Prepulse inhibition of the acoustic startle reflex and P50 gating in aging and alzheimer’s disease

Inhibition plays a crucial role in many functional domains, such as cognition, emotion, and actions. Studies on cognitive aging demonstrate changes in inhibitory mechanisms are age- and pathology-related. Prepulse inhibition (PPI) is the suppression of an acoustic startle reflex (ASR) to an intense stimulus when a weak prepulse stimulus precedes the startle stimulus. A reduction of PPI is thought to reflect dysfunction of sensorimotor gating which normally suppresses excessive behavioral responses to disruptive stimuli. Both human and rodent studies show age-dependent alterations of PPI of the ASR that are further compromised in Alzheimer’s disease (AD). The auditory P50 gating, an index of repetition suppression, also is characterized as a putative electrophysiological biomarker of prodromal AD. This review provides the latest evidence of age- and AD-associated impairment of sensorimotor gating based upon both human and rodent studies, as well as the AD-related disruption of P50 gating in humans. It begins with a concise review of neural networks underlying PPI regulation. Then, evidence of age- and AD-related dysfunction of both PPI and P50 gating is discussed. The attentional/ emotional aspects of sensorimotor gating and the neurotransmitter mechanisms underpinning PPI and P50 gating are also reviewed. The review ends with conclusions and research directions.     

Effects of prepulse intensity, duration, and bandwidth on perceived intensity of startling acoustic stimuli

Intense abrupt stimuli can elicit a startle reflex; a weak "prepulse" 30-300 ms earlier can reduce both startle and perceived stimulus intensity. Prepulse inhibition (PPI) of startle, an operational measure of sensorimotor gating, is used to understand brain disorders characterized by gating deficits. Compared to startle, PPI of perceived stimulus intensity (PPIPSI) may provide information that is distinct, and easier to acquire and analyze. To develop this experimental measure, we examined PPIPSI under different stimulus conditions. Both PPI and PPIPSI exhibited a non-linear relationship to prepulse intensity, with prepulses 15 dB(A) above background causing maximal inhibition of both measures. A 50 ms broadband noise prepulse produced maximal PPI and PPIPSI, whereas 5 and 20 ms pure tone prepulses produced maximal PPIPSI and PPI, respectively. PPIPSI is a robust, parametrically sensitive and "low tech" measure of sensory gating that may become a valuable tool for understanding the biology of certain mental disorders.     

Menstrual cycle phase effects on prepulse inhibition of acoustic startle

Prepulse inhibition (PPI) represents an attenuation of the startle reflex following the presentation of a weak prepulse at brief intervals prior to the startle eliciting pulse. It has been shown that increases in striatal dopamine levels decrease PPI; because dopamine release is sensitive to estrogen, it is likely that PPI varies across the menstrual cycle. Cross-sectional studies looking at estrogen effects suggest that this may be true. In this study, we compare effects of menstrual phase on PPI in a between-group design (men, follicular phase women, and luteal phase women) as well as a within-subjects design (women across the two phases). The study found a between-group as well as a within-subjects effect of phase on PPI. PPI in follicular phase women did not differ significantly from PPI in men. However, PPI was reduced in luteal women compared to follicular women. These data provide evidence that ovarian hormones affect sensorimotor gating.     

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.     

The chakragati mouse shows deficits in prepulse inhibition of acoustic startle and latent inhibition

The chakragati (ckr) mouse, which was serendipitously created as a result of a transgenic insertional mutation, has been proposed as a model of aspects of schizophrenia. The mice exhibit circling, hyperactivity, reduced social interactions, and enlarged lateral ventricles, which parallel aspects of the pathophysiology of schizophrenia. Deficits in sensorimotor gating and processing of the relevance of stimuli are core features of schizophrenia, which underlie many of the symptoms presented. Measures of prepulse inhibition (PPI) and latent inhibition (LI) can assess sensorimotor gating and processing of relevance in both humans and animal models. We investigated PPI of acoustic startle and LI of aversive conditioning in wild-type, heterozygous, and ckr mice. The ckr mice, which are homozygous for the transgene insertion, but not heterozygous littermates, showed impaired PPI in the absence of any difference in acoustic startle amplitude and showed deficits in LI of conditioning of a light stimulus to footshock, measured as suppression of licking for water in water-restricted mice. Together with the previous evidence for hyperactivity, reduced social interactions, and enlarged lateral ventricles, these data lend further support to the suggestion that the ckr mouse has utility as an animal model of aspects of schizophrenia.     

Relationship of prepulse inhibition of the startle reflex to attentional and executive mechanisms in man.

