Prepulse startle deficit in the Brown Norway rat: A potential genetic model.

Prepulse inhibition (PPI), an operational measure of sensorimotor gating, is deficient in schizophrenia patients. PPI was compared among 4 strains of rats: Sprague-Dawley, Spontaneously Hypertensive, Wistar Kyoto (WKY), and Brown Norway (BN). PPI was dramatically lower in BN versus the other strains, especially WKY, for both acoustic and airpuff startle stimuli, whereas startle amplitude was similar between BN and WKY. Female BN also had lower PPI than did female WKY. Response to increasing prepulse intensities showed a right shift in the BN relative to the WKY. Visual prepulses also showed deficiencies in BN versus WKY. The absence of background noise did not negate strain differences. Auditory brainstem response to clicks and tone pips revealed no differences in auditory threshold between the 2 strains. These results are the first to demonstrate that BN have impaired sensorimotor gating compared with WKY, without impaired acoustic acuity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of the first prepulse on the blink response to a startling noise.

Startle is inhibited when a startling stimulus follows 30–300 ms after a weak prepulse. Prepulse inhibition (PPI) is an operational measure of sensorimotor gating and is deficient in several neuropsychiatric disorders. Previous reports argue both for and against a learned component to the inhibitory effects of prepulses, but this issue has yet to be fully investigated using stimuli that most commonly detect PPI deficits in clinical populations. If the inhibitory impact of a prepulse is learned, PPI should not be evident when the prepulse is the first stimulus experienced by the subject. Eyeblink electromyography in normal adults was recorded after either a 118 dB(A) 40-ms noise pulse alone (PA) or the same pulse preceded 120 ms by an 86 dB(A) 5-ms noise prepulse (pp + P). In 25 subjects (Order 1), Trial 1 was a PA, and Trial 2 was a pp + P; 23 subjects experienced the opposite order (Order 2). In 34 subjects, Trials 1 and 2 were both PA (control order). Background was 70 dB(A). Startle magnitude increased from Trial 1 to 2 if no prepulse was presented (control order). Compared with the control order, startle inhibition by prepulses was evident in both Orders 1 and 2, and was more robust in Order 2 (first trial = pp + P). Startle magnitude was significantly lower on pp + P than on PA trials in Order 2 but not Order 1 (F     

Caudal pontine reticular formation of C57BL/6J mice: responses to startle stimuli, inhibition by tones, and plasticity

C57BL/6J (C57) mice were used to examine relationships between the behavioral acoustic startle response (ASR) and the responses of neurons in the caudal pontine reticular formation (PnC) in three contexts: 1) responses evoked by basic startle stimuli; 2) the prepulse inhibition (PPI) paradigm; and 3) the effects of high-frequency hearing loss and concomitant neural plasticity that occurs in middle-aged C57 mice. 1) Responses (evoked action potentials) of PnC neurons closely paralleled the ASR with respect to latency, threshold, and responses to rapidly presented stimuli. 2) "Neural PPI" (inhibition of responses evoked by a startle stimulus when preceded by a tone prepulse) was observed in all PnC neurons studied. 3) In PnC neurons of 6-mo-old mice with high-frequency (>20 kHz) hearing loss, neural PPI was enhanced with 12- and 4-kHz prepulses, as it is behaviorally. These are frequencies that have become "overrepresented" in the central auditory system of 6-mo-old C57 mice. Thus neural plasticity in the auditory system, induced by high-frequency hearing loss, is correlated with increased salience of the inhibiting tones in both behavioral and neural PPI paradigms.     

Motivated attention and prepulse inhibition of startle in rats: Using conditioned reinforcers as prepulses.

In humans, prepulse inhibition (PPI) of startle is greater during attended prestimuli than it is during ignored prestimuli, whereas in rats, most work has focused on passive PPI, which does not require attention. In the work described in this article, researchers developed a paradigm to assess attentional modification of PPI in rats using motivationally salient prepulses. Water-deprived rats were either conditioned to attend to a conditioned stimulus (CS; 1-s, 7-dB increase in white noise) paired with water (CS+ group), or they received uncorrelated presentations of white noise and water (CSo group). After 10 conditioning sessions, startle probes (50 ms, 115 dB) were introduced, with the CS serving as a continuous prepulse. Three experiments examined PPI across a range of prepulse intensities (4-10 dB) and stimulus onset asynchronies (SOAs; 30-960 ms). PPI was consistently reduced in the CS+ group, particularly with a 10-dB prepulse and a 60-ms SOA. Thus, PPI in rats differed between attended and ignored prestimuli, but the effect was reversed in the results of research with humans. A fourth study eliminated the group difference by reversing the CS-water contingency. Methodological and motivational hypotheses regarding the current findings are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differences in prepulse inhibition (PPI) between Wistar and Sprague-Dawley rats clarified by a new method of PPI standardization.

