Loss of prestin does not alter the development of auditory cortical dendritic spines.

Disturbance of sensory input during development can have disastrous effects on the development of sensory cortical areas. To examine how moderate perturbations of hearing can impact the development of primary auditory cortex, we examined markers of excitatory synapses in mice who lacked prestin, a protein responsible for somatic electromotility of cochlear outer hair cells. While auditory brain stem responses of these mice show an approximately 40 dB increase in threshold, we found that loss of prestin produced no changes in spine density or morphological characteristics on apical dendrites of cortical layer 5 pyramidal neurons. PSD-95 immunostaining also showed no changes in overall excitatory synapse density. Surprisingly, behavioral assessments of auditory function using the acoustic startle response showed only modest changes in prestin KO animals. These results suggest that moderate developmental hearing deficits produce minor changes in the excitatory connectivity of layer 5 neurons of primary auditory cortex and surprisingly mild auditory behavioral deficits in the startle response.

Scopolamine reduces sensitivity to auditory gaps in the rat, suggesting a cholinergic contribution to temporal acuity.

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.

A behavioral study of temporal processing and visual persistence in young and aged rats.

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.

The effect of spatial separation of signal and noise on masking in the free field as a function of signal frequency and age in the mouse.

Masking of low- (4 kHz) and high-frequency (25 kHz) signals by one-octave bandpass maskers either spatially coincident with the signal or contralateral to it was examined in mice, 4-6 and 20-22 months of age, in the free field. Signals were presented 120 ms prior to a startle stimulus and differences in their inhibition of the startle reflex, relative to startle stimulus alone trials, were used to measure the severity of masking. Inhibition was reduced or eliminated by spatially coincident noise for weak but not for relatively intense signals, providing the type of "loudness recruitment" effect characteristic of human listeners in similar stimulus conditions. The spatial separation of the signal and its masker relieved this maskinglike effect for the high-frequency pair in both young and old mice. In contrast there was no beneficial effect of the shift in spatial location for the low-frequency pair at either age. This finding of masking release for high- but not low-frequency stimuli supports the hypothesis that the sound shadow provided by the head and pinna would yield a favorable signal-to-noise level difference for a contralateral masker and an ipsilateral signal only at very high frequencies in the mouse. The presence of masking release in these old mice, a first generation hybrid strain with near-normal high-frequency hearing in ABR measures, agrees with reports that the masking release resulting from a similar manipulation in aged human listeners with minimal high-frequency hearing loss is the equal of that obtained in the young listener.

Changes in temporal acuity with age and with hearing impairment in the mouse: a study of the acoustic startle reflex and its inhibition by brief decrements in noise level.

Temporal acuity for brief gaps in noise was studied in mice of different ages (1-36 months) from strains with differing susceptibility to age-related hearing loss, using reflex modification audiometry. Prepulse inhibition of the acoustic startle reflex (ASR) increased with gap depth (GD: 10-40 dB in 70 dB SPL noise) and lead time (LT: 1-15 ms). The increase in inhibition with LT followed an exponential function in which the two parameters, asymptotic inhibition (AINH) and the time constant (tau), were both affected by GD. AINH rapidly declined from 1 to 6 and then to 18 months of age in C57BL/6J mice with progressively severe hearing loss, but first increased with maturation and then gradually declined beyond 6-12 months of age in CBA/CaJ and CBA x C57BL Fl-hybrid mice, which show no apparent change in sensory function at these ages. In contrast, tau was unaffected by hearing loss or by age, this suggesting that age-related changes in this form of temporal acuity occur because of a reduction in the efficiency with which gaps are centrally processed, not from any reduced ability to follow their rapid shift in noise level.

Neural correlates of behavioral gap detection in the inferior colliculus of the young CBA mouse.

The gap detection paradigm is frequently used in psychoacoustics to characterize the temporal acuity of the auditory system. Neural responses to silent gaps embedded in white-noise carriers, were obtained from mouse inferior colliculus (IC) neurons and the results compared to behavioral estimates of gap detection. Neural correlates of gap detection were obtained from 78 single neurons located in the central nucleus of the IC. Minimal gap thresholds (MGTs) were computed from single-unit gap functions and were found to be comparable, 1-2 ms, to the behavioral gap threshold (2 ms). There was no difference in MGTs for units in which both carrier intensities were collected. Single unit responses were classified based on temporal discharge patterns to steady-state noise bursts. Onset and primary-like units had the shortest mean MGTs (2.0 ms), followed by sustained units (4.0 ms) and phasic-off units (4.2 ms). The longest MGTs were obtained for inhibitory neurons (x = 14 ms). Finally, the time-course of behavioral and neurophysiological gap functions were found to be in good agreement. The results of the present study indicate the neural code necessary for behavioral gap detection is present in the temporal discharge patterns of the majority of IC neurons.

Nimodipine at a dose that slows ABR latencies does not protect the ear against noise.