Prepulse inhibition (PPI) of the startle reflex at short lead intervals is thought to reflect the operation of a preattentive "sensorimotor gating" mechanism, which suggests that processing of the prepulse stimulus should not be modulated prior to its inhibitory effects on startle. To test this hypothesis, we examined whether PPI is affected following habituation to the prepulse. PPI was measured in two sessions associated with either the presence (habituation condition) or the absence (control condition) of prepulse repetition. There was a trend for prepulse repetition to reduce the effectiveness of that prepulse in inhibiting the startle response. We also explored the relationship of PPI to scores in tests of selective and sustained attention and planning ability. Overall PPI performance was correlated to performance indices of planning ability and there was a trend level correlation with scores in selective but not sustained attention tests. These preliminary results merit further investigation.     

Enhanced prepulse inhibition of startle using salient prepulses in rats.

Prepulse inhibition (PPI) of the startle reflex occurs when a non-startling stimulus is presented shortly prior to the startling stimulus. PPI is an operational measure for sensorimotor gating. PPI in humans is enhanced by attention, but there is no evidence yet for attentional modulation of PPI in animals. We here combined PPI and conditioned inhibition paradigms in order to investigate attentional modulation of PPI in rats. PPI was assessed before and after training for conditioned inhibition of fear with the conditioned stimulus (auditory CS) and conditioned inhibitor (visual CI) as prepulses. The CI significantly enhanced PPI after training, whereas presentation of the CS had no effect on PPI. These data suggest attentional modulation of PPI in rats by biologically salient prestimuli. This new paradigm may be useful for examining attentional modulation of PPI in animals and to compare attentional modulation in humans and animals.     

The effects of A1 and A2A adenosine receptor agonists on kainic acid excitotoxicity in the guinea pig cochlea

Prepulse inhibition (PPI) is the reduction in the startle response caused by a low intensity non-startling stimulus (prepulse) which is presented shortly before the startle stimulus and is an operational measure of sensorimotor gating. PPI is impaired in schizophrenia patients and in rats with central dopamine (DA) activation. The inferior colliculus (IC) is a critical part of the auditory pathway mediating acoustic PPI. The activation of the IC by the acoustic prepulse reduces startle magnitude. The aim of this study was to elucidate the role of DA transmission of the IC on the development of acoustic PPI. Bilateral microinjections of apomorphine (9.0 μg/0.5 μL), an agonist of D₂ receptors, into the IC disrupted PPI while microinjections of haloperidol (0.5 μg/0.5 μL), an antagonist of D₂ receptors, into this structure did not alter PPI. These results suggest that dopamine-mediated mechanisms of the IC are involved in the expression of PPI in rodents.     

Prepulse inhibition deficits in women with PTSD

Prepulse inhibition (PPI) is an automatic and preattentive process, whereby a weak stimulus attenuates responding to a sudden and intense startle stimulus. PPI is a measure of sensorimotor filtering, which is conceptualized as a mechanism that facilitates processing of an initial stimulus and is protective from interruption by a later response. Impaired PPI has been found in (a) healthy women during the luteal phase of the menstrual cycle, and (b) individuals with types of psychopathology characterized by difficulty suppressing and filtering sensory, motor, or cognitive information. In the current study, 47 trauma‐exposed women with or without posttraumatic stress disorder (PTSD) completed a PPI session during two different phases of the menstrual cycle: the early follicular phase, when estradiol and progesterone are both low, and the midluteal phase, when estradiol and progesterone are both high. Startle stimuli were 100 dB white noise bursts presented for 50 ms, and prepulses were 70 dB white noise bursts presented for 20 ms that preceded the startle stimuli by 120 ms. Women with PTSD showed deficits in PPI relative to the healthy trauma‐exposed participants. Menstrual phase had no effect on PPI. These results provide empirical support for individuals with PTSD having difficulty with sensorimotor filtering. The potential utility of PPI as a Research Domain Criteria (RDoC) phenotype is discussed.     

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.     

Stimulus quality affects expression of the acoustic startle response and prepulse inhibition in mice

The relationship between stimulus intensity and startle response magnitude (SIRM) can assess the startle reflex and prepulse inhibition (PPI) with advantages over more commonly used methods. The current study used the SIRM relationships in mice to determine differences between white noise and pure tone (5 kHz) stimuli. Similarly to rats, the SIRM relationship showed a sigmoid pattern. The SIRM-derived reflex capacity (RMAX) and response efficacy (slope) of the white noise and pure tone stimuli in the absence of prepulses were equivalent. However, the pure tone startle response threshold (DMIN) was increased whereas the stimulus potency (1/ES50) was decreased when compared to white noise. Prepulses of both stimulus types inhibited RMAX and increased DMIN, but the white noise prepulses were more effective. Both stimulus intensity gating and motor capacity gating processes are shown to occur, dependent on prepulse intensity and stimulus onset asynchrony. Prepulse intensities greater than 10 dB below the startle threshold appear to produce PPI via stimulus intensity gating, whereas a motor capacity gating component appears at prepulse intensities near to the startle threshold.     

