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The acoustic startle reflex (ASR) and prepulse inhibition of the ASR (PPI) assess the efficiency of salience processing, a fundamental brain function that is impaired in many psychiatric conditions. Both ASR and PPI depend on noradrenergic transmission, yet the modulatory role of the locus coeruleus (LC) remains controversial. Clonidine (0.05 mg/kg, i.p.), an alpha2‐adrenoreceptor agonist, strongly reduced the ASR amplitude. In contrast, chemogenetic LC inhibition only mildly suppressed the ASR and did affect the PPI in virus‐transduced rats. The canine adenovirus type 2 (CAV2)–based vector carrying a gene cassette for the expression of inhibitory receptors (hM4Di) and noradrenergic cell–specific promoter (PRSx8) had high cell‐type specificity (94.4 ± 3.1%) but resulted in heterogeneous virus transduction of DbH‐positive LC neurons (range: 9.2–94.4%). Clozapine‐N‐oxide (CNO; 1 mg/kg, i.p.), a hM4Di actuator, caused the firing cessation of hM4Di‐expressing LC neurons, yet complete inhibition of the entire population of LC neurons was not achieved. Case‐based immunohistochemistry revealed that virus injections distal (> 150 μm) to the LC core resulted in partial LC transduction, while proximal (< 50 μm) injections caused neuronal loss due to virus neurotoxicity. Neither the ASR nor PPI differed between the intact and virus‐transduced rats. Our results suggest that a residual activity of virus‐non‐transduced LC neurons might have been sufficient for mediating an unaltered ASR and PPI. Our study highlights the importance of a case‐based assessment of the virus efficiency, specificity, and neurotoxicity for targeted cell populations and of considering these factors when interpreting behavioral effects in experiments employing chemogenetic modulation. [ABSTRACT FROM AUTHOR]

Metabotropic glutamate receptor 8 (mGlu8) is a heterogeneously expressed and poorly understood glutamate receptor with potential pharmacological significance. The thalamic reticular nucleus (TRN) is a critical inhibitory modulator of the thalamocortical-corticothalamic (TC-CT) network and plays a crucial role in information processing throughout the brain, is implicated in a variety of psychiatric conditions, and is also a site of significant mGlu8 expression. Using both male and female mice, we determined via fluorescent in situ hybridization that parvalbumin-expressing cells in the TRN core and shell matrices (identified by spp1+ and ecel1+ expression, respectively), as well as the cortical layers involved in CT signaling, express grm8 mRNA. We then assayed the physiological and behavioral impacts of perturbing grm8 signaling in the TC circuit through conditional (adeno-associated virus-CRE mediated) and cell-type-specific constitutive deletion strategies. We show that constitutive parvalbumin grm8 knock-out (PVgrm8 knock-out) mice exhibited (1) increased spontaneous excitatory drive onto dorsal thalamus relay cells and (2) impaired sensorimotor gating, measured via paired-pulse inhibition, but observed no differences in locomotion and thigmotaxis in repeated bouts of open field test (OFT). Conversely, we observed hyperlocomotive phenotypes and anxiolytic effects of AAV-mediated conditional knockdown of grm8 in the TRN (TRNgrm8 knockdown) in repeated OFT. Our findings underscore a role for mGlu8 in regulating excitatory neurotransmission as well as anxiety-related locomotor behavior and sensorimotor gating, revealing potential therapeutic applications for various neuropsychiatric disorders and guiding future research endeavors into mGlu8 signaling and TRN function. [ABSTRACT FROM AUTHOR]

