Auditory information processing in rat genotypes with different dopaminergic properties.

Stimulation of the dopamine (DA) system disrupts prepulse inhibition (PPI) of the acoustic startle response. On the basis of rat studies, it appeared that DA D2 receptors (D2Rs) rather than D1 receptors (D1Rs) regulate PPI, albeit possibly in synergism with D1Rs. To characterize the DA receptor modulation of PPI in another species, we tested DA D1R and D2R mutant mice with direct and indirect DA agonists and with the glutamate receptor antagonist, dizocilpine (MK-801). Neither the mixed D1/D2 agonist apomorphine (5 mg/kg) nor the more selective D1-like agonist SKF82958 (0.3 mg/kg) altered PPI in D1R knock-out mice, although both compounds disrupted PPI in D2R mutant and wild-type mice, suggesting that the D1R alone might modulate PPI in mice. However, amphetamine (10 mg/kg) significantly lowered PPI in each genotype of D1R mice, suggesting that the D1R is not necessary for the PPI-disruptive effect of the indirect agonist in mice. As reported previously, amphetamine (10 mg/kg) failed to disrupt PPI in D2R knock-out mice, supporting a unique role of the D2R in the modulation of PPI. Dizocilpine (0.3 mg/kg) induced similar PPI deficits in D1R and D2R mutant mice, confirming that the influences of the NMDA receptor on PPI are independent of D1Rs and D2Rs in rodents. Thus, both D1Rs and D2Rs modulate aspects of PPI in mice in a manner that differs from dopaminergic modulation in rats. These findings emphasize that further cross-species comparisons of the pharmacology of PPI are essential to understand the relevance of rodent PPI studies to the deficits in PPI observed in patients with schizophrenia.

Since the mid-1970s, cross-species translational studies of prepulse inhibition (PPI) have increased at an astounding pace as the value of this neurobiologically informative measure has been optimized. PPI occurs when a relatively weak sensory event (the prepulse) is presented 30-500 ms before a strong startle-inducing stimulus, and reduces the magnitude of the startle response. In humans, PPI occurs in a robust, predictable manner when the prepulse and startling stimuli occur in either the same or different modalities (acoustic, visual, or cutaneous). This review covers three areas of interest in human PPI studies. First, we review the normal influences on PPI related to the underlying construct of sensori- (prepulse) motor (startle reflex) gating. Second, we review PPI studies in psychopathological disorders that form a family of gating disorders. Third, we review the relatively limited but interesting and rapidly expanding literature on pharmacological influences on PPI in humans. All studies identified by a computerized literature search that addressed the three topics of this review were compiled and evaluated. The principal studies were summarized in appropriate tables. The major influences on PPI as a measure of sensorimotor gating can be grouped into 11 domains. Most of these domains are similar across species, supporting the value of PPI studies in translational comparisons across species. The most prominent literature describing deficits in PPI in psychiatrically defined groups features schizophrenia-spectrum patients and their clinically unaffected relatives. These findings support the use of PPI as an endophenotype in genetic studies. Additional groups of psychopathologically disordered patients with neuropathology involving cortico-striato-pallido-pontine circuits exhibit poor gating of motor, sensory, or cognitive information and corresponding PPI deficits. These groups include patients with obsessive compulsive disorder, Tourette's syndrome, blepharospasm, temporal lobe epilepsy with psychosis, enuresis, and perhaps posttraumatic stress disorder (PTSD). Several pharmacological manipulations have been examined for their effects on PPI in healthy human subjects. In some cases, the alterations in PPI produced by these drugs in animals correspond to similar effects in humans. Specifically, dopamine agonists disrupt and nicotine increases PPI in at least some human studies. With some other compounds, however, the effects seen in humans appear to differ from those reported in animals. For example, the PPI-increasing effects of the glutamate antagonist ketamine and the serotonin releaser MDMA in humans are opposite to the PPI-disruptive effects of these compounds in rodents. Considerable evidence supports a high degree of homology between measures of PPI in rodents and humans, consistent with the use of PPI as a cross-species measure of sensorimotor gating. Multiple investigations of PPI using a variety of methods and parameters confirm that deficits in PPI are evident in schizophrenia-spectrum patients and in certain other disorders in which gating mechanisms are disturbed. In contrast to the extensive literature on clinical populations, much more work is required to clarify the degree of correspondence between pharmacological effects on PPI in healthy humans and those reported in animals.

