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Neuroscience Program, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas
Submitted 28 April 2005; accepted in final form 1 August 2005
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ABSTRACT |
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INTRODUCTION |
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). Humans, non-human primates, and rodents exhibit temporal processing deficits after auditory cortex lesions (Clark et al. 2000a,b; Fitch et al. 1994; Harrington et al. 2001; Herman et al. 1997; Mummery et al. 1999).
Sensory enrichment has been suggested as a treatment for temporal processing deficits found in some central auditory processing disorders. Training improves cortical processing of temporal information in humans and animals (Beitel et al. 2003; Hayes et al. 2003; Merzenich et al. 1996; Nagarajan et al. 1998; Recanzone et al. 1992; Tallal et al. 1996; Tremblay et al. 2001; Warrier et al. 2004). Collectively, these results indicate that cortical temporal information processing can be altered by an intense schedule of exposure to modulated stimuli.
In our previous study, we demonstrated that rats exposed to an enriched environment exhibited improved selectivity, sensitivity, latency, and magnitude of primary auditory cortex responses (Engineer et al. 2004). The experiments reported here document the effects of sensory enrichment on the processing of temporally modulated acoustic stimuli. An earlier study reported that environmental enrichment increased the preferred temporal frequency of cat primary visual cortex neurons (Beaulieu and Cynader 1990). To test whether enrichment would increase or decrease the preferred modulation frequency of auditory cortex neurons, we collected extracellular recordings from anesthetized rats and surface evoked potentials from unanesthetized rats housed in standard and enriched conditions.
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METHODS |
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Environmental conditions
Thirty-five female Sprague-Dawley rats were used in this study. Rats in both housing conditions were on a reverse 12-h light/dark cycle and heard the sounds of room traffic, feeding, and cleaning while they were most active. Constant temperature and humidity were maintained, and food and water were provided ad libitum for all rats. All the animals used in this study were housed with their mothers and littermates until weaning at 4 wk of age. The environmental conditions are identical to those described in our previous study (Engineer et al. 2004).
The standard housing condition consisted of 1–2 rats per cage (26 x 18 x 18 cm, Fig. 1A). The acoustic environment of this condition included vocalizations from 20 to 30 other rats housed in the same room. In the enriched environment, four to eight rats were housed together in a single large cage in a separate room from the main rat colony (Fig. 1B). Because rats reach sexual maturation between 8 and 12 wk of age, after 1 mo in the enriched environment, a vasectomized male rat was introduced into the cage to encourage natural social interactions.
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A CD player presented randomly selected sounds every 2–60 s, including simple tones, amplitude- and frequency-modulated tones, noise bursts, and other complex sounds (rat vocalizations, classical music, rustling leaves, etc.). Seven of the 74 sounds activated a pellet dispenser (Med Associates) that delivered a sugary food reward to encourage attention to the sounds. The rewarded tracks included interleaved tones of different carrier frequencies (25-ms-long 4-, 5-, 9-, 12-, 14-, and 19-kHz tones with interstimulus intervals ranging from 50 ms to 2 s) and frequency modulated sweeps (1 octave up or down in a 140- or 300-ms sweep with interstimulus intervals ranging from 80 to 800 ms).
The power spectrums of sounds in the enriched environment spanned the entire hearing range of the rat (1–45 kHz) and were <75 dB SPL. The sound sources added to the enriched environment were provided 24 h/day and were designed to be more diverse and to provide more behaviorally relevant information than sounds in the standard condition. The average interval between the components of complex sounds in the enriched environment was significantly shorter compared with the standard environment [108 ± 73 vs. 133 ± 80 (SD) ms, P < 0.001]. Our definition of a complex sound was any sound louder than 50 dB SPL with more than one onset separated by no more than 300 ms. The total number of sounds (>50 dB SPL) was not significantly different between the enriched and standard environments 23 ± 23 vs. 19 ± 15 (SD) sound onsets/min.
Although it is possible that the enriched environment was mildly stressful, we observed no evidence of distress in any of the rats at anytime (i.e., excessive licking, hair loss, fighting, etc.). Rats actively explored the environment, voluntarily activated sound sources, and engaged in playful behaviors. Additionally, our behavioral observations and electroencephalographic (EEG) data indicate that enrichment did not interfere with normal sleep-wake behavior.