Introduction: Restless leg syndrome (RLS) is an invalidating neurological disorder with a complex, largely unknown pathophysiology. While RLS is observed in Parkinson's disease and in renal failure, idiopathic cases are common. Limited reports associate RLS with parathyroid hormone (PTH). This study analyzes a cohort of patients with primary hyperparathyroidism (PHPT) and chronic post-surgical hypoparathyroidism (hypo PTH), to investigate RLS prevalence, and associated risk factors. Methods: Ninety-five patients (54 PHPT, 41 hypo PTH) were consecutively enrolled at the bone metabolism outpatient clinic. The revised IRLSSG diagnostic criteria were used to diagnose RLS, with assessments conducted through face-to-face interviews and neurological examination. When RLS was confirmed, the RLS severity scale was applied. Retrospective records included calcium–phosphate metabolism–related parameters, surgery details, renal lithiasis, fragility fractures, and densitometric features (T-score). Results: RLS was diagnosed in 22.2% PHPT patients, compared to 4.9% of patients with hypo PTH (p = 0.02). Of RLS diagnosed patients, 91.7% had a history of parathyroidectomy, compared to 47.6% of patients without RLS (p = 0.01). Most of the operated patients reported that surgery determined an improvement of symptoms; however, mean score severity of RLS at our evaluation was 15/40, defined as moderate. PTH and calcium levels were not statistically associated to the presence of RLS. Conclusion: Our study suggests that PHPT may be one of the etiologies of RLS. Parathyroidectomy alleviates symptoms in the vast majority of the cases but does not remove them. [ABSTRACT FROM AUTHOR]

Background: Sleep deprivation (SD) impairs pre-stimulus inhibition, but the effect of quetiapine (QET) remains largely unknown. Objective: This study aimed to investigate the behavioral and cognitive effects of QET in both naïve and sleep-deprived rats. Materials and methods: Seven groups (n = 49) of male Wistar Albino rats were used in this study. SD was performed using the modified multiple platform technique in a water tank for 72 h. Our study consists of two experiments investigating the effect of QET on pre-pulse inhibition (PPI) of the acoustic startle reflex. The first experiment tested the effect of short- and long-term administration of QET on PPI response in non-sleeping (NSD) rats. The second experiment used 72 h REM sleep deprivation as a model for SD-induced impairment of the PPI response. Here, we tested the effect of QET on the % PPI of SD rats by short- and long-term intraperitoneal injection at the last 90 min of sleep SD and immediately subsequently tested for PPI. Results: 72 h SD impaired PPI, reduced startle amplitude, and attenuated the PPI% at + 4 dB, + 8 dB, and + 16 dB prepulse intensities. 10 mg/kg short and long-term QET administration completely improved sensorimotor gating deficit, increased startle amplitude, and restored the impaired PPI% at + 4 dB, + 8 dB, and + 16 dB after 72 h SD in rats. Conclusion: Our results showed short- and long-term administration of QET improved sensorimotor gating deficit in 72 h SD. Further research is required for the etiology of insomnia and the dose-related behavioral effects of QET. [ABSTRACT FROM AUTHOR]

Abstract Aim Proinflammatory cytokines such as interleukin‐6 (IL‐6) and IL‐17A have been implicated in the pathophysiology of schizophrenia which often shows sensorimotor gating abnormalities. This study aimed to examine whether a proinflammatory cytokine, IL‐17A, induces impairment in sensorimotor gating in mice. We also examined whether IL‐17A administration affects GSK3α/β protein level or phosphorylation in the striatum. Methods Recombinant mouse IL‐17A (low‐dose: 0.5 ng/mL and high‐dose: 50 ng/mL with 10 μL/g mouse body weight, respectively) or vehicle was intraperitoneally administered into C57BL/6 male mice 10 times in 3 weeks (sub‐chronic administration). Prepulse inhibition test using acoustic startle stimulus was conducted 4 weeks after the final IL‐17A administration. We evaluated the effect of IL‐17A administration on protein level or phosphorylation of GSK3α/β in the striatum by using Western blot analysis. Results Administration of IL‐17A induced significant PPI deterioration. Low‐dose of IL‐17A administration significantly decreased both GSK3α (Ser21) and GSK3β (Ser9) phosphorylation in mouse striatum. There was no significant alteration of GSK3α/β protein levels except for GSK3α in low‐dose IL‐17A administration group. Conclusion We demonstrated for the first time that sub‐chronic IL‐17A administration induced PPI disruption and that IL‐17A administration resulted in decreased phosphorylation of GSKα/β at the striatum. These results suggest that IL‐17A could be a target molecule in the prevention and treatment of sensorimotor gating abnormalities observed in schizophrenia.