Rat strain differences in the acoustic startle response (ASR) and prepulse inhibition (PPI) of that response are of increasing interest, especially as the genetics of PPI may provide an approach to studying the genetics of certain mental illnesses. However, strain differences in PPI are confounded by differences in ASR. To clarify this issue, the authors investigated the ASR and PPI across a range of startling stimulus intensities (70 dB-120 dB) in Wistar and Sprague-Dawley rats (N=96). Sprague-Dawleys showed more PPI of ASR capacity (response limit) than Wistars. In contrast, Wistars exhibited greater PPI than Sprague-Dawleys, as measured by an increase in response threshold. This dissociation suggests that PPI is more complex than that assessed by single startling stimulus intensity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prepulse inhibition of acoustic startle in rats after lesions of the pedunculopontine tegmental nucleus.

Prepulse inhibition (PPI) of startle is impaired in schizophrenics, which suggests they have disturbances in circuitry that controls PPI. How activity in forebrain circuitry is communicated to the primary startle circuit to modulate PPI was explored. Subpallidal cells innervate the pedunculopontine tegmental nucleus (PPTg). Infusion of the γ-aminobutyric acid antagonist picrotoxin into the subpallidum impaired PPI. In other rats, electrolytic PPTg lesions decreased or eliminated PPI, potentiated startle amplitude, and did not alter habituation. The disruption of PPI correlated significantly with the extent of PPTg damage. PPTg lesions reduced PPI when startle stimuli were weak or intense (104 or 140 db) and when prepulse stimuli ranged from 2 to 17 db above background but were most profound with prepulses 5–8 db above background. The PPTg modulates sensorimotor gating and may process and transmit information from forebrain structures to the primary startle curcuit. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of single oral administrations of haloperidol and d-amphetamine on prepulse inhibition of the acoustic startle reflex in healthy male volunteers

The effects of acute administration of an indirect dopamine-agonist, d-amphetamine, and a non-selective dopamine receptor antagonist, haloperidol, were investigated in normal male volunteers on habituation and prepulse inhibition (PPI) of the acoustic startle reflex in two experiments. In Experiment 1, 40 male non-smoker volunteers were tested for habituation and PPI (defined as percentage reduction of the pulse-alone amplitude; prepulses 9 dB above background) before and after double-blind administration of either 2 mg haloperidol or placebo. No influence of haloperidol was observed on either habituation or PPI of the startle reflex in this experiment. In Experiment 2, 60 male volunteers underwent startle testing before and after double-blind administration of a single oral dose of 5 mg haloperidol, 5 mg d-amphetamine or placebo. Habituation and PPI (prepulses 15 dB above background) for the placebo group did not differ significantly from that observed for the d-amphetamine or for the haloperidol group. However, in a subgroup of smoking subjects, both d-amphetamine and haloperidol reduced PPI as compared to that observed prior to drug administration. The implications of these findings in relation to animal pharmacological studies and observed sensorimotor gating deficits in schizophrenia are discussed.     

Sexual orientation-related differences in prepulse inhibition of the human startle response.

Prepulse inhibition (PPI) refers to a reduction in the startle response to a strong sensory stimulus when this stimulus is preceded by a weaker stimulus--the prepulse. PPI reflects a nonlearned sensorimotor gating mechanism and also shows a robust gender difference, with women exhibiting lower PPI than men. The present study examined the eyeblink startle responses to acoustic stimuli of 59 healthy heterosexual and homosexual men and women. Homosexual women showed significantly masculinized PPI compared with heterosexual women, whereas no difference was observed in PPI between homosexual and heterosexual men. These data provide the first evidence for within-gender differences in basic sensorimotor gating mechanisms and implicate the known neural substrates of PPI in human sexual orientation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of nicotine, lobeline, and mecamylamine on sensory gating in the rat