Experiment 1
EXTRACELLULAR RECORDINGS. Thirty-day-old female Sprague-Dawley rats were randomly assigned to either the enriched environment (n = 8) or the standard condition (n = 6). The enriched rats were raised four to five per cage (in 2 sessions). Rats in the standard condition were raised two per cage. Acute microelectrode mapping was performed after 8 wk in each environment (Fig. 2, A and B). Although acute experiments were interspersed, it should be noted that some experimenters were not blind to the identity of the animal because of the unkempt state of the rats' fur typical of enriched animals. However, the sampling density and depth of recordings made in enriched and standard housed rats were indistinguishable, and all analysis was performed blind to housing condition.
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0.5 ml/h). Body temperature was maintained at 37°C. The trachea was cannulated to ensure adequate ventilation and minimize breathing sounds. Humidified air was delivered to the open end of the cannula. After the cisterna magnum was drained to minimize cerebral edema, the right auditory cortex was exposed and the dura removed. Because previous studies implicated the importance of the right hemisphere in processing temporally modulated sounds, this hemisphere was selected for recording responses to complex tone trains (Wetzel et al. 1998).
The cortex was maintained under a layer of viscous silicon oil to prevent desiccation during the 24- to 30-h experiment. Penetration locations were referenced using cortical vasculature as landmarks. A detailed map of auditory cortex was generated from 50 to 100 microelectrode penetrations. A pair of parylene-coated tungsten microelectrodes (FHC, 250-µm separation, 2 M
) was lowered 550 µm below the pial surface (layer 4/5) of the auditory cortex. Action potentials from a small cluster of neurons were collected at each penetration site.
Action potentials were recorded simultaneously from two tungsten microelectrodes. The neural signals were filtered (0.3–15 kHz) and amplified (10,000 times). As in our earlier experiment, potentials above 0.18mV were considered to be action potentials (Pandya et al. 2005). The borders of A1 were defined based on continuous topography of characteristic frequency (CF) and short response latency. Sites with high thresholds, long latencies, broad tuning, and discontinuities in CF topography were considered non-A1 and excluded from further analysis (Kilgard et al. 2001). Criteria for identifying nonA1 sites were subjectively applied by well-trained blind observers.
STIMULUS PRESENTATION AND DATA ANALYSIS. Sounds were delivered in a shielded double-walled sound-attenuated chamber via a speaker (Motorola model No. 40–1221) positioned directly opposite the contralateral (left) ear at a distance of 10 cm. Frequency and intensity calibrations were performed with an ACO Pacific microphone (PS9200-7016) and Tucker-Davis SigCal software. After collecting frequency-intensity tuning curves at each site, Brainware (Tucker-Davis Technologies) presented tones at 12 repetitions of 14 modulation rates (3–20 Hz) and noise bursts at four repetition rates (5, 10, 15, and 20 Hz). The tone frequency was selected to generate the strongest response at each recording site. A 2-s silent period separated each randomly interleaved train. All stimuli were presented at 70 dB SPL and were 25 ms long with 3-ms rise and fall times.
Temporal processing was quantified using three different measures. Tone and noise burst repetition-rate transfer functions (RRTF) were derived at each site by quantifying action potentials per stimulus. Action potentials per stimulus was simply the average response occurring between 8 and 38 ms after the second, third, fourth, fifth, and sixth sounds in each train minus the spontaneous rate. The responses to tone and noise burst trains were also quantified using vector strength and Rayleigh statistic measures (Liang et al. 2002). Vector strength (VS) quantifies the degree of synchronization between action potentials and repeated tones pips, and is calculated with the formula
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). Values >13.8 (P < 0.001) are considered significant (Liang and Wang 2002). The number of evoked action potentials, vector strength, and Rayleigh statistic at each repetition rate and the best rate for each measure were compared across groups using unpaired two-tailed t-test. Experiment 2–evoked potential recordings
EXPERIMENTAL TIME COURSE. Evoked potentials were recorded each week from an electrode implanted over left auditory cortex. Twenty-one female Sprague-Dawley rats were randomly assigned to one of two groups. Rats in experiment 2a (n = 12) were housed in the enriched environment for 8 wk (4–12 wk of age) and then moved to the standard condition and housed singly until 26 wk of age (Fig. 2C). Rats in experiment 2b (n = 9) were housed singly in the standard condition for 9 wk (4–13 wk of age), then moved to the enriched environment for 8 wk, and then back to the standard condition until 26 wk of age (Fig. 2D). In this series of experiments, four to eight rats were housed in the enriched environment at any given time.