Abstract Background Psychopathological research is moving from a specific approach towards transdiagnosis through the analysis of processes that appear transversally to multiple pathologies. A phenomenon disrupted in several disorders is prepulse inhibition (PPI) of the startle response, in which startle to an intense sensory stimulus, or pulse, is reduced if a weak stimulus, or prepulse, is previously presented. Objective and methods The present systematic review analyzed the role of PPI deficit as a possible transdiagnostic process for four main groups of neuropsychiatric disorders: (1) trauma-, stress-, and anxiety-related disorders (2) mood-related disorders, (3) neurocognitive disorders, and (4) other disorders such as obsessive-compulsive, tic-related, and substance use disorders. We used Web of Science, PubMed and PsycInfo databases to search for experimental case-control articles that were analyzed both qualitatively and based on their potential risk of bias. A total of 64 studies were included in this systematic review. Protocol was submitted prospectively to PROSPERO 04/30/2022 (CRD42022322031). Results and conclusion The results showed a general PPI deficit in the diagnostic groups mentioned, with associated deficits in the dopaminergic neurotransmission system, several areas implied such as the medial prefrontal cortex or the amygdala, and related variables such as cognitive deficits and anxiety symptoms. It can be concluded that the PPI deficit appears across most of the neuropsychiatric disorders examined, and it could be considered as a relevant measure in translational research for the early detection of such disorders.

Aim: Proinflammatory cytokines such as interleukin‐6 (IL‐6) and IL‐17A have been implicated in the pathophysiology of schizophrenia which often shows sensorimotor gating abnormalities. This study aimed to examine whether a proinflammatory cytokine, IL‐17A, induces impairment in sensorimotor gating in mice. We also examined whether IL‐17A administration affects GSK3α/β protein level or phosphorylation in the striatum. Methods: Recombinant mouse IL‐17A (low‐dose: 0.5 ng/mL and high‐dose: 50 ng/mL with 10 μL/g mouse body weight, respectively) or vehicle was intraperitoneally administered into C57BL/6 male mice 10 times in 3 weeks (sub‐chronic administration). Prepulse inhibition test using acoustic startle stimulus was conducted 4 weeks after the final IL‐17A administration. We evaluated the effect of IL‐17A administration on protein level or phosphorylation of GSK3α/β in the striatum by using Western blot analysis. Results: Administration of IL‐17A induced significant PPI deterioration. Low‐dose of IL‐17A administration significantly decreased both GSK3α (Ser21) and GSK3β (Ser9) phosphorylation in mouse striatum. There was no significant alteration of GSK3α/β protein levels except for GSK3α in low‐dose IL‐17A administration group. Conclusion: We demonstrated for the first time that sub‐chronic IL‐17A administration induced PPI disruption and that IL‐17A administration resulted in decreased phosphorylation of GSKα/β at the striatum. These results suggest that IL‐17A could be a target molecule in the prevention and treatment of sensorimotor gating abnormalities observed in schizophrenia. [ABSTRACT FROM AUTHOR]

HIV infection and methamphetamine (METH) use are highly comorbid and represent a significant public health problem. Both conditions are known to negatively impact a variety of brain functions. One brain function that may be affected by HIV and METH use is sensorimotor gating, an automatic, pre-conscious filtering of sensory information that is thought to contribute to higher order cognitive processes. Sensorimotor gating is often measured using prepulse inhibition (PPI), a paradigm that can be conducted in both humans and animals, thereby enabling cross-species translational studies. While previous studies suggest HIV and METH may individually impair PPI, little research has been conducted on the effects of combined HIV and METH on PPI. The goal of this cross-species study was to determine the effects of METH on PPI in the inducible Tat (iTat) mouse model of HIV and in people with HIV. PPI was measured in the iTat mouse model before, during, and after chronic METH treatment and after Tat induction. Chronic METH treatment decreased PPI in male but not female mice. PPI normalized with cessation of METH. Inducing Tat expression decreased PPI in male but not in female mice. No interactions between chronic METH treatment and Tat expression were observed in mice. In humans, HIV was associated with decreased PPI in both men and women. Furthermore, PPI was lowest in people with HIV who also had a history of METH dependence. Overall, these results suggest HIV and METH may additively impair early information processing in humans, potentially affecting downstream cognitive function.

