Assessing replicability and power estimates of behavioral performance of control rats across standardized pre-clinical and toxicology studies.

Provisional Mapping of Quantitative Trait Loci Modulating the Acoustic Startle Response and Prepulse Inhibition of Acoustic Startle

Environmental enrichment and isolation rearing in the rat: effects on locomotor behavior and startle response plasticity

The sensorimotor gating is a nervous system function that modulates the acoustic startle response (ASR). Prepulse inhibition (PPI) phenomenon is an operational measure of sensorimotor gating, defined as the reduction of ASR when a high intensity sound (pulse) is preceded in milliseconds by a weaker stimulus (prepulse). Brainstem nuclei are associated with the mediation of ASR and PPI, whereas cortical and subcortical regions are associated with their modulation. However, it is still unclear how the modulatory units can influence PPI. In the present work, we developed a computational model of a neural circuit involved in the mediation (brainstem units) and modulation (cortical and subcortical units) of ASR and PPI. The activities of all units were modeled by the leaky-integrator formalism for neural population. The model reproduces basic features of PPI observed in experiments, such as the effects of changes in interstimulus interval, prepulse intensity, and habituation of ASR. The simulation of GABAergic and dopaminergic drugs impaired PPI by their effects over subcortical units activity. The results show that subcortical units constitute a central hub for PPI modulation. The presented computational model offers a valuable tool to investigate the neurobiology associated with disorder-related impairments in PPI.

Prepulse inhibition (PPI) is the suppression of a startle reflex response to a startle stimulus that occurs when a weak prepulse stimulus precedes the startle stimulus. PPI is measured to assess sensorimotor gating across species, including humans and rodents. Reduced PPI, which is thought to reflect dysfunction of sensorimotor gating, is reported in patients with psychiatric disorders, such as schizophrenia, bipolar disorder, and post-traumatic stress disorder (PTSD), and in animal models of these disorders. Individual differences in basal startle reactivity occur even in a genetically homogenous group of animals; however, there is limited information regarding whether basal levels of the startle response are associated with variations in PPI levels. Here, to explore the relationship between an acoustic startle response (ASR) and PPI, we performed a meta-analysis of data obtained from more than 1300 C57BL/6J male mice on the influence of an ASR to 110- and 120-dB startle stimuli on the PPI levels of the ASR at 74- and 78-dB prepulse intensities. Examination of scatter plots of the ASR amplitudes and PPI levels followed by correlation analyses indicated that there is no simple linear relationship between the two measures; when mice were divided into three groups on the basis of their startle amplitudes, there were positive correlations between the amplitude of the ASR to the 110-dB stimulus and PPI levels in a group of mice that showed lower ASR amplitudes among the genetically homogenous group, whereas no significant correlations were identified in groups of mice that showed intermediate and higher ASR amplitudes. As indicated by the correlation analysis, the lowest responders to the 110-dB stimulus exhibited lower levels of PPI than the intermediate or higher responders. In contrast, for the 120-dB stimulus, a negative correlation was identified between the amplitude of the ASR to the 120-dB stimulus and the PPI levels in the groups of mice that showed intermediate or higher ASR amplitudes. Lower and intermediate responders showed higher levels of PPI than higher responders to the 120-dB stimulus. These findings suggest that basal startle reactivity may affect PPI levels in male C57BL/6J mice, thus representing one potential confounding factor that may confuse the interpretation of PPI results. These findings emphasize the importance of careful examination of startle reactivity to ensure a reliable assessment of PPI.

Sensory processing disruptions are a core symptom of autism spectrum disorder (ASD) and other neurological disorders. The acoustic startle response and prepulse inhibition (PPI) are common metrics used to assess disruptions in sensory processing and sensorimotor gating in clinical studies and animal models. However, often there are inconsistent findings on ASD-related PPI deficits across different studies. Here, we used a novel method for assessing changes in startle and PPI in rodents, using the Cntnap2 knock-out (KO) rat model for neurodevelopmental disorder/ASD that has consistently shown PPI disruptions in past studies. We discovered that not only sex and prepulse intensity but also the intensity of the startle stimulus profoundly impacts whether PPI deficits are evident in the Cntnap2 KO rat or not. We show that rats do not universally exhibit a PPI deficit; instead, impaired PPI is contingent on specific testing conditions. Notably, at lower startle stimulus intensities, Cntnap2 KO rats not only demonstrated intact PPI but also exhibited evidence of enhanced PPI compared with their wild-type counterparts. This finding emphasizes the importance of considering specific testing conditions when evaluating startle and PPI in the context of ASD and other neuropsychiatric conditions and might explain some of the inconsistencies between different studies.