CHRONIC IMPLANTATION. Rats were chronically implanted at 28 days of age with a ball electrode over A1 and a ground screw over the cerebellum. Surgical anesthesia was induced with pentobarbital sodium (50 mg/kg ip). A state of areflexia was maintained throughout the surgery, and supplemental doses of dilute pentobarbital were administered subcutaneously if needed (0.2 ml; 8 mg/ml). Anesthesia level was monitored by response to toe pinch. Atropine (1 mg/kg) and dexamethasone (4 mg/kg) were administered subcutaneously to minimize lung secretions and brain edema during the procedure and recovery. Animals received antibiotic injections (ceftriaxone : 20 mg/kg) before and after surgery. Body temperature was maintained at 37°C. Four to five structural screws were used to anchor the implant on the skull. The 4-pin connector was held in place with dental acrylic.
Although some implants remained firmly in place for 5 mo, many implants were lost due to skull growth after implantation. Implanted rats were housed singly when not in the enriched environment to minimize the tendency of rats in small cages to damage implants by grooming excessively.
STIMULUS PRESENTATION. Middle-latency-evoked potential data were collected once each week for 21 wk from each rat in a sound-attenuated booth. Recordings were made during the dark cycle in both housing conditions to encourage rats to be as alert as possible. However, the rats did spend some time sleeping. EEG recordings indicate that rats were in slow wave sleep no more than 25% of the time during each recording session. Overall no differences in activity level, exploration, time spent sleeping, or arousal level were noted between enriched and standard rats during recording sessions.
Acoustic stimuli included pairs of 25-ms, 9-kHz tones with inter-stimulus intervals of 500, 200, 100, or 50 ms. Tones pairs were presented from a speaker centered above the cage and randomly interleaved every 10 s. The stimuli used for the awake recordings corresponds to the 2-, 5-, 10-, and 20-Hz intervals used in experiment 1. All stimuli were 70 dB SPL with 3-ms rise and fall times. Signals were low-passed filtered (800 Hz), amplified (10,000 times), and displayed on an oscilloscope for monitoring. Data-acquisition computers collected cortical responses to 125 tone pair presentations. Trials with excessive motion artifacts (>0.1 mV) were discarded prior to analysis of the mean evoked potential.
Data analysis
The first negative peak in the evoked response is referred to as N1 (30 ms). The second negative peak is N2 (140 ms). The first positive peak is referred to as P1 (75 ms; Fig. 6A). Only the eight rats (of the 21 implanted) that maintained their implants for the duration of the 5-mo study were included in this analysis. For each rat, the response to the second tone was calculated by subtracting the response to a single tone (derived from the first pulse of the 500-ms tone pair) from the overlapping response to two tones separated by shorter (200, 100, or 50 ms) interstimulus intervals. We estimated the waveform of the response 500 ms after a single tone onset by using the waveform 500 ms after onset of the 50-ms pair of tones since we did not present the tone in isolation. The waveform was indistinguishable from baseline 500 ms after onset of the 50-ms pair (Fig. 7D). Response strength was quantified as the root-mean-square of the evoked potential 10–175 ms after each tone onset (N1–P1 complex). Paired-pulse depression was quantified as the response to the second tone divided by the response to the first. Paired t-test were used to determine whether differences in evoked potential response strength and paired-pulse depression were statistically significant (alpha = 0.01).
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RESULTS |
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5 mo. Although similar environmental plasticity was observed in all the rats, only the eight rats that maintained their implants for the duration of the 21-wk study were included in the analysis reported in the following text. Experiment 1
EXTRACELLULAR RECORDINGS: REPETITION RATE TRANSFER FUNCTIONS. Responses from animals housed in enriched (n = 8 rats; 462 sites) and standard (n = 6 rats; 263 sites) conditions indicate that environment substantially altered A1 responses to modulated noise bursts and tones that had no special significance in the enriched environment.