Background: System Xc ̅ (Sxc ̅) is an important heteromeric amino acid cystine/glutamate exchanger that plays a pivotal role in the CNS by importing cystine into cells while exporting glutamate. Although certain behaviors have been identified as altered in SXc ̅ null mutant mice, our understanding of the comprehensive impact of SXc ̅ on behavior remains incomplete. Methods: To address this gap, we compared motor, sensory and social behaviors of male and female mice in mice null for SXc ̅ (SLC7A11sut/sut) with wildtype littermates (SLC7A11+/+) in a comprehensive and systematic manner to determine effects of genotype, sex, age, and their potential interactions. Results: Motor performance was not affected by loss of Sxc ̅ in both males and females, although it was impacted negatively by age. Motor learning was specifically disrupted in female mice lacking Sxc ̅ at both 2 and 6 months of age. Further, female SLC7A11sut/sut mice at both ages exhibited impaired sociability, but normal spatial and recognition memory, as well as sensorimotor gating. Finally, pronounced open-space anxiety was displayed by female SLC7A11sut/sut when they were young. In contrast, young SLC7A11sut/sut male mice demonstrated normal sociability, delayed spatial learning, increased open-space anxiety and heightened sensitivity to noise. As they aged, anxiety and noise sensitivity abated but hyperactivity emerged. Discussion: We find that the behavioral phenotypes of female SLC7A11sut/sut are similar to those observed in mouse models of autism spectrum disorder, while behaviors of male SLC7A11sut/sut resemble those seen in mouse models of attention deficit hyperactivity disorder. These results underscore the need for further investigation of SLC7A11 in neurodevelopment. By expanding our understanding of the potential involvement of Sxc ̅, we may gain additional insights into the mechanisms underlying complex neurodevelopmental conditions. [ABSTRACT FROM AUTHOR]

Background: Psychopathological research is moving from a specific approach towards transdiagnosis through the analysis of processes that appear transversally to multiple pathologies. A phenomenon disrupted in several disorders is prepulse inhibition (PPI) of the startle response, in which startle to an intense sensory stimulus, or pulse, is reduced if a weak stimulus, or prepulse, is previously presented. Objective and methods: The present systematic review analyzed the role of PPI deficit as a possible transdiagnostic process for four main groups of neuropsychiatric disorders: (1) trauma-, stress-, and anxiety-related disorders (2) mood-related disorders, (3) neurocognitive disorders, and (4) other disorders such as obsessive-compulsive, tic-related, and substance use disorders. We used Web of Science, PubMed and PsycInfo databases to search for experimental case-control articles that were analyzed both qualitatively and based on their potential risk of bias. A total of 64 studies were included in this systematic review. Protocol was submitted prospectively to PROSPERO 04/30/2022 (CRD42022322031). Results and conclusion: The results showed a general PPI deficit in the diagnostic groups mentioned, with associated deficits in the dopaminergic neurotransmission system, several areas implied such as the medial prefrontal cortex or the amygdala, and related variables such as cognitive deficits and anxiety symptoms. It can be concluded that the PPI deficit appears across most of the neuropsychiatric disorders examined, and it could be considered as a relevant measure in translational research for the early detection of such disorders. [ABSTRACT FROM AUTHOR]

