Factors governing prepulse inhibition and prepulse facilitation of the acoustic startle response in mice

The influence of prepulses on the acoustic startle response (ASR) was measured in three inbred mouse strains, C57BL/6J, 129/SvHsd, and AKR/OlaHsd, and one hybrid strain produced by crossing wild mice and NMRI mice. Prepulse inhibition (PPI), i.e. reduction of ASR by prepulses, was maximal when the interval between prepulses and startle stimuli was in the range of 37.5-100 ms. Prepulse facilitation (PPF), i.e. increase of ASR by prepulses, was maximal when the prepulse preceded the startle stimulus by 12.5 ms. PPI increased with increasing prepulse SPL, PPF first increased then decreased when prepulse SPL was increased. Percent PPI was independent from startle stimulus SPL. All strains showed a long-term increase of PPI when tested for several days; one strain (129) also showed an increase of PPF over days. The present results clearly show that PPI and PPF are independent processes, which add to yield the final response change. PPF and the observed long-term changes of PPI and PPF are stronger expressed in mice than have been observed in rats under similar conditions. Since there were significant differences between the strains of mice with respect to PPI and PPF, genetically different strains of mice are a promising tool to study these two processes.     

Sex differences in the acoustic startle response and prepulse inhibition in Wistar rats

The prepulse inhibition paradigm (PPI) is based on the phenomenon that the acoustic startle response (ASR) to an acoustic stimulus is reduced when the stimulus is preceded by a weak prepulse. It has been shown that PPI is dramatically disrupted in patients with schizotypic disorders. Since PPI can be easily tested in animals as well as in humans it is a widely used model to investigate the neurobiological mechanisms underlying those disorders. In humans it has been demonstrated that men show increased PPI at weak prepulses relative to women. Only very few studies have investigated PPI sex differences in rats and these report negative findings. Studies are reported on here where consistent differences have been found in ASR and PPI between adult male and female Wistar rats. Compilation of data from a series of experiments demonstrates that ASR and PPI are both greater in males than in females in this rat strain, a finding which is largely in line with the human evidence. This study therefore adds weight to the argument that PPI of the ASR provides an animal model with high validity for the study of important human disorders which are characterized by sensorimotor gating deficits.     

Isolation rearing of mice induces deficits in prepulse inhibition of the startle response

Male 129T2 and C57BL/6J mice were housed either in groups of three (socials) or singly (isolates) at weaning. Six and seven weeks later, prepulse inhibition (PPI), startle reactivity, and locomotor activity (LMA) were measured. Isolation-reared mice of both strains exhibited PPI deficits compared to socially reared controls in at least one of the two PPI test sessions. Isolation rearing had no effect on startle reactivity or habituation and only 129T2 isolates exhibited increased LMA. Isolation rearing induced locomotor hyperactivity and PPI deficits in mice and may be an effective developmental manipulation to use in combination with studies of genetically altered mice.     

Attentional modulation of prepulse inhibition: a new startle paradigm

There is increasing evidence for an influence of directed attention on prepulse inhibition (PPI) of the acoustic startle reflex. However, the existing paradigms for the assessment of this effect have methodological problems and pitfalls. In particular, most previous studies used a paradigm which directed the attention of subjects to the prepulse only. In the present study, we used a modified paradigm which directed the attention of the subjects both to the prepulse and the pulse. Twenty healthy male subjects were instructed trial by trial either to relax or to attend to the startle stimulus and decide whether it was a 'simple' (prepulse alone or pulse alone) or a 'composite' trial (pulse plus a prepulse or postpulse). Directed attention enhanced PPI at the lead interval of 240 ms, but not at the lead interval of 100 ms. This finding is in line with the idea that attention contributes to PPI when there is enough time for the attentional mechanisms to exert an influence. This new paradigm offers a valuable tool for the study of attentional modulation of sensorimotor gating in humans.     