Enduring sensorimotor gating abnormalities following predator exposure or corticotropin-releasing factor in rats: A model for PTSD-like information-processing deficits?

Prepulse inhibition (PPI) of the acoustic startle reflex is a sensorimotor gating process known to be deficient in a number of neurologic and psychiatric conditions, including schizophrenia. Multiple lines of evidence have indicated that the dopaminergic and muscarinic cholinergic systems play an important role in modulating PPI. Moreover, interactions between the dopaminergic and muscarinic cholinergic systems are well known; however, little is known about potential interactions between the two systems in modulating PPI. Therefore, the purpose of the present studies was to determine whether interactions occur between the muscarinic cholinergic and dopaminergic systems in modulating PPI. The efficacy of muscarinic cholinergic receptor agonists in reversing the disruption of PPI induced by apomorphine, a D1/D2 dopamine receptor agonist, was evaluated in male Sprague-Dawley rats. The M1/M4-preferring muscarinic agonist xanomeline and the M2/M4-preferring agonist BuTAC [([5R-[exo]-6-[butylthio]-1,2,5-thiadiazol-3-yl-]-1-azabyciclo-[3.2.1])octane oxalate] reversed the apomorphine-induced disruption of PPI in a manner similar to that produced by the D2-like dopamine receptor antagonists haloperidol and olanzapine. The muscarinic agonists oxotremorine, RS86 [[2-ethyl-8-methyl-2,8-diazaspiro(4.5)decane-1,3-dione] hydrochloride], pilocarpine, milameline, and sabcomeline also reversed the apomorphine-induced disruption of PPI. Moreover, the muscarinic antagonist scopolamine also disrupted PPI, and the D2-like receptor antagonist haloperidol, but not the D1-like receptor antagonist SCH23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine], reversed the scopolamine-induced disruption. In addition, xanomeline produced a significant reversal of the disruption in PPI produced by scopolamine. Collectively, the present findings demonstrate that a functional interaction occurs between the muscarinic cholinergic and dopaminergic systems in modulating PPI and that muscarinic cholinergic agonists may be effective in the treatment of the PPI and other cognitive impairments observed in schizophrenia.

Animal models of schizophrenia-relevant symptoms are increasingly important for progress in our understanding of the neurobiological basis of the disorder and for discovering novel and more specific treatments. Prepulse inhibition (PPI) and working memory, which are impaired in schizophrenic patients, are among the symptoms/processes modeled in those animal analogs. We have evaluated whether a genetically-selected rat model, the Roman high-avoidance inbred strain (RHA-I), displays PPI deficits as compared with its Roman low-avoidance (RLA-I) counterpart and the genetically heterogeneous NIH-HS rat stock. We have investigated whether PPI deficits predict spatial working memory impairments (in the Morris water maze; MWM) in these three rat types (Experiment 1), as well as in a separate sample of NIH-HS rats stratified according to their extreme (High, Medium, Low) PPI scores (Experiment 2). The results from Experiment 1 show that RHA-I rats display PPI and spatial working memory deficits compared to both RLA-I and NIH-HS rats. Likewise, in Experiment 2, “Low-PPI” NIH-HS rats present significantly impaired working memory with respect to “Medium-PPI” and “High-PPI” NIH-HS subgroups. Further support to these results comes from correlational, factorial, and multiple regression analyses, which reveal that PPI is positively associated with spatial working memory performance. Conversely, cued learning in the MWM was not associated with PPI. Thus, using genetically-selected and genetically heterogeneous rats, the present study shows, for the first time, that PPI is a positive predictor of performance in a spatial working memory task. These results may have translational value for schizophrenia symptom research in humans, as they suggest that either by psychogenetic selection or by focusing on extreme PPI scores from a genetically heterogeneous rat stock, it is possible to detect a useful (perhaps “at risk”) phenotype to study cognitive anomalies linked to schizophrenia.

