Prepulse inhibition predicts subjective hearing in rats.
Ontology highlight
ABSTRACT:
SUBMITTER: Wake N
PROVIDER: S-EPMC8460677 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:In schizophrenia, cognitive overload is thought to reflect an inability to suppress non-salient information, a process which is studied using prepulse inhibition (PPI) of the startle response. PPI is reduced in schizophrenia and routinely tested in animal models and preclinical trials of antipsychotic drugs. However, the underlying neuronal circuitry is not well understood. We used a novel genetic screen in larval zebrafish to reveal the molecular identity of neurons that are required for PPI in fish and mice. Ablation or optogenetic silencing of neurons with developmental expression of the transcription factor genomic screen homeobox 1 (gsx1) produced profound defects in PPI in zebrafish, and PPI was similarly impaired in Gsx1 knockout mice. Gsx1-expressing neurons reside in the dorsal brainstem and form synapses closely apposed to neurons that initiate the startle response. Surprisingly, brainstem Gsx1 neurons are primarily glutamatergic despite their role in a functionally inhibitory pathway. As Gsx1 has an important role in regulating interneuron development in the forebrain, these findings reveal a molecular link between control of interneuron specification and circuits that gate sensory information across brain regions.
| S-EPMC4362800 | biostudies-literature
Project description:The neural mechanisms of psychiatric diseases like autism spectrum disorder and schizophrenia have been intensively studied, and a number of candidate genes have been identified. However, the relationship between genes and neural system functioning remains unclear. Model organisms may serve as a powerful tool for addressing this question due to the availability of established genetic tools. Here, we report prepulse inhibition (PPI) in Drosophila larvae for the first time. PPI is a neurological phenomenon found in humans and other organisms and is used in the diagnosis of schizophrenia and other psychiatric disorders. A weaker prestimulus (prepulse) inhibits the reaction to a subsequent strong, startling stimulus (pulse). Using the larval startle response to the buzz of a predator (wasp), we examined PPI in wild-type flies and two mutants: an fmr1 mutant, which is implicated in Fragile X syndrome, and a centaurin gamma 1A (CenG1A) mutant, which is associated with GTPase, PH, ArfGAP, and ANK domains and implicated in autism. Both mutants showed decreased PPI, whereas, interestingly, double mutants showed substantial PPI. The PPI phenomenon described here can provide a useful tool for the study of neural mechanisms of synaptic modification and psychiatric diseases.
| S-EPMC6176951 | biostudies-literature
Project description:Cocaine addiction is frequently associated with different psychiatric disorders, especially schizophrenia and antisocial personality disorder. A small number of studies have used prepulse inhibition (PPI) as a discriminating factor between these disorders. This work evaluated PPI and the phenotype of patients with cocaine-related disorder (CRD) who presented a dual diagnosis of schizophrenia or antisocial personality disorder. A total of 74 men aged 18-60 years were recruited for this research. The sample was divided into four groups: CRD (n = 14), CRD and schizophrenia (n = 21), CRD and antisocial personality disorder (n = 16), and a control group (n = 23). We evaluated the PPI and other possible vulnerability factors in these patients by using different assessment scales. PPI was higher in the CRD group at 30 ms (F(3, 64) = 2.972, p = 0.038). Three discriminant functions were obtained which allowed us to use the overall Hare Psychopathy Checklist Revised score, reward sensitivity, and PPI at 30 ms to predict inclusion of these patients in the different groups with a success rate of 79.7% (42.9% for CRD, 76.2% for CRD and schizophrenia, 100% for CRD and antisocial personality disorder, and 91.3% in the control group). Despite the differences we observed in PPI, this factor is of little use for discriminating between the different diagnostic groups and it acts more as a non-specific endophenotype in certain mental disorders, such as in patients with a dual diagnosis.
| S-EPMC7924364 | biostudies-literature
Project description:BACKGROUND AND PURPOSE: Prepulse inhibition (PPI) of the acoustic startle response is a model of sensorimotor gating which is disrupted in schizophrenia and other mental illnesses. We and others have shown that treatment with the 5-hydroxytryptamine-1A (5-HT(1A)) receptor agonist, 8-OH-DPAT, disrupts PPI in rats. In the present study, we highlight the importance of baseline levels on the effect of 8-OH-DPAT on PPI. EXPERIMENTAL APPROACH: Adult male and female Sprague-Dawley rats were gonadectomised. These rats were treated with saline, 0.02 and 0.5 mg kg(-1) of 8-OH-DPAT using a random-sequence, repeated-measures protocol. The rats were allocated into high and low baseline groups depending on their baseline PPI observed after saline treatment. KEY RESULTS: Treatment with 0.5 mg kg(-1) of 8-OH-DPAT significantly disrupted PPI in both male and female rats. In male rats only, 0.02 mg kg(-1) 8-OH-DPAT caused a small, but significant, increase in PPI. When these male rats were allocated to either a high or low baseline PPI group, 0.5 mg kg(-1) 8-OH-DPAT disrupted PPI in the high baseline group only. In contrast, treatment with 0.02 mg kg(-1) 8-OH-DPAT increased PPI only in the low baseline PPI group. There were no changes in the effect of 8-OH-DPAT administration in female rats when they were divided into high and low baseline PPI groups. CONCLUSIONS AND IMPLICATIONS: The level of baseline PPI is an important variable that can influence the direction of drug effects induced by 8-OH-DPAT. The explanation for this phenomenon could be differential activation of pre- and postsynaptic 5-HT(1A) receptors.