Isolation-induced changes in ultrasonic vocalization, fear-potentiated startle and prepulse inhibition in rats

Isolation causes important changes in the behavioral reactivity of rats to environmental stimuli. These changes include deficit in sensorimotor gating and altered fear-like responses to aversive stimuli. Measures of ultrasound vocalizations at 20-22 kHz when rats are exposed to threatening conditions, such as novelty, have been taken as a good measure of fear. The fear-potentiated startle to loud sounds and the prepulse inhibition tests have been considered reliable indicators of anxiety and attention impairments, respectively. Rats reared under conditions of isolation from weaning display clear deficits in prepulse inhibition. Taking into account that housing condition changes the emotional state of the animals, we evaluated in this work the performance of rats in the fear-potentiated startle test, prepulse inhibition and emission of ultrasound vocalizations to novelty when isolated for 10 days and after resocialization for 1 week in comparison to grouped rats. Isolated rats showed greater reactivity to loud sounds in the fear-potentiated startle test than grouped animals. They also emitted less ultrasound vocalizations at 20-22 kHz than grouped animals when exposed to a novel environment. In contrast to the well-known deficit in prepulse inhibition displayed by isolation-reared animals, in the present study isolation for 10 days caused a significant increase in prepulse inhibition. Resocialization was not able to counteract the effects of isolation in all three tests. The results suggest that the emotional state of the animals is altered by 10 days of isolation; they do not vocalize characteristically as grouped rats when submitted to novelty; unconditioned responses to loud sounds are enhanced and increased prepulse inhibition is shown rather than a deficit as largely documented in studies with isolation-reared animals. It is suggested that the assessment of the emotional state of the animals is a prerequisite in the evaluation of prepulse inhibition. The level of defensive reactivity displayed by isolated animals is crucial for the functioning of sensory gating and, by extension, to the expression of prepulse inhibition.     

P50 suppression and prepulse inhibition of the startle reflex in humans: a correlational study.

BACKGROUND: Sensory gating is an important feature of the normally functioning brain. When not operating correctly, it can contribute to different kinds of psychiatric illnesses by flooding the higher brain functions with useless information. Over the years, two paradigms have evolved to quantify the amount of sensory gating: the prepulse inhibition (PPI) of the startle reflex and the suppression of the P50 evoked potential. To enable comparison across studies it is important to find out to what extent these paradigms reflect the same processes. In the present study, this relationship was explored. METHODS: Thirty-one healthy male volunteers with no personal or family history of mental illness were tested on their ability to suppress the P50 wave and to inhibit the startle reflex. RESULTS: A significant positive correlation was found between PPI and P50 suppression mainly early in testing, when habituation of the startle reflex is taking place. Furthermore, a significant negative correlation was found between P50 suppression in the second half of testing and the habituation of the startle reflex. CONCLUSIONS: PPI and P50 suppression are correlated at an early stage of testing, when the process of habituation of the startle reflex is active. The role of the habituation in the correlation between these two measures needs to be further explored.     

Acoustic startle response, prepulse inhibition, and spontaneous locomotor activity in MPTP-treated mice

Parkinson's disease (PD) is marked by characterised motor deficits and is accompanied by a severe degeneration of the nigrostriatal dopamine (DA) pathway. It has also been reported that PD patients exhibited additional behavioural deficits, including a deficiency in sensorimotor gating mechanisms. We therefore examined whether the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in mice could lead to a sensorimotor gating deficit in the prepulse inhibition (PPI) of the acoustic startle response (ASR) paradigm. Two MPTP treatment schedules were separately examined here in male C57BL/6 mice. Post-mortem HPLC analysis confirmed that they were effective in depleting DA in the dorsal striatum (75-88%). PPI was evaluated on days 2, 9 and 16 after the last MPTP treatment; spontaneous locomotor activity was assessed 24 h before each PPI test. No significant change in the expression of PPI was detected across the three time points. On the other hand, the MPTP treatment reduced activity on post-treatment day 1. This effect subsided on post-treatment day 8, and was reversed on day 15. The possibility remains therefore that the reported sensorimotor gating deficits in PD patients might stem from structural or neurochemical aberrations beyond those induced by MPTP treatment.     

