lead times (20-40 ms) and was replaced by prepulse inhibition (PPI) for higher values, especially in the later test days. Diazepam reduced baseline ASR and diminished PPI, but it did not affect PPF. These data argue against hypotheses that attribute PPF of this sort to either temporal integration within the ASR pathways or to the elicitation of a nonspecific arousal reaction by the prepulse.
Asunto(s)
Estimulación Acústica , Conducción Nerviosa/fisiología , Inhibición Neural/fisiología , Ruido , Reflejo de Sobresalto/fisiología , Animales , Nivel de Alerta/efectos de los fármacos , Nivel de Alerta/fisiología , Diazepam/farmacología , Moduladores del GABA/farmacología , Hipnóticos y Sedantes/farmacología , Masculino , Conducción Nerviosa/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Psicoacústica , Ratas , Ratas Endogámicas , Reflejo de Sobresalto/efectos de los fármacos , Factores de TiempoRESUMEN
We have previously described how the expression of photoreceptor cell degeneration in the Fischer 344 rat is affected by age, retinal topography, and gender. Degeneration in the central and equatorial regions progresses linearly with age throughout the life span of the animal, while the periphery of the male is subject to sudden and dramatic losses of cells in the superior hemisphere after 12 months and in the inferior hemisphere after 18 months of age. The purpose of the present study was to determine how this degeneration affected retinal function and visual ability in the male Fischer 344 from 3 to 24 months of age. Functional testing included the electroretinogram (ERG, measuring both a-wave and b-wave amplitudes and implicit times) and the behavioral method of startle reflex modification (RM, which measures the degree to which a light flash inhibits the response to an immediately subsequent loud noise). All of the functional measures showed a decline with age, but varied in their time course. ERG amplitudes showed a linear decline in amplitude over the entire age range. In contrast, the implicit times of the ERG waves and the degree to which the light flash inhibited the startle reaction both showed a slight maturation in function (faster implicit times and greater inhibition) from 8 or 12 months of age. After 18 months of age, the implicit time showed a significant increase and the startle response showed a significant decrease. This study shows how visual function correlates with the histopathological changes seen in age-related retinal degeneration.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Envejecimiento/fisiología , Células Fotorreceptoras/fisiología , Degeneración Retiniana/fisiopatología , Animales , Conducta Animal/fisiología , Electrorretinografía , Masculino , Células Fotorreceptoras/patología , Ratas , Ratas Endogámicas F344 , Reflejo de Sobresalto/fisiología , Degeneración Retiniana/patología , Visión Ocular/fisiologíaRESUMEN
In the rat with normal sight, the acoustic startle reflex to a sound burst is suppressed when the sound is preceded by a brief light pulse. This effect of light in the rat with retinal damage is reduced and peak suppression is seen at a greater delay. Both observations are expected consequences of the loss of visual sensitivity that should accompany photoreceptor loss. However, in an early stage of retinal damage, the peak of the suppressive effect is so delayed that at long lead times the light flash is a more effective stimulus in the rat with the damaged retina than in the normal rat. Two experiments tested the hypothesis that this crossing over of the two groups is a secondary consequence of a nonspecific loss of visual sensitivity in the visually impaired rat. If the hypothesis is correct, reductions in the intensity or duration of the light flash and the degree of dark adaptation should model the effect in normal rats. The overall amount of reflex suppression was diminished with these manipulations, but none diminished the temporal development of reflex suppression to a degree sufficient to produce the paradoxical crossover effect characteristic of retinal damage. These data indicate that decrements in the speed of visual processing are not secondary to the changes in sensitivity that accompany retinal damage, but should be viewed as a separate and independent form of visual impairment.
Asunto(s)
Estimulación Luminosa , Retina/fisiopatología , Trastornos de la Visión/fisiopatología , Animales , Adaptación a la Oscuridad , Electrorretinografía , Femenino , Cinética , Masculino , Ratas , Ratas Endogámicas F344 , Reflejo Acústico , Retina/lesiones , Umbral SensorialRESUMEN
In seeing rats light flashes inhibit acoustic startle reflexes at short lead times. In contrast, visually impaired (light-blinded) rats show an early phase of exaggerated reflex expression, revealing the presence of pathological visual processing, and then an aberrant late phase of delayed inhibition. Grafting fetal retinal cells into the damaged retina entirely removed reflex facilitation and restored a modest degree of properly timed and statistically significant reflex inhibition. This restoration of visually-mediated behaviour, observed in two independent groups, reveals that intraretinal grafts provide useful information to blinded hosts.
Asunto(s)
Trasplante de Tejido Fetal , Reflejo Acústico/fisiología , Retina/trasplante , Trastornos de la Visión/fisiopatología , Estimulación Acústica , Animales , Luz/efectos adversos , Masculino , Estimulación Luminosa , Ratas , Ratas Endogámicas F344/embriología , Reflejo Acústico/efectos de la radiación , Retina/embriología , Trastornos de la Visión/etiologíaRESUMEN
In Experiment 1 (N = 8), a 20-ms light pulse, given at various times before a noise burst, inhibited reflex expression with a single trough at a lead time of 70 ms, whereas a dark pulse facilitated the reflex with two peaks at 40 and 160 ms. In Experiment 2 (N = 18) facilitation by dark onset had a single peak, and inhibition by light onset a single trough; thus, the double peak of the dark pulse may result because inhibition from light onset at the end of the dark pulse was briefly impressed on the facilitatory effect of dark onset. In Experiment 3 (N = 12), diazepam (2.5 mg/kg, but not 1 mg/kg) eliminated dark facilitation but not light inhibition. These diazepam data reveal a basic similarity, perhaps identity, of the mechanisms responsible for the effect of dark onset and those producing reflex facilitation by Pavlovian fear conditioning and prolonged background noise, because all are moderated by a GABAergic system.
Asunto(s)
Nivel de Alerta , Atención , Percepción Auditiva , Ritmo Circadiano , Adaptación a la Oscuridad , Reflejo de Sobresalto , Animales , Emociones , Femenino , Inhibición Psicológica , Luz , Masculino , RatasRESUMEN
In Experiment 1 (n = 8), the rat's ability to detect brief gaps in white noise was measured by gap-produced inhibition of an acoustic startle reflex, elicited 100 ms after the gap. After bilateral application of KCl to the cortex, gaps as long as 15 ms provided no reflex inhibition; in contrast, the inhibitory threshold was between 2 and 4 ms in the saline control condition. In Experiment 2 (n = 13), noise pulses of 40, 50, or 70 dB were presented 20-500 ms before the startle stimulus, and in Experiment 3 (n = 5) noise offsets occurred so that the startle stimulus was presented at the end of a 2-30-ms gap. Noise pulses and offsets both inhibited reflex expression equally in saline- and KCl-treated animals. Differences between the normal (saline) functions of noise offsets and gaps suggest additional sensory processing with the longer lead time. The loss of gap sensitivity after KCl application indicates that gap processing, unlike pulses and offsets, depends on cortical mechanisms.