Rationale: The prepulse inhibition (PPI) of the startle reflex is the best-established index of sensorimotor gating. We documented that the neurosteroid allopregnanolone (AP) is necessary to reduce PPI in response to D1 dopamine receptor agonists. Since Sprague-Dawley (SD) rats are poorly sensitive to the PPI-disrupting effects of these drugs, we hypothesized that AP might increase this susceptibility. Objectives: We tested whether AP is sufficient to increase the vulnerability of SD rats to PPI deficits in response to the D1 receptor full agonist SKF82958. Methods: SD rats were tested for PPI after treatment with SKF82958 (0.05-0.3 mg/kg, SC) in combination with either intraperitoneal (1-10 mg/kg) or intracerebral (0.5 μg/μl/side) AP administration into the medial prefrontal cortex (mPFC) or nucleus accumbens shell. To rule out potential confounds, we measured whether SKF82958 affected the endogenous mPFC levels of AP. Results: SD rats exhibited marked PPI deficits in response to the combination of systemic and intra-mPFC AP with SKF82958 but not with the D2 receptor agonist quinpirole (0.3-0.6 mg/kg, SC). SKF82958 did not elevate mPFC levels of AP but enhanced the content of its precursor progesterone. The PPI deficits caused by SKF82958 in combination with AP were opposed by the AP antagonist isoallopregnanolone (10 mg/kg, IP) and the glutamate NMDA receptor positive modulator CIQ (5 mg/kg, IP). Conclusion: These results suggest that AP enables the detrimental effects of D1 receptor activation on sensorimotor gating. AP antagonism or glutamatergic modulation counters these effects and may have therapeutic potential for neuropsychiatric disorders characterized by gating deficits. [ABSTRACT FROM AUTHOR]

Noradrenergic imbalance in the brain of schizophrenia patients may underlie both symptomatology and deficits in basic information processing. The current study investigated whether augmentation with the noradrenergic α2-agonist clonidine might alleviate these symptoms. In a double-blind placebo-controlled randomized clinical trial, 32 chronic schizophrenia patients were randomly assigned to six-weeks augmentation with either 50 μg clonidine or placebo to their current medication. Effects on symptom severity and both sensory- and sensorimotor gating were assessed at baseline, 3- and 6-weeks. Results were compared with 21 age- and sex-matched healthy controls (HC) who received no treatment. Only patients treated with clonidine showed significantly reduced PANSS negative, general and total scores at follow-up compared to baseline. On average, also patients treated with placebo showed minor (non-significant) reductions in these scores, likely indicating a placebo effect. Sensorimotor gating of patients was significantly lower at baseline compared to controls. It increased in patients treated with clonidine over the treatment period, whereas it decreased in both the HC and patients treated with placebo. However, neither treatment nor group effects were found in sensory gating. Clonidine treatment was very well tolerated. Only patients treated with clonidine showed a significant decrease on two out of the three PANSS subscales, while additionally retained their levels of sensorimotor gating. Given that there are only a few reports on effective treatment for negative symptoms in particular, our current results support augmentation of antipsychotics with clonidine as a promising, low-cost and safe treatment strategy for schizophrenia. [ABSTRACT FROM AUTHOR]

Simple Summary: In our study, we looked at a behavior called prepulse inhibition (PPI) in Drosophila melanogaster, commonly known as the fruit fly. For many animals, the sudden presentation of strong sensorial stimuli can induce a defensive response or motor reflex. PPI is a phenomenon where a small stimulus, named "prepulse," is presented shortly before a larger stimulus, so the larger stimulus induces a weaker response than it normally would. This behavior is seen in many different types of animals and is used to study conditions such as anxiety and schizophrenia. For this study, the chosen stimulus is the sudden presentation of one-second darkness, or lights-off, shown to evoke an immediate locomotion response in Drosophila. Our research found that PPI can also be seen in adult flies, which has not been reported before. Additionally, we confirmed our results by showing that a drug that affects an important brain component, called the NMDA receptor, can change PPI in flies. We suggest that studying this behavior in fruit flies could help us understand how it works in other animals, including humans. Prepulse inhibition (PPI) is a widely investigated behavior to study the mechanisms of disorders such as anxiety, schizophrenia, and bipolar mania. PPI has been observed across various vertebrate and invertebrate species; however, it has not yet been reported in adult Drosophila melanogaster. In this study, we describe the first detection of PPI of visually evoked locomotor arousal in flies. To validate our findings, we demonstrate that PPI in Drosophila can be partially reverted by the N-methyl D-aspartate (NMDA) receptor antagonist MK-801, known for inducing sensorimotor gating deficits in rodent models. Additionally, we show that the visually evoked response can be inhibited by multiple stimuli presentation, which can also be affected by MK-801. Given the versatility of Drosophila as a model organism for genetic screening and analysis, our results suggest that high-throughput behavioral screenings of adult flies can become a valuable tool for investigating the mechanisms behind PPI. [ABSTRACT FROM AUTHOR]