The effect of aripiprazole on prepulse inhibition of the startle response in normal and hyperdopaminergic states in rats

This study compared the D(2) partial agonists, aripiprazole, (R(+)-terguride; S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [S(-)-3-PPP]; 7-[3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy]-2(1H)-quinolinone [OPC-4392]) and D(2) antagonists (haloperidol, olanzapine, clozapine, risperidone, and quetiapine) on prepulse inhibition (PPI) of the startle response, and the ability to reverse apomorphine-induced deficits in the PPI response. Aripiprazole did not essentially affect PPI in na?ve rats but dose-dependently restored apomorphine-induced PPI disruption. R(+)-terguride restored PPI disruption but suppressed PPI significantly in na?ve rats, S(-)-3-PPP partially restored whereas OPC-4392 did not restore PPI disruption. Haloperidol and risperidone restored PPI disruption whereas olanzapine and quetiapine partially restored PPI disruption and clozapine had no restorative effect. In conclusion, aripiprazole, unlike other antipsychotic agents, failed to suppress PPI significantly and restored PPI disruption.     

Neural cell adhesion molecule-null mice are not deficient in prepulse inhibition of the startle response

Mice constitutively deficient in the neural cell adhesion molecule have morphological changes in the brain, which are hallmarks of schizophrenia. Schizophrenic patients are impaired in sensorimotor processing indicated by a deficit in prepulse inhibition of the acoustic startle response. Here we tested whether prepulse inhibition and prepulse facilitation are changed in neural cell adhesion molecule-deficient mice compared with their wild-type littermates. Neither prepulse inhibition nor prepulse facilitation (which occurred only at the lowest prepulse intensity used and was weak) was altered. This result is discussed in the light of the 'two-hit' hypothesis of schizophrenia, suggesting that in neural cell adhesion molecule-deficient mice, a prepulse inhibition deficit may become apparent only after treatment with a 'second hit' (such as increased stress).     

Effects of antipsychotics on prepulse inhibition of the startle response in drug-na?ve schizophrenic patients.

BACKGROUND: Disturbances in sensorimotor gating measured by prepulse inhibition of the startle response (PPI) have frequently been reported in medicated and unmedicated schizophrenia spectrum patients and in their relatives, suggesting that the deficit represents a stable vulnerability marker for schizophrenia. Clinical data on the effects of antipsychotics on PPI disturbances are scarce, but from preclinical studies, antipsychotics have been shown to influence PPI. To differentiate pathogenetic mechanisms from drug related effects, longitudinal clinical studies on the effect of antipsychotic treatment on PPI in drug-naive first-episode schizophrenic patients are needed. METHODS: First-episode schizophrenic patients never previously medicated with antipsychotics were examined at inclusion and after 3 months of treatment with the atypical antipsychotic compound, risperidone, or the typical drug, zuclopenthixol. Healthy controls were used as a comparison group. RESULTS: The results confirm deficits in PPI in drug-naive first-episode patients. No effect of antipsychotic treatment on PPI dysfunction was observed in any of the treatment groups. CONCLUSIONS: The data are the first to show the possible effect of treatment with antipsychotic drugs on PPI disturbances in a longitudinal study of drug-naive schizophrenic patients. The data do not support any influence of treatment with antipsychotic drugs on sensorimotor gating deficits. Instead, the results point to the impairment in PPI as a stable vulnerability indicator.     

Impaired prepulse inhibition of acoustic and tactile startle response in patients with Huntington''s disease.

The corpus striatum serves a critical function in inhibiting involuntary, intrusive movements. Striatal degeneration in Huntington's disease results in a loss of motor inhibition, manifested by abnormal involuntary choreiform movements. Sensorimotor inhibition, or "gating", can be measured in humans using the startle reflex: the startle reflex is normally inhibited when the startling stimulus is preceded 30-500 ms earlier by a weak prepulse. In the present study, prepulse inhibition (PPI) was measured in patients with Huntington's disease to quantify and characterise sensorimotor gating. Compared with age matched controls, patients with Huntington's disease exhibit less PPI. Startle gating deficits are evident in patients with Huntington's disease when startle is elicited by either acoustic or tactile stimuli. Even with stimuli that elicit maximal PPI in normal subjects, patients with Huntington's disease exhibit little or no PPI, and their pattern of startle gating does not show the normal modulatory effects usually elicited by changing the prepulse interval or intensity. Startle amplitude and habituation and latency facilitation are largely intact in these patients, although reflex latency is significantly slowed. In patients with Huntington's disease, startle reflex slowing correlates with cognitive impairment measured by the dementia rating scale, and with the performance disruptive effects of interference measured by the Stroop test. These findings document a profound disruption of sensorimotor gating in patients with Huntington's disease and are consistent with preclinical findings that identify the striatum and striatopallidal GABAergic efferent circuitry as critical substrates for sensorimotor gating of the startle reflex.     