Prepulse inhibition, one of the main indices of the autonomous inhibitory capacity of the central nervous system, is deficient in psychiatric pathologies associated with dopaminergic system alterations, such as schizophrenia, post-traumatic stress disorder, or substance use disorder. Stress is one of the main risk factors related to the development of these psychiatric disorders. To know the relationship between stress and prepulse inhibition as possible biomarker and predictor of related pathologies, based on recent literature. A systematic review was carried out in PubMed and Web of Science databases from 2011 to 2020. The studies reviewed, including both animal model studies and clinical articles, have shown that intense or repeated stress, whether social, physical or drug-induced, leads to a deterioration of prepulse inhibition, while moderate stress seems to improve its levels. The results demonstrate a clear relationship between stress and a deficit in prepulse inhibition, which occurs mainly through the dopaminergic system and the corticotropin-releasing factor in the extended amygdala. Prepulse inhibition levels reflect the state of brain dopaminergic activity, being able to identify the most vulnerable subjects to develop stress-related psychiatric pathologies.

Functional and structural imaging studies suggest that obsessive-compulsive disorder (OCD) symptoms arise from dysfunction in cortico-striato-thalamo-cortical circuits. It has therefore been hypothesized that neurophysiological tasks subserved by these circuits should be abnormal in OCD patients. One neurocognitive probe associated with this circuitry is prepulse inhibition (PPI) of the acoustic startle response. PPI deficits are thought to reflect abnormalities in processing and integration of sensory and motor information. Two prior studies found that OCD patients had PPI deficits at single prepulse (PP) intensities. However, most patients in these studies were taking psychotropic medications at the time of PPI testing, and preclinical studies have demonstrated effects of psychotropic medications on PPI. We examined PPI in 22 unmedicated OCD patients and 22 matched healthy controls at three different PP intensities (74, 78, and 86 dB). OCD patients had significantly less PPI across all three PP intensities compared with controls. Exploratory analyses indicated that OCD patients with a history of tics had lower levels of PPI. Our results demonstrate that unmedicated OCD patients have impaired sensorimotor gating as measured by PPI. This indicates that PPI deficits are present in OCD patients and are not the result of medication effects. Our findings also suggest that OCD patients with a history of tics may have greater impairment in sensorimotor gating than the general OCD population. Future studies should be designed to examine whether PPI deficits characterize tic-related OCD.

Schizophrenia is a severe psychiatric disorder whose etiology is unknown; however, disruptions in glutamatergic and dopaminergic transmission may play a role. The NMDAR antagonist, phencyclidine (PCP), has been shown to mimic both the positive and negative symptoms of the disease and is widely used in animal studies as a model of schizophrenia. PCP administration results in increased locomotor activity and deficits in pre-pulse inhibition (PPI) of acoustic startle. Locomotor sensitization is thought to model the positive symptoms while deficits in PPI are correlated to the negative symptoms of the disease. Sprague-Dawley rat pups were treated with saline or PCP (10 mg/kg) on postnatal day (PN) 7, 9, and 11 and PPI was measured on PN24-25. On PN28-35 animals were administered a challenge dose of 4 mg/kg PCP and locomotor activity was measured. PCP administration resulted in a deficit in PPI as well as locomotor sensitization. Additional experiments tested the effect of pretreatment with the typical antipsychotic haloperidol or the atypical antipsychotics, olanzapine and risperidone. Haloperidol (0.1 mg/kg), olanzapine (1 mg/kg), and risperidone (0.25 mg/kg) were able to prevent the deficits in PPI caused by PCP administration. Risperidone (0.25 mg/kg) was also able to prevent locomotor sensitization in animals administered PCP. Future experiments will further investigate the role of haloperidol and olanzapine as well as selective DA and 5-HT antagonists in this behavioral model of schizophrenia in order to determine the mechanism of protection by typical and atypical antipsychotics. Supported by DA-07287, MH-63871 and Eli Lilly and Co.