In normal subjects, if an acoustic startle stimulus is immediately preceded by a small brief change in background noise intensity, the magnitude of the subsequent startle response is decreased. This prepulse inhibition (PPI) of an acoustic startle response has been shown to be associated with sensorimotor gating. PPI is disrupted in schizophrenic patients and has been linked to attentional disorders characteristic of this disease. We tested the effects of (-)-nicotine, (0.19, 0.62, and 1.9 mumol/kg IP) (equivalent to 0.03, 0.1, and 0.3 mg/kg base) and the nicotinic cholinergic receptor (nAChR) channel blocker, mecamylamine (5.0 and 50 mumol/kg IP) (equivalent to 1.0 and 10.0 mg/kg) on PPI of the acoustic startle response in the rat. Nicotine increased the PPI at the lowest prepulse signal levels but not at the stronger levels. Mecamylamine was without effect at 5.0 mumol/kg, but the 50 mumol/kg dose decreased the inhibition at both weak and strong prepulse (PP) levels. Mecamylamine (5.0 mumol/kg) pretreatment did not block the (-)-nicotine-induced increase in PPI. Lobeline (0.19, 0.62, 1.9, and 6.2 mumol/kg IP) (equivalent to 0.071, 0.23, 0.71, and 2.3 mg/kg) was without effect. These results are consistent with a mecamylamine-insensitive effect of nicotine to improve gating in normal rats. The nAChR subtype involved in producing nicotine's increase of PPI needs further investigation.     

Activation of a distinct arousal state immediately after spontaneous awakening from sleep

In contrast to the many neural studies into the mechanisms of sleep onset and maintenance, few studies have focused specifically on awakening from sleep. However, the abrupt electrographic changes and large brief cardio-respiratory activation at awakening suggest that a distinct, transiently aroused, awake state may exist compared to later wakefulness. To test this hypothesis we utilized the acoustic startle reflex, a standard un-conditioned reflex elicited by a sudden loud noise. This reflex is modulated under specific conditions, one being a diminution of startle when a quieter pre-stimulus is presented immediately before the loud stimulus. This pre-pulse inhibition (PPI) is used as a measure of sensorimotor gating, with smaller PPI indicating less filtering of sensory inputs and increased responsiveness to external stimuli. Eight rats with electrodes for recording sleep-wake state were studied. An accelerometer measured startle responses. The startle reflex was elicited by 115 dB, 40 ms tones. PPI was produced by 74 dB, 20 ms tones preceding the 115 dB tone by 100 ms. Responses within 100 ms were measured. Stimuli were applied either 3-10 s after spontaneous awakenings, or in established wakefulness (> 30 s). Responses to the startle stimuli alone were similar in the different awake states (P = 0.821). However, PPI was smaller at awakening from non-REM sleep compared to established wakefulness (45.4 +/- 7.5% vs. 74.3 +/- 6.1%, P = 0.0002). PPI after awakening from REM sleep (52.8 +/- 17.9%) was not significantly different than established wakefulness (P = 0.297). Reduced PPI of the startle reflex at awakening from non-REM sleep supports the hypothesis that wakefulness immediately after spontaneous sleep episodes is neurophysiologically distinct from later wakefulness and associated with reduced gating of motor responses to sensory inputs. Spontaneous activation of this distinct, transiently aroused, state upon awakening may serve a protective function, preparing an animal to respond immediately to potentially threatening stimuli.     

Experience increases the prepulse inhibition of the acoustic startle response in mice.

The authors have previously shown that inhibition of the acoustic startle response by a prepulse increases when it is repetitively elicited over days. The present experiments show in C3H and C57 mice that this change is caused by an increase in prepulse inhibition (PPI) and not by a decrease in prepulse facilitation. This PPI increase is only evoked if prepulses and startle stimuli are repeatedly given in a temporally paired ("contingent") order, proposing an associative learning process. (Only in C57 mice, PPI was additionally increased by adaptation in the same, but not in a different, context). As an underlying mechanism for this PPI increase by experience, the authors hypothesize Hebbian plasticity of an inhibitory synapse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

On the influence of baseline startle reactivity on the indexation of prepulse inhibition.