Neonatal hippocampal Tat injections: developmental effects on prepulse inhibition (PPI) of the auditory startle response

The current estimate of children (<15 years) living with HIV and AIDS is 2.2 million. The major source of infection occurs through vertical transmission of the virus from mother to child during delivery [UNAIDS/WHO, 2005. AIDS Epidemic Update. UNAIDS, Geneva]. Recent studies have shown that timing of HIV-1 infection might be related to the onset and rate of progression of CNS disease. The effects of HIV on the brain are thought to be mediated indirectly through the viral toxins Tat and gp120. This study characterized developmental effects on PPI following intrahippocampal administration of Tat. On postnatal day (P)1, one male and one female pup from each of eight Sprague-Dawley litters were bilaterally injected with 50 microg Tat or saline (1 microl volume). Animals were tested for PPI of the auditory startle response (ASR) (ISIs of 0, 8, 40, 80, 120, and 4000 ms, six trial blocks, Latin-square design) on days 30, 60 and 90. Tat altered PPI and the pattern of alterations was different for males and females. For males, a leftward shift was evident in the ISI for maximal inhibition of the response on day 30 and on day 60 (chi(2)(1)=4.7, p< or =.03, and chi(2)(1)=5.3, p< or =.02, respectively), but not on day 90. For females, Tat altered peak ASR latency across PPI trials (8-120 ms) at all days of testing (30, 60, and 90 days of age), as indexed by orthogonal component analyses, indicating less modulation of PPI by ISI. Data collected from a second group that were tested only once at 90 days of age, suggested that the observed adverse Tat effects for males and females early in development were maintained with age. Thus, the diminishing TAT effect on PPI at day 90 in a longitudinal study design was attributed to repeated testing, rather than 'recovery of function'. Collectively, the data suggested that hippocampal Tat injections in neonatal rats produced alterations in the pre-attentive process of sensorimotor gating, as indexed by PPI.     

Amphetamine dose dependently disrupts prepulse inhibition of the acoustic startle response in rats within a narrow time window

Prepulse inhibition (PPI) of the acoustic startle response refers to the reduction in startle amplitude when a weak prepulse precedes a startle-inducing pulse. Prepulse inhibition has been shown to be disrupted by amphetamine at doses that also stimulate locomotor activity, and it has been suggested that the same neuroanatomical substrate, mesolimbic dopamine activation, mediates the effects of amphetamine on locomotor activity and PPI. Amphetamine stimulates locomotor activity and mesolimbic dopamine release over a 1- to 3-h period, whereas PPI is typically measured within the first 30 min following amphetamine treatment. The present study therefore determined whether delays in testing would alter the PPI-disruptive effect of amphetamine in male Wistar rats. Amphetamine dose dependently disrupted PPI when the test session occurred 10 min following amphetamine treatment and only when the prepulse intensity was 5-10 dB above background. Delays of 40 and 60 min post-amphetamine injection, however, resulted in a loss of the ability of amphetamine to disrupt PPI although locomotor activity was significantly stimulated by amphetamine at these time points. The data from the present study therefore do not readily fit with the notion that the effects of amphetamine on locomotion and PPI are mediated by the same substrate.     