Large sexual-orientation-related differences in performance on mental rotation and judgment of line orientation tasks

This study examined the performance of heterosexual and homosexual men and women on 2 tests of spatial processing, mental rotation (MR) and Benton Judgment of Line Orientation (JLO). The sample comprised 60 heterosexual men, 60 heterosexual women, 60 homosexual men, and 60 homosexual women. There were significant main effects of gender (men achieving higher scores overall) and Gender x Sexual Orientation interactions. Decomposing these interactions revealed large differences between the male groups in favor of heterosexual men on JLO and MR performance. There was a modest difference between the female groups on MR total correct scores in favor of homosexual women but no differences in MR percentage correct. The evidence suggests possible variations in the parietal cortex between homosexual and heterosexual persons.     

Dopaminergic-induced changes in Mauthner cell excitability disrupt prepulse inhibition in the startle circuit of goldfish

Prepulse inhibition (PPI) is a widespread sensorimotor gating phenomenon characterized by a decrease in startle magnitude if a nonstartling stimulus is presented 20-1,000 ms before a startling stimulus. Dopaminergic agonists disrupt behavioral PPI in various animal models. This provides an important neuropharmacological link to schizophrenia patients that typically show PPI deficits at distinct (60 ms) prepulse-pulse intervals. Here, we study time-dependent effects of dopaminergic modulation in the goldfish Mauthner cell (M-cell) startle network, which shows PPI-like behavioral and physiological startle attenuations. The unique experimental accessibility of the M-cell system allows investigating the underlying cellular mechanism with physiological stimuli in vivo. Our results show that the dopaminergic agonist apomorphine (2 mg/kg body wt) reduced synaptic M-cell PPI by 23.6% (n = 18; P = 0.009) for prepulse-pulse intervals of 50 ms, whereas other intervals showed no reduction. Consistently, application of the dopamine antagonist haloperidol (0.4 mg/kg body wt) restored PPI to control level. Current ramp injections while recording M-cell membrane potential revealed that apomorphine acts through a postsynaptic, time-dependent mechanism by deinactivating a M-cell membrane nonlinearity, effectively increasing input resistance close to threshold. This increase is most pronounced for prepulse-pulse intervals of 50 ms (47.9%, n = 8; P < 0.05) providing a time-dependent, cellular mechanism for dopaminergic disruption of PPI. These results provide, for the first time, direct evidence of dopaminergic modulation of PPI in the elementary startle circuit of vertebrates and reemphasize the potential of characterizing temporal aspects of PPI at the physiological level to understand its underlying mechanisms.     

Selective Breeding of Reduced Sensorimotor Gating in Wistar Rats

Prepulse inhibition (PPI) of startle is an operational measure of sensorimotor gating that is reduced in some neuropsychiatric disorders (e.g. schizophrenia). Animal models have revealed insight into the neuronal and pharmacological underpinnings of PPI-deficits. Recent work has shown that a PPI-deficit can be selectively bred in Wistar rats and is already stable in the second filial generation. We here report on developmental and parametric characteristics of sensorimotor gating deficits in the 4th and 6th filial generation of male rats selectively bred for low PPI (low PPI) compared to rats with normal levels of PPI (high PPI). Low PPI rats showed significantly reduced PPI and variable startle magnitude (in pulse alone trials) along with reduced short-term habituation of startle as adults. Reduced PPI in the low PPI rats was found throughout development (tested on postnatal days 21, 35, 49, 70). PPI-deficits in the low PPI rats were evident at prepulse intensities ranging from 62–86 dB and for interstimulus intervals ranging between 30–1000 ms. These behavioral data add to a growing body of knowledge about the genetic basis of sensorimotor gating deficits and suggest that low PPI rats have potential use as an intermediate phenotype in schizophrenia research. The stable phenotype of breeding-induced PPI-deficits and reduced startle habituation indicates that PPI has strong genetic determinants and that selectively bred rats can be used for future neurophysiological, anatomical, pharmacological, and genomic analyses. Edited by Stephen Maxson.     

Ontogeny of isolation rearing-induced deficits in sensorimotor gating in rats.