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• Cntnap2−/− rats show higher startle and disrupted prepulse inhibition. • Increased activity in startle-mediating brainstem neurons in Cntnap2−/− females explain higher startle. • Males do not show this increased activity, despite higher startle, indicating sex-specific effects. • PPI deficits do not correlate with altered signaling in the pedunculopontine tegmental nucleus. • Mechanisms and structures outside primary startle pathway contribute to Cntnap2 phenotype. The contactin-associated protein-like 2 (CNTNAP2) gene encodes for the CASPR2 protein, which plays an essential role in neurodevelopment. Mutations in CNTNAP2 are associated with neurodevelopmental disorders, including autism spectrum disorder and schizophrenia. Rats with a loss of function mutation in the Cntnap2 gene show increased acoustic startle response (ASR) and decreased prepulse inhibition (PPI). The neural basis of this altered auditory processing in Cntnap2 knock-out rats is currently unknown. Auditory brainstem recordings previously revealed no differences between the genotypes. The next step is to investigate brainstem structures outside of the primary auditory pathway that mediate ASR and PPI, which are the pontine reticular nucleus (PnC) and pedunculopontine tegmentum (PPTg), respectively. Multi-unit responses from the PnC and PPTg in vivo of the same rats revealed sex-specific effects of loss of CASPR2 expression on PnC activity, but no effects on PPTg activity. Female Cntnap2−/− rats showed considerably increased PnC firing rates compared with female wildtypes, whereas the difference between the genotypes was modest in male rats. In contrast, for both females and males we found meager differences between the genotypes for PPTg firing rates and inhibition of PnC firing rates, indicating that altered firing rates of these brainstem structures are not responsible for decreased PPI in Cntnap2−/− rats. We conclude that the auditory processing changes seen in Cntnap2−/− rats are associated with, but cannot be fully explained by, differences in PnC firing rates, and that a loss of function mutation in the Cntnap2 gene has differential effects depending on sex. [ABSTRACT FROM AUTHOR]

BackgroundSystem xc– (Sxc–) is an important heteromeric amino acid cystine/glutamate exchanger that plays a pivotal role in the CNS by importing cystine into cells while exporting glutamate. Although certain behaviors have been identified as altered in Sxc– null mutant mice, our understanding of the comprehensive impact of Sxc– on behavior remains incomplete.MethodsTo address this gap, we compared motor, sensory and social behaviors of male and female mice in mice null for Sxc– (SLC7A11sut/sut) with wildtype littermates (SLC7A11+/+) in a comprehensive and systematic manner to determine effects of genotype, sex, age, and their potential interactions.ResultsMotor performance was not affected by loss of Sxc– in both males and females, although it was impacted negatively by age. Motor learning was specifically disrupted in female mice lacking Sxc– at both 2 and 6 months of age. Further, female SLC7A11sut/sut mice at both ages exhibited impaired sociability, but normal spatial and recognition memory, as well as sensorimotor gating. Finally, pronounced open-space anxiety was displayed by female SLC7A11sut/sut when they were young. In contrast, young SLC7A11sut/sut male mice demonstrated normal sociability, delayed spatial learning, increased open-space anxiety and heightened sensitivity to noise. As they aged, anxiety and noise sensitivity abated but hyperactivity emerged.DiscussionWe find that the behavioral phenotypes of female SLC7A11sut/sut are similar to those observed in mouse models of autism spectrum disorder, while behaviors of male SLC7A11sut/sut resemble those seen in mouse models of attention deficit hyperactivity disorder. These results underscore the need for further investigation of SLC7A11 in neurodevelopment. By expanding our understanding of the potential involvement of Sxc–, we may gain additional insights into the mechanisms underlying complex neurodevelopmental conditions.