A representative example of a dot raster plot from a single site is shown in Fig. 3, A and B. Each point represents an action potential. A shows responses to tone trains, B shows responses to noise burst trains. The number of action potentials evoked per sound declines rapidly at repetition rates >12 Hz (Fig. 3C).
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A1 neurons from enriched rats also responded with more action potentials to noise bursts when presented at rates <10 Hz (Fig. 5). Once again, the average vector strength at the best rate for each site was not significantly different between the two groups (0.86 ± 0.01 vs. 0.87 ± 0.01, P > 0.05).
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EVOKED POTENTIAL RECORDINGS: TONE-EVOKED RESPONSES. To determine if enrichment also increases response strength and paired-pulse depression in unanesthetized rats and whether or not this increase is reversible, we recorded auditory evoked potentials weekly during periods of standard and enriched housing. We previously reported that the grand mean average cortical evoked potential increased significantly during enrichment and reversed within a week when rats were returned to standard housing conditions. Chronic recordings from unanesthetized rats indicate that paired-pulse depression is also increased during periods of enrichment and returns to normal levels during standard housing (Fig. 6, A and B).
To improve the signal-to-noise ratio, we compared the average of each individual's mean evoked potential for all presentations during the standard housing condition, including before and after enrichment, with all presentations during the enriched housing condition. The amplitudes of the N1, P1, and N2 peaks in the grand mean average response to the first tone during enrichment were 211, 243, and 167% of their amplitude during standard housing (Fig. 7A). The amplitudes of each peak in response to a second tone presented 500 ms later were 163, 182, and 167% of their amplitude during standard housing (Fig. 7A). These results suggest that enrichment causes greater paired-pulse depression by increasing the N1 and P1 responses of the first tone compared with the second tone.
The surface potential in response to the second of two tones separated by 500 ms was smaller than the first when rats were housed in the standard and the enriched conditions. The peak-to-peak amplitude of the response to the second tone was reduced by 11% during standard housing and by 37% during enrichment (Fig. 7A). Because the evoked responses of some rats were different from the grand mean average, we used the root mean square of the N1–P1 complex to quantify the power of the average evoked potential in each individual. Paired-pulse depression was quantified as the ratio of the response to the second tone divided by the response to the first. For the 500-ms inter-stimulus interval, this ratio was 64 ± 4% for rats during periods of housing in the enriched environment compared with 87 ± 7% for rats during periods of housing in the standard condition (P < 0.05; Fig. 9). Collectively, these results indicate that enrichment significantly increases the response to the first tone and significantly enhances the degree of paired-pulse depression of the second tone 500 ms later compared with standard housing.
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DISCUSSION |
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). The current study was designed to evaluate the neurophysiologic consequences of environmental enrichment on temporal information processing in the auditory cortex. Action potentials from anesthetized rats were collected in response to tone and noise burst trains of varying repetition rates. Compared with standard housed rats, A1 responses from enriched rats were stronger and more synchronized at rates <10 Hz and weaker and less synchronized at higher rates. Evoked potentials were also recorded from auditory cortex in awake rats to compare the degree of paired-pulse depression during housing in standard and enriched conditions. Paired-pulse depression increased while rats were housed in the enriched environment and returned to normal levels within days of transfer back to standard housing. Collectively, these studies demonstrate that environment can substantially alter temporal processing in the auditory cortex of anesthetized and awake rats. Temporal processing
Neurons in the visual, auditory, and somatosensory cortex fail to respond at high modulation rates. Repetition rate transfer functions in the primary auditory cortex of naïve monkeys, cats, and rats are predominantly low- or band-pass (Bao et al. 2004; Beitel et al. 2003; Eggermont 1999; Gaese and Ostwald 1995; Kilgard and Merzenich 1998). Neurons with shorter latencies typically exhibit faster recovery from forward masking and higher best repetition rates than neurons with longer latencies (Brosch and Schreiner 1997; Kilgard and Merzenich 1999; Schreiner et al. 1997). Our observation that enrichment increases time to peak and decreases best repetition rate of A1 neurons is consistent with this correlation. The enrichment-induced decrease in the maximum following rate and increased paired-pulse depression is not due to a greater number of sounds with slow modulation rates in the enriched environment compared with the standard environment. In fact, the average modulation rate in the enriched environment was higher due to the greater complexity of the sound sources (music, chimes, etc).