GluN1 antibody causes behavioral deficits in prepulse inhibition and memory through CaMKIIβ signaling

Deficits in prepulse inhibition may be a common feature in first-episode schizophrenia, bipolar disorder (BD) and major depressive disorder (MDD). We sought to explore the levels and viability of prepulse inhibition to differentiate first-episode schizophrenia, BD and MDD in patient populations. We tested patients with first-episode schizophrenia, BD or MDD and healthy controls using prepulse inhibition paradigms, namely perceived spatial co-location (PSC-PPI) and perceived spatial separation (PSS-PPI). We included 53 patients with first-episode schizophrenia, 30 with BD and 25 with MDD, as well as 82 healthy controls. The PSS-PPI indicated that the levels of prepulse inhibition were smallest to largest, respectively, in the first-episode schizophrenia, BD, MDD and control groups. Relative to the healthy controls, the prepulse inhibition deficits in the first-episode schizophrenia group were significant (p < 0.001), but the prepulse inhibitions were similar between patients with BD and healthy controls, and between patients with MDD and healthy controls. The receiver operating characteristic curve analysis showed that PSS-PPI (area under the curve [AUC] 0.73, p < 0.001) and latency (AUC 0.72, p < 0.001) were significant for differentiating patients with first-episode schizophrenia or BD from healthy controls. The demographics of the 4 groups were not ideally matched. We did not perform cognitive assessments. The possible confounding effect of medications on prepulse inhibition could not be eliminated. The level of prepulse inhibition among patients with first-episode schizophrenia was the lowest, with levels among patients with BD, patients with MDD and healthy controls increasingly higher. The PSS-PPI paradigm was more effective than PSC-PPI to recognize deficits in prepulse inhibition. These results provide a basis for further research on biological indicators that can assist differential diagnoses in psychosis.

Prepulse inhibition (PPI) deficits are among the most reproducible phenotypic markers found in schizophrenic patients. We recently reported that nisoxetine, a selective norepinephrine transporter (NET) inhibitor, reversed the PPI deficits that have been identified in dopamine transporter (DAT) knockout (KO) mice. However, the mechanisms underlying nisoxetine-induced PPI recovery in DAT KO mice were unclear in previous experiments. To clarify these mechanisms, PPI was tested after microinjections of nisoxetine into the medial prefrontal cortex (mPFc) or nucleus accumbens (NAc) in wildtype (WT) and DAT KO mice. c-Fos immunohistochemistry provided an indicator of neural activation. Multiple-fluorescent-labeling procedures and the retrograde tracer fluorogold were employed to identify nisoxetine-activated neurons and circuits. Systemic nisoxetine activated the mPFc, the NAc shell, the basolateral amygdala, and the subiculum. Infusions of nisoxetine into the mPFc reversed PPI deficits in DAT KO mice, but produced no changes in WT mice, while infusion of nisoxetine into the NAc had no effect on PPI in both WT and DAT KO mice. Experiments using multiple-fluorescent labeling/fluorogold revealed that nisoxetine activates presumed glutamatergic pyramidal cells that project from the mPFc to the NAc. Activated glutamatergic projections from the mPFc to the NAc appear to have substantial roles in the ability of a NET inhibitor to normalize PPI deficits in DAT KO. Thus, this data suggest that selective NET inhibitors such as nisoxetine might improve information processing deficits in schizophrenia via regulation of cortico-subcortical neuromodulation.