Lipopolysaccharide produces dose-dependent reductions of the acoustic startle response without impairing prepulse inhibition in male rats

This study examined the dose-dependent effects of Lipopolysaccharide (LPS) on the acoustic startle response and prepulse inhibition (PPI) in male Long-Evans rats. LPS is known to stimulate the innate immune system and result in behavior modifications referred to as "sickness behaviors". The purpose of this study was to assess the ability of LPS to modulate sensorimotor reflexes (Startle-Only trials) and/or sensory processing (PPI trials). Rats were injected intraperitoneally with LPS (50, 100 or 200 microg/kg LPS, n=9/group) or saline vehicle (n=14) on 2 test days 72 h apart. Subjects were placed in a familiar startle box apparatus where startle response magnitudes were recorded following 115 dB Startle-Only trials and PPI trials (with prepulses at +3, +6 and +12 dB above background noise). Analysis of Startle-Only trials indicated a significant dose-dependent effect of LPS on Test Day 1. The 200 microg/kg LPS group exhibited significantly reduced startle response magnitude relative to all other treatments. On the PPI trials no LPS groups displayed significantly different performance from vehicle controls. Also, DayxDrug interactions for both Startle-Only and PPI trial types indicated behavioral tolerance to LPS. LPS reduced the acoustic startle response in a dose-dependent manner on Test Day 1. From the PPI data, it is evident that all treatment groups elicited near-normal inhibition levels indicating adequate sensory function. In combination, the results suggest that the range of sickness behaviors following LPS-administration to adult rats includes decreased non-voluntary motor activity as reflected by reduced startle magnitude.     

Dissociative identity disorder and prepulse inhibition of the acoustic startle reflex

A group of persons with dissociative identity disorder (DID) was compared with a group of persons with other dissociative disorders, and a group of nondiagnosed controls with regard to prepulse inhibition (PPI) of the acoustic startle reflex. The findings suggest maladaptive attentional processes at a controlled level, but not at a preattentive automatic level, in persons with DID. The prepulse occupied more controlled attentional resources in the DID group compared with the other two groups. Preattentive automatic processing, on the other hand, was normal in the DID group. Moreover, startle reflexes did not habituate in the DID group. In conclusion, increased PPI and delayed habituation is consistent with increased vigilance in individuals with DID. The present findings of reduced habituation of startle reflexes and increased PPI in persons with DID suggest the operation of a voluntary process that directs attention away from unpleasant or threatening stimuli. Aberrant voluntary attentional processes may thus be a defining characteristic in DID.     

Lower levels of prepulse inhibition of startle response in pregnant women compared to postpartum women

OBJECTIVE: During the postpartum period, estradiol and progesterone levels decline from very high levels during late pregnancy to low levels within 48h of parturition. This period is associated with dysphoric states such as the postpartum blues. Animal studies have suggested an enhanced acoustic startle response and deficient prepulse inhibition (PPI) of startle response following progesterone withdrawal and during the postpartum period. The aim of the current study was to compare acoustic startle response and PPI in healthy third trimester pregnant women and healthy postpartum women. METHODS: Twenty-eight healthy pregnant and 21 healthy postpartum women (examined between 48h and 1 week after delivery) were recruited for the study. In addition, to evaluate the time-course of postpartum changes 11 early postpartum women (examined within 48h following delivery) were included in the study. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of m. Orbicularis Oculi. Twenty pulse-alone trials (115dB 40ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115dB 40ms noise burst preceded at a 100ms interval by 20ms prepulses that were 72, 74, 78 or 86dB. RESULTS: Pregnant women exhibited lower levels of PPI compared to late postpartum women, p<0.05. There was no difference between pregnant women and postpartum women examined within 48h of delivery. There was no difference in startle response or habituation to startle response between pregnant women and either of the two groups of postpartum women. CONCLUSION: Healthy women display lower levels of PPI during late pregnancy when estradiol and progesterone levels are high compared to the late postpartum period when ovarian steroid levels have declined.     

Attenuation of auditory startle and prepulse inhibition by unexpected changes in ambient illumination through dopaminergic mechanisms

We investigated the role of dopaminergic mechanisms in the attenuation of the acoustic startle response and prepulse inhibition (PPI) in rats by the introduction of unexpected changes in environment illumination. Experiment 1 showed that Dark-to-Light transitions robustly reduce startle responses and PPI. Experiment 2 showed that this phenomenon habituates across repeated testing sessions and reappears after an interval without testing. Experiment 3 demonstrated that haloperidol blocks the startle and PPI-reducing effect of the Dark-to-Light transition. We show how a computational model of acoustic startle response and prepulse inhibition can be extended to incorporate the empirical effects demonstrated in this study. We conclude that sensory gating as measured by prepulse inhibition is markedly attenuated in situations where novel stimuli are introduced during a test session and that dopaminergic systems may be involved in the dynamic changes evoked by the onset of illumination.     