Recently, schizophrenia endophenotypes have been actively investigated to better understand the pathophysiology of schizophrenia. Past studies have shown that cognitive functions, including working memory and executive function, correlate with acoustic startle responses, such as prepulse inhibition (PPI), in patients with schizophrenia. The aim of this study was to investigate the relationship between cognitive functions and acoustic startle response in Japanese patients with schizophrenia. In 100 patients with schizophrenia, we evaluated cognitive function, using the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J), and acoustic startle responses, including acoustic startle reflex, habituation, and PPI (three different intensities: 82, 86, and 90dB SPL, equivalent to signal-to-noise ratios of +12, +16, and +20dB, respectively). Using multiple regression analysis, we examined the relationship between acoustic startle responses and BACS-J primary measures or composite score. Level of attention was associated with magnitude of habituation in schizophrenia (P=0.0009, β=-0.357). None of the other domains of cognitive function were significantly associated with any measure of acoustic startle response. This included attention regarding ASR (P=0.513), PPI (P=0.521-0.842), verbal memory (P=0.423-0.981), working memory (P=0.312-0.966), motor speed (P=0.323-0.955), verbal fluency (P=0.125-0.920), executive function (P=0.118-0.470), and the BACS-J composite score (P=0.230-0.912). In this first investigation of the relationship between cognitive functions and acoustic startle responses in Japanese patients with schizophrenia, attentional deficits correlated highly with the level of habituation. However, a replication study using other population samples is required to further investigate this relationship.

In patients with schizophrenia, information processing deficits, such as those reported in studies that measured prepulse inhibition of the human startle response and habituation of startle magnitude, may be improved with atypical antipsychotic treatment. However, it remains unclear whether antipsychotic medication is directly responsible for the improvement or whether differences in prepulse inhibition reflect other factors, such as acuity status. The present study investigated the effects of antipsychotics on prepulse inhibition and startle habituation in acutely hospitalized patients with schizophrenia. Forty-one acutely psychotic schizophrenia patients (21 who were unmedicated at the time of admission and 20 who had been receiving antipsychotic treatment) were tested within 72 hours of hospital admission. Thirteen healthy subjects were also studied for comparative purposes. Primary dependent measures were startle responsivity, reactivity, prepulse inhibition, and startle habituation. Schizophrenia patients, whether medicated or unmedicated at admission, showed prepulse inhibition deficits compared with healthy subjects and did not statistically differ from each other in startle magnitude, prepulse inhibition, or habituation. There was a higher number of startle "nonresponders" among those who had been receiving medication versus those unmedicated at the time of admission. The present findings suggest that antipsychotic effects on prepulse inhibition may not be evident at a time when schizophrenia patients are acutely symptomatic. These results suggest that the neurobiological substrate underlying prepulse inhibition deficits may be dysregulated during acute psychotic states while the patients are in early phases of medication treatment.

Impaired Sensorimotor Gating of the Acoustic Startle Response in the Prodrome of Schizophrenia

Concurrent assessment of acoustic startle and auditory P50 evoked potential measures of sensory inhibition

Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle

Amphetamine-modified acoustic startle responding and prepulse inhibition in adult and adolescent alcohol-preferring and -nonpreferring rats

Prepulse inhibition deficits in inbred and outbred rats and between-strain differences in startle habituation do not depend on startle reactivity levels

Interaction between the effects of corticotropin-releasing factor and prepulse parameters on prepulse inhibition in two inbred rat strains and the F1 generation of a cross between them

Is there a critical developmental `window' for isolation rearing-induced changes in prepulse inhibition of the acoustic startle response?

It has been recently shown that Catechol O-methyltransferase (COMT) Val(158)Met polymorphism strongly influences prepulse inhibition (PPI) of the acoustic startle response (ASR) in healthy human volunteers. Given that schizophrenia patients exhibit impairment in PPI and that COMT is a putative susceptibility gene for schizophrenia, we investigated the impact of the COMT Val(158)Met polymorphisms on PPI in schizophrenic inpatients. We analyzed COMT Val(158)Met polymorphisms and assessed startle reactivity, habituation, and PPI of ASR in 68 Caucasian schizophrenia inpatients. Clinical symptoms were measured with the Positive and Negative Syndrome Scale (PANSS). Patients carrying the Val(158)Met Met/Met allele showed elevated PPI levels whereas startle reactivity and habituation did not differ from the other two genotypes. These preliminary results imply that PPI is influenced by COMT Val(158)Met genotype in schizophrenia as well. In concert with other findings, our data suggest that PPI is a polygenic trait.