| S-EPMC2013865 | biostudies-other
Project description:Compounds that activate the 5-HT(2A) receptor, such as lysergic acid diethylamide (LSD), act as hallucinogens in humans. One notable exception is the LSD congener lisuride, which does not have hallucinogenic effects in humans even though it is a potent 5-HT(2A) agonist. LSD and other hallucinogens have been shown to disrupt prepulse inhibition (PPI), an operational measure of sensorimotor gating, by activating 5-HT(2A) receptors in rats.We tested whether lisuride disrupts PPI in male Sprague-Dawley rats. Experiments were also conducted to identify the mechanism(s) responsible for the effect of lisuride on PPI and to compare the effects of lisuride to those of LSD.Confirming a previous report, LSD (0.05, 0.1, and 0.2 mg/kg, s.c.) reduced PPI, and the effect of LSD was blocked by pretreatment with the selective 5-HT(2A) antagonist MDL 11,939. Administration of lisuride (0.0375, 0.075, and 0.15 mg/kg, s.c.) also reduced PPI. However, the PPI disruption induced by lisuride (0.075 mg/kg) was not blocked by pretreatment with MDL 11,939 or the selective 5-HT(1A) antagonist WAY-100635 but was prevented by pretreatment with the selective dopamine D(2)/D(3) receptor antagonist raclopride (0.1 mg/kg, s.c).The effect of LSD on PPI is mediated by the 5-HT(2A) receptor, whereas activation of the 5-HT(2A) receptor does not appear to contribute to the effect of lisuride on PPI. These findings demonstrate that lisuride and LSD disrupt PPI via distinct receptor mechanisms and provide additional support for the classification of lisuride as a non-hallucinogenic 5-HT(2A) agonist.
| S-EPMC2797624 | biostudies-other
Project description:Megalin has been proposed as an endocytic receptor for aminoglycosides as well as estrogen and androgen. We aimed to investigate the otoprotective effects of antiandrogens (flutamide, FM) on kanamycin (KM)-induced hearing loss in rats. Rats were divided into four groups. The KM group was administered KM (20 mg/kg/day) for 5 days, while the FM group received FM (15 mg/kg/day) for 10 days. In the KM + FM group, KM and FM (15 mg/kg/day) were simultaneously injected for 5 days and then FM was injected for 5 days. Auditory brainstem responses were measured. Western blotting and/or quantitative reverse transcriptase-polymerase chain reaction were performed for megalin, cytochrome P450 1A1 (Cyp1a1), Cyp1b1, metallothionein 1A (MT1A), MT2A, tumor necrosis factor (TNF)-α, caspase 3, and cleaved caspase 3. The FM + KM group showed attenuated auditory thresholds when compared with the KM group at 4, 8, 16, and 32 kHz (all p < 0.05). The KM + FM group showed lower megalin and Cyp1b1 levels than the KM group (all p < 0.05). The KM + FM group revealed lower MT1A, TNFα, and caspase 3 protein levels, compared with those in the KM group (all p < 0.05). Androgen receptor inhibition protects against cochlear injuries in KM-induced hearing loss rats by attenuating megalin expression, revealing anti-inflammatory and anti-apoptotic effects.
| S-EPMC8158097 | biostudies-literature
Project description:Prepulse inhibition (PPI) is an operational measure of sensorimotor gating. It is defined as a reduction in magnitude of a startle response when a startling stimulus is preceded by a weaker "prepulse." PPI has been found to be altered in patients with schizophrenia, autism spectrum disorders, and other neuropsychiatric illnesses. As such, the neural substrates regulating PPI are of particular interest. Previous studies using lesions, selective blockade of N-methyl-d-aspartate (NMDA) receptors, and pharmacological disinhibition have demonstrated that impairment of the function of the basolateral and lateral nuclei of the amygdala (BLA) disrupts PPI. However, transient gamma aminobutyric acid-mediated (GABA-mediated) inactivation of BLA has not been evaluated for effects on PPI. Furthermore, the downstream projection targets that mediate BLA-evoked disruptions of PPI have not been elucidated. Thus, in the present study, we evaluated the effect on PPI of bilateral and unilateral inactivation of BLA, by microinfusion of the GABA-A receptor agonist, muscimol. We found that either bilateral or unilateral inactivation impaired PPI. Because unilateral inactivation was sufficient to impair PPI, we hypothesized that this was due to an indirect activation of a downstream target of BLA, the ventral pallidum (VP). Because VP inhibition normalizes PPI deficits evoked from nucleus accumbens (Kodsi & Swerdlow, 1994), we next tested the degree to which VP inhibition would normalize PPI deficits evoked from BLA. We unilaterally inactivated BLA with concurrent inactivation of VP and found that VP inactivation blocked BLA-evoked deficits in PPI. We suggest that BLA inactivation disrupts PPI through disinhibition of VP.