Using intracranial electrical stimulation to study the timing of prepulse inhibition of the startle reflex

Due to the short latency and briefness of the startle reflex, event-related inhibition of startle has high temporal resolution and is useful for studying the hierarchical organization of sensorimotor gating and motive-motor gating. In this article, we describe methods for measuring the inhibitory effects of electrically stimulating each of the following four brain structures on startle in awake rats: the inferior colliculus (IC), the deeper layers of the superior colliculus (SC), the pedunculopontine tegmental nucleus (PPTg), and the ventral pallidum (VP). These four brain structures have been reported to be important in mediating sensorimotor or motive-motor gating. Startle responses are elicited by either intense noise bursts or electrical stimulation of the principal trigeminal nucleus. The time course of the IC-inhibited startle reflex is used as a standard for estimating timing of the neural transfer of startle-inhibitory information to motor outputs. We also discuss how these methods can be used in combination with neuropharmacology.     

Primary and secondary neural networks of auditory prepulse inhibition: a functional magnetic resonance imaging study of sensorimotor gating of the human acoustic startle response

Feedforward inhibition deficits have been consistently demonstrated in a range of neuropsychiatric conditions using prepulse inhibition (PPI) of the acoustic startle eye-blink reflex when assessing sensorimotor gating. While PPI can be recorded in acutely decerebrated rats, behavioural, pharmacological and psychophysiological studies suggest the involvement of a complex neural network extending from brainstem nuclei to higher order cortical areas. The current functional magnetic resonance imaging study investigated the neural network underlying PPI and its association with electromyographically (EMG) recorded PPI of the acoustic startle eye-blink reflex in 16 healthy volunteers. A sparse imaging design was employed to model signal changes in blood oxygenation level-dependent (BOLD) responses to acoustic startle probes that were preceded by a prepulse at 120 ms or 480 ms stimulus onset asynchrony or without prepulse. Sensorimotor gating was EMG confirmed for the 120-ms prepulse condition, while startle responses in the 480-ms prepulse condition did not differ from startle alone. Multiple regression analysis of BOLD contrasts identified activation in pons, thalamus, caudate nuclei, left angular gyrus and bilaterally in anterior cingulate, associated with EMG-recorded sensorimotor gating. Planned contrasts confirmed increased pons activation for startle alone vs 120-ms prepulse condition, while increased anterior superior frontal gyrus activation was confirmed for the reverse contrast. Our findings are consistent with a primary pontine circuitry of sensorimotor gating that interconnects with inferior parietal, superior temporal, frontal and prefrontal cortices via thalamus and striatum. PPI processes in the prefrontal, frontal and superior temporal cortex were functionally distinct from sensorimotor gating.     

Association between violent behaviour and impaired prepulse inhibition of the startle response in antisocial personality disorder and schizophrenia

Violent behaviour has a strong association with antisocial personality disorder (APD) and schizophrenia. Although developments in the understanding of socio-environmental factors associated with violence should not be ignored, advances in prevention and treatment of violent behaviour would benefit by improved understanding of its neurobiological and cognitive basis. The authors, therefore, investigated prepulse inhibition (PPI) of the startle response in APD and schizophrenia in relation to a history of serious violence. The neural substrates of PPI, especially the hippocampus, amygdala, thalamus and basal ganglia, are implicated in violence as well as in APD and schizophrenia. The study included four groups: (i) patients with APD and a history of violence, (ii) patients with schizophrenia and a history of violence, (iii) patients with schizophrenia without a history of violence, and (iv) healthy subjects with no history of violence or a mental disorder. All subjects were assessed identically on acoustic PPI. Compared to healthy subjects, significantly reduced PPI occurred in APD, violent schizophrenia and non-violent schizophrenia patients. Although PPI did not significantly differentiate the three clinical groups, high ratings of violence were modestly associated with reduced PPI across the entire study sample. Violent patients with impulsive and premeditated violence showed comparable PPI. The association between violent behaviour and impaired PPI suggests that neural structures and functions underlying PPI are implicated in (inhibition of) violence.