One potential consequence of enrichment may be more accurate perceptual judgments to sounds with modulation rates <10 Hz, given the greater response strength and synchronization to these sounds. However, the greater paired-pulse depression observed in enriched rats may impair their ability to detect stimuli in a forward masking protocol. Detailed psychophysical experiments will be needed to fully evaluate the perceptual consequences of environmental enrichment. In any case, enriched housing provides sensory stimulation and social interactions that are common in natural environments, and it is likely that the greater paired-pulse depression observed in enriched rats more accurately reflects typical cortical temporal information processing compared with results from animals housed in standard laboratory conditions.
Potential mechanisms
Plasticity of synaptic, cellular, or network properties may contribute to the changes in temporal processing induced by environmental conditions (Gilbert 1998; Katz and Shatz 1996; Syka 2002). Two distinct types of excitatory synapses have been described in layer II/III auditory cortex neurons of standard housed rats (Atzori et al. 2001). Two of three have weak connection strengths with a low probability of release, while the remaining synapses have strong connection strengths and a high probability of release. The strong synapses exhibited substantially more paired-pulse depression than the weak syn-apses, presumably due to faster depletion of the synaptic vesicle pool. Earlier studies have shown that long-term potentiation of cortical synapses is often accompanied by higher probability of release and increased paired-pulse depression (Markram and Tsodyks 1996). If enrichment increases the proportion of synapses with a high release probability, both our earlier observation of increased response strength and our current observation of increased response depression could be explained by a single mechanism.
Enrichment could also strengthen paired-pulse depression by increasing long-lasting inhibition. However, in cat visual cortex enrichment decreases, rather than increases, the number of inhibitory synapses and increases, rather than decreases, the ability of neurons to follow rapid stimuli (Beaulieu and Colonnier 1987; Beaulieu and Cynader 1990). Although enrichment resulted in increased responsiveness and selectivity similar to that seen in rat auditory cortex, the opposite effects on temporal processing suggest different synaptic mechanisms may be involved.
Recent in vivo findings indicate that at interstimulus intervals >150-ms synaptic depression, rather than inhibition, is the primary mechanism responsible for paired-pulse depression in rat auditory cortex (Tan et al. 2004; Wehr and Zador 2003, 2005). Although it is possible that enrichment could strengthen paired-pulse depression by increasing long-lasting inhibition (or even the amplitude of postresponse hyperpolarization or oscillatory conductance periodicity), each of these explanations would also require an increase in excitatory drive to explain the stronger response to isolated sounds (D'Angelo et al. 2001; Gaese and Ostwald 1995; He 2003).
The increased paired-pulse depression observed in enriched rats is likely to be a consequence of the increased response magnitude to the first tone in a pair. Several experiments have shown that greater stimulus intensity causes greater paired-pulse depression. Increasing tone amplitude typically increased the duration of forward masking (Brosch and Schreiner 1997). In addition, we observed more paired-pulse depression of evoked potentials with louder (90 dB) tones compared with quieter (50 dB) tones in standard housed rats (unpublished data). These results suggest enrichment has the same effect on response strength and paired-pulse depression as increasing stimulus intensity.
Although numerous cellular mechanisms are possible, increased probability of synaptic release is the most likely explanation because a single mechanism (well documented with in vitro studies of auditory cortex) would explain both the increased response strength and decreased temporal after rate observed in enriched rat auditory cortex. Clearly, further studies are needed to characterize the cellular and molecular basis of enrichment-induced plasticity.
Finally, because both response strength and paired-pulse depression increase during the transition from an alert state to a quiet awake state, it is possible that enriched rats spend more time in the quiet awake state than standard housed rats (Castro-Alamancos 2004). However, because the enrichment-induced increases in response strength and paired-pulse depression are maintained under general anesthesia, we believe that differences in global state are unlikely to explain our observations.