| S-EPMC3314164 | biostudies-literature
Project description:Altered prepulse inhibition (PPI) is an endophenotype associated with multiple brain disorders, including schizophrenia. Circuit mechanisms that regulate PPI have been suggested, but none has been demonstrated through direct manipulations. IRSp53 is an abundant excitatory postsynaptic scaffold implicated in schizophrenia, autism spectrum disorders, and attention-deficit/hyperactivity disorder. We found that mice lacking IRSp53 in cortical excitatory neurons display decreased PPI. IRSp53-mutant layer 6 cortical neurons in the anterior cingulate cortex (ACC) displayed decreased excitatory synaptic input but markedly increased neuronal excitability, which was associated with excessive excitatory synaptic input in downstream mediodorsal thalamic (MDT) neurons. Importantly, chemogenetic inhibition of mutant neurons projecting to MDT normalized the decreased PPI and increased excitatory synaptic input onto MDT neurons. In addition, chemogenetic activation of MDT-projecting layer 6 neurons in the ACC decreased PPI in wild-type mice. These results suggest that the hyperactive ACC-MDT pathway suppresses PPI in wild-type and IRSp53-mutant mice.
| S-EPMC7825003 | biostudies-literature
Project description:Prepulse inhibition (PPI) is a measure of sensorimotor gating, a pre-attentional inhibitory brain mechanism that filters extraneous stimuli. Prepulse inhibition is correlated with measures of cognition and executive functioning, and is considered an endophenotype of schizophrenia and other psychiatric illnesses in which patients show PPI impairments. As a first step toward identifying genes that regulate PPI, we performed a quantitative trait locus (QTL) screen of PPI phenotypes in a panel of mouse chromosome substitution strains (CSSs). We identified five CSSs with altered PPI compared with the host C57BL/6J strain: CSS-4 exhibited decreased PPI, whereas CSS-10, -11, -16 and -Y exhibited higher PPI compared with C57BL/6J. These data indicate that A/J chromosomes 4, 10, 11, 16 and Y harbor at least one QTL region that modulates PPI in these CSSs. Quantitative trait loci for the acoustic startle response were identified on seven chromosomes. Like PPI, habituation of the startle response is also disrupted in schizophrenia, and in the present study CSS-7 and -8 exhibited deficits in startle habituation. Linkage analysis of an F(2) intercross identified a highly significant QTL for PPI on chromosome 11 between positions 101.5 and 114.4 Mb (peak LOD = 4.54). Future studies will map the specific genes contributing to these QTLs using congenic strains and other genomic approaches. Identification of genes that modulate PPI will provide insight into the neural mechanisms underlying sensorimotor gating, as well as the psychopathology of disorders characterized by gating deficits.
| S-EPMC3746005 | biostudies-literature
Project description:BACKGROUND: The complex trait of prepulse inhibition (PPI) is a sensory gating measure related to schizophrenia and can be measured in mice. Large-scale public repositories of inbred mouse strain genotypes and phenotypes such as PPI can be used to detect Quantitative Trait Loci (QTLs) in silico. However, the method has been criticized for issues including insufficient number of strains, not controlling for false discoveries, the complex haplotype structure of inbred mice, and failing to account for genotypic and phenotypic subgroups. METHODOLOGY/PRINCIPAL FINDINGS: We have implemented a method that addresses these issues by incorporating phylogenetic analyses, multilevel regression with mixed effects, and false discovery rate (FDR) control. A genome-wide scan for PPI was conducted using over 17,000 single nucleotide polymorphisms (SNPs) in 37 strains phenotyped. Eighty-nine SNPs were significant at a false discovery rate (FDR) of 5%. After accounting for long-range linkage disequilibrium, we found 3 independent QTLs located on murine chromosomes 1 and 13. One of the PPI positives corresponds to a region of human chromosome 6p which includes DTNBP1, a gene implicated in schizophrenia. Another region includes the gene Tsn which alters PPI when knocked out. These genes also appear to have correlated expression with PPI. CONCLUSIONS/SIGNIFICANCE: These results support the usefulness of using an improved in silico mapping method to identify QTLs for complex traits such as PPI which can be then be used for to help identify loci influencing schizophrenia in humans.
| S-EPMC2666808 | biostudies-literature