We tested the hypothesis that nimodipine, a dihydropyridine reported to increase blood flow, block calcium and potassium channels, and reduce ischemic damage, would alleviate noise-induced hearing loss. Young C57B1/6J mice were exposed to wide-band noise (2 min, 120 dB SPL), with ABR thresholds (4-50 kHz) determined before noise exposure, and from 1 h to 2 weeks afterwards. One group (n = 7) received nimodipine (30 mg/kg/day) in daily peanut butter food supplements beginning 24 h before exposure; the other group (n = 6) received peanut butter alone. In the pretest nimodipine significantly increased the latency of Wave P1 of the ABR (mean difference: 0.16 ms; P < 0.02), showing that calcium blockade depressed sensorineural efficiency, but ABR thresholds were not affected. Noise exposure produced a severe threshold loss that partially recovered in the first week after exposure, and then suffered a slight but significant loss in the second week. These effects were seen equally in both groups: nimodipine did not reduce the severity of the immediate hearing loss following noise exposure, nor did it benefit recovery.

Facilitation and inhibition of the acoustic startle reflex in the rat after a momentary increase in background noise level.

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.

Effects of haloperidol and SCH 23390 on acoustic startle in animals depleted of dopamine as neonates: implications for neuropsychiatric syndromes.

Animals depleted of dopamine (DA) in the neonatal period and tested in adulthood exhibit some similarities to patients with schizophrenia, including increased sensitivity to DA agonists, altered sensitivity to DA receptor antagonists, and abnormalities of the acoustic startle response (ASR). In this study, we examined the contributions of D1-like and D2-like DA receptors to ASR measures in animals depleted of DA as neonates. Male rat pups received intracerebroventricular injections of 6-hydroxydopamine (DA depleted) or its vehicle (controls) at 3 days of age. Animals underwent startle testing as adults (60-75 days of age) after administration of DA antagonists (haloperidol: 0.1 or 0.3 mg/kg, SCH 23390:0.01 or 0.05 mg/kg) with and without DA agonist administration (apomorphine 0.5 mg/kg). ASR amplitude and prepulse inhibition (PPI: percentage decrease in startle amplitude due to a low intensity prepulse) were measured. DA depleted animals showed increased ASR amplitude and reduced PPI compared to controls. Administration of D1-like or D2-like DA antagonists significantly reduced overall ASR and increased PPI in both control and DA depleted animals, with DA depleted animals showing a relatively greater sensitivity to the D1-like antagonist SCH 23390. Findings are discussed in terms of the role of residual DA in mediating ASR phenomena in depleted animals, differences between D1/D2 DA receptor mediation of ASR compared to other behaviors in DA depleted animals, and potential implications for neuropsychiatric syndromes such as schizophrenia.

Effects of single and repeated exposure to apomorphine on the acoustic startle reflex and its inhibition by a visual prepulse.

The acoustic startle reflex (ASR) is inhibited by startle-irrelevant stimuli that briefly precede reflex elicitation. This effect, prepulse inhibition (PPI), is reduced in strength for animals that have received dopamine agonists, such as apomorphine (APO). Reduction in PPI is most evident for weak masked noise prepulses, thus suggesting that APO disrupts the reception of stimuli to the extent that they present a low signal-to-noise ratio. Here we examine the effect of APO on PPI produced by non-masked visual prepulses. Light flashes were given at two intensities, 40, 70, 110, or 220 ms before ASR elicitation. In phase 1 (5 weeks in duration) half of the animals received one weekly injection of APO (0.5 mg/kg, IP) and one of vehicle (VEH), while the other half received two injections of VEH. Within these groups, half were tested 30 min after the injections, the other half kept test naive (four groups total). In phase 2, following a 4-week rest, all groups were tested after a low dose of APO (0.1 mg/kg) and VEH, 1 week apart. APO eliminated PPI for a dim flash and reduced PPI for a brighter flash to a level normally obtained with the dim flash, while increasing both ASR control values and activity. The bright light was maximally effective at a lead time of 70 ms and APO did not alter this value. Because in general the time of maximal inhibition varies with prepulse intensity for visual stimuli, the finding that the time of the peak remained constant reveals that APO has its effect on inhibition rather than on effective stimulus intensity. In phase 2, APO reduced PPI with no sign of sensitization from past drug exposure. However, APO increased the ASR only in groups previously exposed to APO, indicating behavioral sensitization. The differential effects of repeated exposure on these response measures suggest that neural substrates for the several behavioral effects of APO function at least in part independently.

A functional analysis of the age-related degeneration in the Fischer 344 rat.

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)

The effects of signal frequency and absolute bandwidth on gap detection in noise.