Restraint stress-induced reduction in prepulse inhibition in Brown Norway rats: Role of the CRF 2 receptor

Dysfunctional play and dopamine physiology in the Fischer 344 rat

Long-term neurological complications, termed sequelae, can result from viral encephalitis, which are not well understood. In human survivors, alphavirus encephalitis can cause severe neurobehavioral changes, in the most extreme cases, a schizophrenic-like syndrome. In the present study, we aimed to adapt an animal model of alphavirus infection survival to study the development of these long-term neurological complications. Upon low-dose infection of wild-type C57B/6 mice, asymptomatic and symptomatic groups were established and compared to mock-infected mice to measure general health and baseline neurological function, including the acoustic startle response and prepulse inhibition paradigm. Prepulse inhibition is a robust operational measure of sensorimotor gating, a fundamental form of information processing. Deficits in prepulse inhibition manifest as the inability to filter out extraneous sensory stimuli. Sensory gating is disrupted in schizophrenia and other mental disorders, as well as neurodegenerative diseases. Symptomatic mice developed deficits in prepulse inhibition that lasted through 6 months post infection; these deficits were absent in asymptomatic or mock-infected groups. Accompanying prepulse inhibition deficits, symptomatic animals exhibited thalamus damage as visualized with H&E staining, as well as increased GFAP expression in the posterior complex of the thalamus and dentate gyrus of the hippocampus. These histological changes and increased GFAP expression were absent in the asymptomatic and mock-infected animals, indicating that glial scarring could have contributed to the prepulse inhibition phenotype observed in the symptomatic animals. This model provides a tool to test mechanisms of and treatments for the neurological sequelae of viral encephalitis and begins to delineate potential explanations for the development of such sequelae post infection.

BackgroundSensorimotor gating is a fundamental pre-attentive process that is defined as the inhibition of a motor response by a sensory event. Sensorimotor gating, commonly measured using the prepulse inhibition (PPI) of the auditory startle reflex task, is impaired in patients suffering from various neurological and psychiatric disorders. PPI deficits are a hallmark of schizophrenia, and they are often associated with attention and other cognitive impairments. Although the reversal of PPI deficits in animal models is widely used in pre-clinical research for antipsychotic drug screening, the neurotransmitter systems and synaptic mechanisms underlying PPI are still not resolved, even under physiological conditions. Recent evidence ruled out the longstanding hypothesis that PPI is mediated by midbrain cholinergic inputs to the caudal pontine reticular nucleus (PnC). Instead, glutamatergic, glycinergic, and GABAergic inhibitory mechanisms are now suggested to be crucial for PPI, at the PnC level. Since amygdalar dysfunctions alter PPI and are common to pathologies displaying sensorimotor gating deficits, the present study was designed to test that direct projections to the PnC originating from the amygdala contribute to PPI.ResultsUsing wild type and transgenic mice expressing eGFP under the control of the glycine transporter type 2 promoter (GlyT2-eGFP mice), we first employed tract-tracing, morphological reconstructions, and immunohistochemical analyses to demonstrate that the central nucleus of the amygdala (CeA) sends glutamatergic inputs lateroventrally to PnC neurons, including GlyT2+ cells. Then, we showed the contribution of the CeA-PnC excitatory synapses to PPI in vivo by demonstrating that optogenetic inhibition of this connection decreases PPI, and optogenetic activation induces partial PPI. Finally, in GlyT2-Cre mice, whole-cell recordings of GlyT2+ PnC neurons in vitro paired with optogenetic stimulation of CeA fibers, as well as photo-inhibition of GlyT2+ PnC neurons in vivo, allowed us to implicate GlyT2+ neurons in the PPI pathway.ConclusionsOur results uncover a feedforward inhibitory mechanism within the brainstem startle circuit by which amygdalar glutamatergic inputs and GlyT2+ PnC neurons contribute to PPI. We are providing new insights to the clinically relevant theoretical construct of PPI, which is disrupted in various neuropsychiatric and neurological diseases.