Prepulse inhibition (PPI) of the startle reflex refers to the reduction of the reflexive startle response to an intense pulse stimulus when its presentation is shortly preceded by a weak prepulse stimulus. PPI is considered as a cross-species translational model of sensorimotor gating, and deficient PPI has been reported in a number of neuropsychiatric disorders. Although a part of the literature is based on the assumption that PPI is independent of the baseline startle reaction, there is accumulating evidence (Csomor et al., 2006; Sandner & Canal, 2007; Yee, Chang, Pietropaolo, & Feldon, 2005) that argues against such an independency. The authors systematically investigated whether PPI indexed as percentage or difference score is dependent on the magnitude of baseline startle reactivity in healthy human volunteers and in C57BL/6 mice. The results revealed that both indexations of PPI were affected by the magnitude of the baseline startle. The authors highlight the pitfalls of different methods to index PPI, especially when startle reactivity differs considerably between groups under comparison, and offer practical recommendations to satisfactorily deal with such baseline differences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Individual differences in prepulse inhibition of startle as a measure of individual dopamine function.

This study investigated whether individual differences in prepulse inhibition (PPI) of the acoustic startle reflex reflect meaningful trait differences in the function of dopaminergic substrates that regulate it. Baseline PPI of individual rats showed strong test-retest reliability across 3 consecutive test days, and there was a significant negative correlation between individual baseline PPI and both disruption of PPI produced by apomorphine and facilitation of PPI by haloperidol. The test-retest reliability and the inverse association between baseline PPI and drug-induced effects were stronger with 8–10 dB prepulses compared with less intense prepulses. These results demonstrate that individual differences in baseline PPI predict individual differences in sensitivity of PPI to drugs that affect the dopamine system and that PPI produced by more intense prepulses may be more representative of these individual differences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prepulse inhibition in the rat is regulated by ventral and caudodorsal striato-pallidal circuitry.

It has been shown that the acoustic startle reflex is inhibited by weak auditory prepulses presented 30–500 ms prior to the startling stimulus and that this prepulse inhibition (PPI) is modulated by ventral striato-pallidal circuitry. However, dorsal striatal modulation of PPI has not been examined. Cell-specific lesions and intracerebral drug infusions were used to elucidate striatal modulation of PPI. Quinolinic acid lesions of the ventral and caudodorsal striatum significantly decreased PPI, whereas lesions of the rostrodorsal and middorsal striatum did not significantly alter PPI. Infusion of the GABA-A antagonist picrotoxin into the ventral and caudal dorsal pallidum also significantly reduced PPI, whereas rostral pallidal picrotoxin infusion had no significant effect. Thus, PPI in the rat seems to be modulated by both ventral and caudodorsal striato-pallidal circuitry, but not by rostrodorsal or middorsal striato-pallidal projections. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Habituation of prepulse inhibition of the startle reflex using an auditory prepulse close to background noise.

This study examined whether prepulse inhibition habituates with repeated presentation of the prepulse alone. Prepulse inhibition was determined by measuring the decrement in the startle response when the acoustic startle-eliciting stimulus was preceded by an auditory prepulse. Rats received repetitive exposures of the same auditory prepulse alone (experimental condition) and of a visual prepulse alone (control condition). To reduce habituation of startle itself and the possible dishabituating influence the startle stimulus might have on habituation of prepulse inhibition, startle stimulus presentations were infrequently interspersed among a much larger number of prepulse-alone presentations. Stimulus-specific habituation of prepulse inhibition occurred using an auditory prepulse 2.5 dB, but not 13 dB, above background noise. Implications are discussed for the role of prepulse inhibition in sensory gating. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Inbred mouse strains differ in the regulation of startle and prepulse inhibition of the startle response.

The startle response and adaptability of the startle response (prepulse inhibition and habituation) have been observed in animals. The studies reported here screened 8 inbred mouse strains to determine whether genetic factors influence these behaviors. Strain differences were found in both the sensitivity to acoustic startle and the magnitude of both the auditory and tactile startle as well as the magnitude of prepulse inhibition (PPI) of both tactile and acoustic startle. Neither the 2 startle responses nor the 2 forms of PPI were significantly correlated with one another, suggesting that different genes regulate these 2 forms of startle and PPI. Acoustic-acoustic PPI was significantly correlated, however, with hippocampal auditory gating (TC ratio) suggesting an overlap in the genes that regulate these 2 forms of sensory gating. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Seroquel restores sensorimotor gating in phencyclidine-treated rats