Whether temporal resolution in noisebursts is primarily determined by the highest frequency component in the signal or its absolute bandwidth remains unclear. In this study, the absolute bandwidths and upper cutoff frequencies of signal noisebursts were varied across broad frequency ranges, several times greater than previously jointly studied. The purpose was to determine how each independently affects detection, taking into consideration that bandwidth effects at one signal frequency might be very different from bandwidth effects at another. Gap detection thresholds were obtained for five subjects with normal hearing in a 2 IFC paradigm. Signals were noisebursts whose bandwidths and upper cutoff frequencies varied among 1, 2, 4, 8, and 12 kHz. Their duration was 150 ms and they were presented at an overall level of 75 dB SPL above a 45 dB SPL white noise floor. The largest mean gap detection threshold, 6.98 ms, was obtained for a noiseburst with a bandwidth of 1 kHz and upper cutoff frequency of 12 kHz. The smallest mean gap detection threshold, 2.22 ms, was found with a bandwidth and upper cutoff frequency of 12 kHz. Significant interactions were found to exist between absolute bandwidth and upper cutoff frequency. Although gap detection thresholds generally decreased with increasing signal frequency and bandwidth, the pattern was complex. When the absolute bandwidth was at least one-half the upper cutoff frequency then upper cutoff frequency and not bandwidth determined gap sensitivity; but when the absolute bandwidth was less than one-half of the upper frequency, then both determined gap thresholds.(ABSTRACT TRUNCATED AT 250 WORDS)

Impoverished stimulus input does not simulate the slowed visual kinetics of retinal damage.

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.

Modulation of noise-potentiated acoustic startle via the benzodiazepine--gamma-aminobutyric acid receptor complex.

Diazepam (DZ), an anxiolytic benzodiazepine (BZD) compound, attenuated the facilitation of the acoustic startle response by background noise. In Experiment 1, using a cumulative dosing paradigm, the effect of DZ on noise potentiation was found to be dose related. In Experiment 2, using a between-animals exposure design, the effect of DZ on noise potentiation was attenuated by coexposure to the central-type BZD receptor antagonist RO 15-1788, which itself was without effect. Using a cumulative dosing design in Experiment 3, RO 15-1788 was found to reverse the effect of DZ, whereas the peripheral-type BZD receptor ligand RO 54864 was without effect. The differences in the effect of cumulative exposure versus single dose exposure to RO 15-1788 were interpreted as indicative of either an intrinsic effect of the antagonist after repeated exposure or an influence of background noise itself on the BZD-gamma-aminobutyric acid receptor complex.

Echoic memory in the rat: effects of inspection time, retention interval, and the spectral composition of masking noise.

Memory for tones (1100 vs. 2330 Hz) was studied in 4 rats (Rattus norvegicus), as affected by the durations of both target tones (30 to 620 ms) and noise-filled retention intervals (0 to 480 ms). With a 0-ms delay, performance was near asymptotic with the 30-ms tone, but the memory of this brief tone suffered a massive decrement at retention intervals as brief as 60 ms; in contrast, memory for the 340-ms tone was stable for at least 240 ms. If the retention interval was filled by band-stop noise (with targets presented in the spectral gap), then the rat's memory for brief tones was superior to that obtained with the standard broad-band noise filler, and band-stop noise was better than a band-pass noise that had the tones embedded in the region of its spectral energy. These findings are consistent with the hypotheses that auditory memory in the rat consists of a transient sensorylike echoic store and a short-term store more resistant to the effects of retroactive interference.

Intraretinal grafting restores visual function in light-blinded rats.

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.

Potentiation of acoustic startle behavior in the rat (Rattus norvegicus) at the onset of darkness.

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.

Temporal resolution of gaps in noise by the rat is lost with functional decortication.

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.

Facilitation and inhibition of the human startle blink reflexes by stimulus anticipation.

The cutaneous eyeblink has 2 electromyographic components, 1 unilateral and early (R1) and 1 bilateral and late (R2), which are served by different neural pathways. These 2 reactions were measured when the eliciting stimulus was expected or relatively surprising. Forewarning was varied in 3 ways: Subjects received notice that the stimulus was about to occur on some trials (Experiment 1); delivered the stimulus to themselves on some trials (Experiments 2 & 3); or experienced a series of trials in which a tone was paired with the eliciting stimulus, followed by tone-alone trials interspersed with test trials (Experiment 4). In each case, forewarning enhanced R1 amplitudes while depressing R2 but reduced the latency of both components. This mixed pattern of effects reveals that the preparatory state provoked by forewarning focuses excitatory and inhibitory processes simultaneously on different reflex pathways: inhibition central and excitation peripheral.

Inhibition of the cutaneous eyeblink reflex by unilateral and bilateral acoustic input: the persistence of contralateral antagonism in auditory processing.

The eyeblink reflex elicited by a cutaneous stimulus is inhibited by weak auditory stimuli that are heard just before the blink. It has been shown that monaural prestimuli produce more reflex depression than binaural prestimuli do, suggesting that reflex modification is sensitive to the outcome of antagonistic connections between contralateral auditory inputs. We examined the time course of this antagonism by giving unilateral versus bilateral pairs of noise pips 100 msec before the reflex eyeblink, with the noise pips separated by 0, 1, 4, or 8 msec. Unilateral stimuli were more effective in every condition, but their advantage diminished with increased delay between the two components. The extended bilateral and unilateral trends of increasing reflex depression with increased delay meet at about 15 msec; if this extrapolation is valid, 15 msec represents the upper limit on this system's retention of the location of a brief noise impulse. The rate of convergence of the two temporal functions reflects the decay of the antagonistic effect of one noise on its contralateral counterpart.