Technical considerations
Both standard and enriched rats have significant paired-pulse depression to subsequent auditory stimuli. However, the degree of paired-pulse depression was different depending on the method of data recording. For surface potentials recorded in awake rats, the time required for the amplitude of the second response to recover to 2/3 of the first response was 10 times longer in enriched compared with standard housed rats (500 vs. 50 ms). In contrast, for action potentials recorded under anesthesia, the time required for the response to the second tone to recover to 2/3 of the first was only 17% longer (83 vs. 71 ms). Three factors could be responsible for the longer time course of paired-pulse depression for evoked potentials compared with action potentials. First, anesthesia may eliminate possible neuromodulatory differences that could be engaged in awake rats during periods of differential housing. Second, nonprimary auditory regions, which likely contribute to evoked potentials, are not included in our microelectrode data. Nonprimary auditory cortex neurons are known to exhibit greater paired-pulse depression (Eggermont and Ponton 2002) and may be more sensitive to environmental conditions. Third, evoked potentials are generated by summed synaptic potentials, which appear to be potentiated during enrichment. Recordings of action potentials would show smaller differences due to the threshold-based mechanism of action potential generation. Further studies will be needed to determine which of these differences is responsible for the greater scale of environmental plasticity observed with evoked potentials.
Multiple factors influence the degree of environmental-induced plasticity including physical activity, social experience, and behavioral relevance of sensory events (van Praag et al. 2000). Social interactions significantly increase brain weight (Ferchmin and Bennett 1975), and wheel running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus (van Praag et al. 1999). Additional experiments are ongoing to evaluate which specific factors contribute to the physiologic changes observed in this study.
Clinical relevance
Several clinical populations exhibit abnormal cortical responses to rapidly presented acoustic signals. Unmedicated patients with schizophrenia exhibit weak responses and less paired-pulse depression compared with normal controls, possibly reflecting their inability to filter incoming sensory stimuli and reported sensations of being "overwhelmed" or "flooded" by sensory stimulation (Braff and Geyer 1990; Erwin et al. 1991; Siegel et al. 1984). Paired-pulse depression is restored to normal when patients are treated with the antipsychotic clozapine (Adler et al. 2004). Individuals with autism also exhibit reduced responses to sensory stimulation that fail to adapt at increased repetition rates (Buchwald et al. 1992). These differences may contribute to abnormal gating of sensory information, abnormal arousal levels, and inattentiveness characteristic of the autistic population.
In contrast, individuals with dyslexia exhibit too much paired-pulse depression. The response to the first acoustic stimulus is stronger, but the response to second and subsequent stimuli is significantly weaker compared with controls (Nagarajan et al. 1999). These differences were especially pronounced at short interstimulus intervals, which is consistent with observations that dyslexic individuals have substantial difficulties processing the rapid spectrotemporal transitions present in language. Although the perceptual consequences of environmental enrichment are not well documented, our observation that environment can significantly influence paired-pulse depression supports earlier hypotheses that focused, intensive sensory enrichment may alter sensory gating in patients with schizophrenia, autism, or dyslexia (Baranek 2002; Gunatilake and Silva 2004; Tallal et al. 1998).
Conclusion
In summary, enrichment strengthens the response of primary auditory cortex neurons to isolated sounds but increases the degree of paired-pulse depression. Both forms of plasticity could be explained if enrichment increases the probability of synaptic release, although several other mechanisms are possible, and may act in concert. A better understanding of the cellular basis for enrichment-induced paired-pulse depression would be helpful in designing effective treatments for neurological disorders characterized by temporal processing abnormalities.
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GRANTS |
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ACKNOWLEDGMENTS |
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Present address of P. K. Pandya; Dept. of Speech and Hearing Science, Univ. of Illinois, 901 S. Sixth St., Champaign, IL 61821.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. P. Kilgard, Neuroscience Program, School of Behavioral and Brain Sciences, GR 41, University of Texas at Dallas, Richardson, Texas 75083-0688 (E-mail: kilgard{at}utdallas.edu)
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