Presentation of a weak stimulus immediately before a startling stimulus decreases the magnitude of the resultant startle response. This phenomenon, termed prepulse inhibition (PPI), provides an operational measure of sensorimotor gating, and is deficient in schizophrenia patients. Clinically observed PPI deficits can be modeled in rodents by housing rats individually from weaning until adulthood. The developmental time course of isolation rearing-induced PPI deficits, however, is unknown. The present studies characterized the ontogeny of isolation-induced PPI deficits and hyperactivity. Separate groups of Sprague-Dawley and Lister hooded rats were either singly housed (ISO) or socially housed (SOC, groups of two to three per cage) upon weaning and then maintained in these housing conditions for different periods of time until assessment of PPI and locomotor activity; animals were tested at time points that roughly corresponded to before puberty (2 weeks postweaning), during puberty (4 weeks postweaning), or after puberty (6-7 weeks post weaning). PPI deficits were seen in Sprague-Dawley ISO rats at either the 4- or 6-, but not the 2-week time points. In contrast, hyperactivity was noted in these animals starting at the 2-week time point. Lister rats showed the same general pattern of ISO-induced effects, with ISO-induced hyperactivity (observed 4 weeks postweaning) preceding ISO-induced PPI deficits (observed 7 weeks postweaning). Therefore, ISO produces dissociable effects on PPI and locomotor activity, with PPI deficits emerging only during or after puberty. ISO might thus provide a useful noninvasive tool with which to study the neural substrates of delayed-onset sensorimotor gating abnormalities.     

Cholinergic neurons in the pedunculopontine tegmental nucleus are involved in the mediation of prepulse inhibition of the acoustic startle response in the rat

The amplitude of the acoustic startle response (ASR) is markedly reduced when the startle eliciting pulse is preceded by a weak, non-startling stimulus at an appropriate lead time, usually about 100 ms. This phenomenon is termed prepulse inhibition (PPI) and has received considerable attention in recent years as a model of sensorimotor gating. We report here on experiments which were undertaken in order to investigate some of the neural mechanisms of PPI. We focused on the characterization of the cholinergic innervation of the pontine reticular nucleus, caudal part (PnC), an obligatory relay station in the primary startle pathway. The combination of retrograde tracing with choline acetyltransferase-immunocytochemistry revealed a cholinergic projection from the pedunculopontine tegmental nucleus (PPTg) and laterodorsal tegmental nucleus (LDTg) to the PnC. Extracellular recording from single PnC units, combined with microiontophoretic application of the acetylcholine (ACh) agonists acetyl--methylcholine (AMCH) and carbachol revealed that ACh inhibits the majority of acoustically responsive PnC neurons. Neurotoxic lesions of the cholinergic neurons of the PPTg significantly reduced PPI without affecting the ASR amplitude in the absence of prepulses. No effect on long-term habituation of the ASR was observed. The present data indicate that the pathway mediating PPI impinges upon the primary acoustic startle circuit through an inhibitory cholinergic projection from the PPTg to the PnC.     

Relationship between prepulse inhibition of acoustic startle response and schizotypy in healthy Japanese subjects

Prepulse inhibition (PPI) of the acoustic startle reflex (ASR) is the most common psychophysiological index of sensorimotor gating. Several studies have investigated the relationship of PPI of ASR to schizotypy in Caucasians. However, little has been reported on this relationship in Asians. We investigated a possible relationship between PPI of ASR and schizotypy in 79 healthy Japanese subjects. Schizotypy was assessed by the Schizotypal personality Questionnaire (SPQ). PPI was evaluated at signal‐to‐noise ratios (SnRs: difference between background noise intensity and prepulse intensity) of +12, +16, and +20 dB. The total SPQ score, cognitive/perceptual score, and interpersonal score correlated negatively with PPI at SnR of +16 and +20 dB. We conclude that PPI is associated with the trait of schizotypy in healthy Asian subjects.     

Gender, sexuality, body image and eating behaviours

One hundred and twenty one participants reported sexual orientation, body mass index, body shape concerns, eating motives and eating styles. Measures of body dissatisfaction were greater in heterosexual women and homosexual men (ps <.05), while heterosexual women had smaller (ps <.001) ideal body shapes. Eating weight control motive was lower in heterosexual men compared to women (ps <.05). Restrained eating was lower in heterosexual men compared to heterosexual women or homosexual men (ps <.001). The findings support the role of socially prescribed body shapes on body shape concerns, eating motivations, and eating styles in men and women and suggest impacts are greater for heterosexual women and homosexual men.     

Sex, beauty and the orbitofrontal cortex.

Face perception is mediated by a distributed neural system in the human brain. Attention, memory and emotion modulate the neural activation evoked by faces, however the effects of gender and sexual orientation are currently unknown. To test whether subjects would respond more to their sexually-preferred faces, we scanned 40 hetero- and homosexual men and women whilst they assessed facial attractiveness. Behaviorally, regardless of their gender and sexual orientation, all subjects similarly rated the attractiveness of both male and female faces. Consistent with our hypothesis, a three-way interaction between stimulus gender, beauty and the sexual preference of the subject was found in the medial orbitofrontal cortex (OFC). In heterosexual women and homosexual men, attractive male faces elicited stronger activation than attractive female faces, whereas in heterosexual men and homosexual women, attractive female faces evoked stronger activation than attractive male faces. These findings suggest that the OFC represents the value of salient sexually-relevant faces, irrespective of their reproductive fitness.