Sensory processing abnormalities are consistently associated with autism, but the underlying mechanisms and treatment options are unclear. Fragile X Syndrome (FXS) is the leading known genetic cause of intellectual disabilities and autism. One debilitating symptom of FXS is hypersensitivity to sensory stimuli. Sensory hypersensitivity is seen in both humans with FXS and FXS mouse model, the Fmr1 knock out (Fmr1 KO) mouse. Abnormal sensorimotor gating may play a role in the hypersensitivity to sensory stimuli. Humans with FXS and Fmr1 KO mice show abnormalities in acoustic startle response (ASR) and prepulse inhibition (PPI) of startle, responses commonly used to quantify sensorimotor gating. Recent studies have suggested high levels of matrix metalloproteinase-9 (MMP-9) as a potential mechanism of sensory abnormalities in FXS. Here we tested the hypothesis that genetic reduction of MMP-9 in Fmr1 KO mice rescues ASR and PPI phenotypes in adult Fmr1 KO mice. We measured MMP-9 levels in the inferior colliculus (IC), an integral region of the PPI circuit, of WT and Fmr1 KO mice at P7, P12, P18, and P40. MMP-9 levels were higher in the IC of Fmr1 KO mice during early development (P7, P12), but not in adults. We compared ASR and PPI responses in young (P23-25) and adult (P50-80) Fmr1 KO mice to their age-matched wildtype (WT) controls. We found that both ASR and PPI were reduced in the young Fmr1 KO mice compared to age-matched WT mice. There was no genotype difference for ASR in the adult mice, but PPI was significantly reduced in the adult Fmr1 KO mice. The adult mouse data are similar to those observed in humans with FXS. Genetic reduction of MMP-9 in the Fmr1 KO mice resulted in a rescue of adult PPI responses to WT levels. Taken together, these results show sensorimotor gating abnormalities in Fmr1 KO mice, and suggest the potential for MMP-9 regulation as a therapeutic target to reduce sensory hypersensitivity.

Abstract Background Cordia myxa L. (Boraginaceae) is widely distributed in tropical regions and it’s fruits, leaves and stem bark have been utilized in folk medicine for treating trypanosomiasis caused by Trypanosoma cruzi. A population-based study showed that T. cruzi infection is associated with cognitive impairments. Therefore, if C. myxa has ameliorating activities on cognitive function, it would be useful for both T. cruzi infection and cognitive impairments. Methods In this study, we evaluated the effects of an ethanol extract of leaves of C. myxa (ELCM) on memory impairments and sensorimotor gating deficits in mice. The phosphorylation level of protein was observed by the Western blot analysis. Results The administration of ELCM significantly attenuated scopolamine-induced cognitive dysfunction in mice, as measured by passive avoidance test and novel object recognition test. Additionally, in the acoustic startle response test, we observed that the administration of ELCM ameliorated MK-801-induced prepulse inhibition deficits. We found that these behavioral outcomes were related with increased levels of phosphorylation phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK-3β) in the cortex and extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in the hippocampus by western blot analysis. Conclusions These results suggest that ELCM would be a potential candidate for treating cognitive dysfunction and sensorimotor gating deficits observed in individuals with neurodegenerative diseases.

Background: Deficient information processing in ADHD theoretically results in sensory overload and may underlie the symptoms of the disorder. Mismatch negativity (MMN) and P3a amplitude reflect an individual's detection and subsequent change in attention to stimulus change in their environment. Our primary aim was to explore MMN and P3a amplitude in adult ADHD patients and to examine the effects of methylphenidate (MPH) on these measures. Methods: Forty initially psychostimulant-naïve, adult ADHD patients without comorbid ASD and 42 matched healthy controls (HC) were assessed with an MMN paradigm at baseline. Both groups were retested after 6 weeks, in which patients were treated with MPH. Results: Neither significant group differences in MMN nor P3a amplitude were found at baseline. Although 6-week MPH treatment significantly reduced symptomatology and improved daily functioning of the patients, it did not significantly affect MMN amplitude; however, it did significantly reduce P3a amplitude compared to the HC. Furthermore, more severe ADHD symptoms were significantly associated with larger MMN amplitudes in the patients, both at baseline and follow-up. Conclusion: We found no evidence for early information processing deficits in patients with ADHD, as measured with MMN and P3a amplitude. Six-week treatment with MPH decreased P3a but not MMN amplitude, although more severe ADHD-symptoms were associated with larger MMN amplitudes in the patients. Given that P3a amplitude represents an important attentional process and that glutamate has been linked to both ADHD and MMN amplitude, future research should investigate augmenting MPH treatment of less responsive adults with ADHD with glutamatergic antagonists. [ABSTRACT FROM AUTHOR]