Phencylidine (PCP) is a psychotomimetic noncompetitive glutamate antagonist that has been used in studies of the neural substrates of psychosis. Both schizophrenic patients and PCP-treated rats exhibit reduced amounts of prepulse inhibition (PPI) of the startle reflex, which is the normal inhibition of startle that occurs when the starting noise is preceded 30 to 500 msec by a weak prepulse. The present study assessed the effects of seroquel (ICI 204,636), a mixed D2/5-hydroxytryptamine2 antagonist with a preclinical profile suggestive of potential antipsychotic efficacy, on the PCP-induced disruption of PPI. Clozapine, risperidone and haloperidol were also studied as comparison compounds. PCP (1.25 mg/kg) significantly reduced PPI, with prepulses that were 1 to 12 dB above background. Seroquel and clozapine significantly restored PPI in PCP-treated rats, whereas haloperidol and risperidone did not. Similar findings were obtained in studies using separate animals, a slightly lower dose of PCP (1.0 mg/kg) and a high dose of each of these antipsychotics. Separate studies verified that risperidone and haloperidol restored PPI in apomorphine-treated rats. In the present studies, seroquel exhibited a profile consistent with those exhibited by other "atypical" antipsychotics.     

Early attentional deficits in an attention-to-prepulse paradigm in ADHD adults.

Adults with attention-deficit/hyperactivity disorder (ADHD) were examined for early and late attentional processes as a function of controlled attention. The test paradigm was the attentional modulation of prepulse inhibition (PPI; early controlled attentional processing) and prepulse facilitation (PPF; late controlled attentional processing). In 49 patients and 49 controls, the authors measured acoustic startle responses to 96-dB startle pulses preceded 120, 240 (for PPI), 2,000, and 4,500 (for PPF) ms by a 68-dB prepulse noise. Geometric figures signaled that prepulses were to be ignored or attended to (automatic vs. controlled attention). ADHD patients exhibited deficits in prepulse modulation, but these reflected an interaction of controlled attention and time of information processing. Normal PPI and PPF occurred under all conditions except for controlled attentional modulation of PPI. Attention deficits in ADHD patients may reflect not general derangements in information processing or ability to attend but, rather, selective disturbances of controlled attention during early information processing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Age-associated improvements in cross-modal prepulse inhibition in mice.

Prepulse inhibition (PPI) is an operational measure of sensorimotor gating that is thought to probe preattentional filtering mechanisms. PPI is deficient in several neuropsychiatric disorders, possibly reflecting abnormalities in frontal-cortical-striatal circuitry. Several studies support the predictive validity of animal PPI to model human sensorimotor gating phenomena but only limited studies have addressed the effects of aging. Studies in humans suggest that PPI is improved or unaffected as humans age (>60 years) and does not correlate with cognitive decline in aged populations. Rodent studies to date, however, suggest that PPI declines with age. Here we tested the hypothesis that PPI measures in rodents are sensitive to stimulus modality, with the prediction that intact sensory modalities in aged animals would be predictive of aging-induced increases in PPI. To test our hypothesis, we assessed PPI using acoustic, tactile, and visual prepulses in young (4 month) and old (23 month) C57BL/6N mice. Consistent with data across species, we observed reduced startle reactivity in older mice. Aging effects on PPI interacted significantly with prepulse modality, with deficient acoustic PPI but increased visual and tactile PPI in aged animals. These data are therefore consistent with PPI studies in older humans when controlling for hearing impairments. The results are discussed in terms of 1) cross-species translational validity for mouse PPI testing, 2) the need for startle reactivity differences to be accounted for in PPI analyses, and 3) the utility of cross-modal PPI testing in subjects where hearing loss has been documented. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Modulation of prepulse inhibition by an augmented acoustic environment in DBA/2J mice.

DBA/2J (DBA) mice exhibit progressive hearing loss, evident for high frequencies (>20 kHz) at age 3–4 weeks and severe by 12–16 weeks. From age 25 days to 12 weeks, DBA mice were exposed for 12 hr nightly to an augmented acoustic environment (AAE): moderately intense broadband noise bursts. After AAE treatment, prepulse inhibition (PPI) to tone prepulses (4–24 kHz, 70 dB SPL) was stronger, and baseline acoustic startle responses were larger, compared with results for age-matched DBA mice (testing performed with AAE off). Nightly AAE treatment was then terminated, and both AAE effects were largely gone 1 week later. Reinstatement of AAE treatment after the 4-week period had no significant effect on startle magnitude, but PPI improved significantly, with the AAE effect reacquired after 3 weeks. It is proposed that AAE modulates neural plasticity induced by high-frequency hearing loss in auditory system components of the PPI pathway. (PsycINFO Database Record (c) 2010 APA, all rights reserved)