Sociocultural attitudes towards cannabis legalization contribute to the common misconception that it is a relatively safe drug and its use during pregnancy poses no risk to the fetus. However, longitudinal studies demonstrate that maternal cannabis exposure results in adverse outcomes in the offspring, with a heightened risk for developing psychopathology. One of the most reported psychiatric outcomes is the proneness to psychotic‐like experiences during childhood. How exposure to cannabis during gestation increases psychosis susceptibility in children and adolescents remains elusive. Preclinical research has indicated that in utero exposure to the major psychoactive component of cannabis, delta‐9‐tetrahydrocannabinol (THC), deranges brain developmental trajectories towards vulnerable psychotic‐like endophenotypes later in life. Here, we present how prenatal THC exposure (PCE) deregulates mesolimbic dopamine development predisposing the offspring to schizophrenia‐relevant phenotypes, exclusively when exposed to environmental challenges, such as stress or THC. Detrimental effects of PCE are sex‐specific because female offspring do not display psychotic‐like outcomes upon exposure to these challenges. Moreover, we present how pregnenolone, a neurosteroid that showed beneficial properties on the effects elicited by cannabis intoxication, normalizes mesolimbic dopamine function and rescues psychotic‐like phenotypes. We, therefore, suggest this neurosteroid as a safe "disease‐modifying" aid to prevent the onset of psychoses in vulnerable individuals. Our findings corroborate clinical evidence and highlight the relevance of early diagnostic screening and preventative strategies for young individuals at risk for mental diseases, such as male PCE offspring. [ABSTRACT FROM AUTHOR]

Despite the clinical significance of prepulse inhibition (PPI), the mechanisms are not well understood. Herein, we present our investigation of PPI in the R1 component of electrically induced blink reflexes. The effect of a prepulse was explored with varying prepulse test intervals (PTIs) of 20–600 ms in 4 females and 12 males. Prepulse–test combinations included the following: stimulation of the supraorbital nerve (SON)–SON [Experiment (Exp) 1], sound–sound (Exp 2), the axon of the facial nerve–SON (Exp 3), sound–SON (Exp 4), and SON–SON with a long trial–trial interval (Exp 5). Results showed that (1) leading weak SON stimulation reduced SON-induced ipsilateral R1 with a maximum effect at a PTI of 140 ms, (2) the sound– sound paradigm resulted in a U-shaped inhibition time course of the auditory startle reflex (ASR) peaking at 140 ms PTI, (3) facial nerve stimulation showed only a weak effect on R1, (4) a weak sound prepulse facilitated R1 but strongly inhibited SON-induced late blink reflexes (LateRs) with a similar U-shaped curve, and (5) LateR in Exp 5 was almost completely absent at PTIs .80 ms. These results indicate that the principal sensory nucleus is responsible for R1 PPI. Inhibition of ASR or LateR occurs at a point in the startle reflex circuit where auditory and somatosensory signals converge. Although the two inhibitions are different in location, their similar time courses suggest similar neural mechanisms. As R1 has a simple circuit and is stable, R1 PPI helps to clarify PPI mechanisms. [ABSTRACT FROM AUTHOR]

Objective: Sensorimotor gating is experimentally operationalized by the prepulse inhibition (PPI) of the startle response (SR). Previous studies suggest high test-retest reliability of PPI and potential correlation with working memory (WM). Here, we aimed to validate and extend the test-retest reliability of PPI in healthy humans and its correlation with WM performance. Methods: We applied an acoustic startle PPI paradigm with four different prepulse intensities (64, 68, 72 and 76 dB) and two different WM tasks [n-back, change detection task (CDT)] in a group of 26 healthy adults (final sample size n = 23). To assess test-retest reliability, we performed all tests on two separate days ~27 days (range: 21–32 days) apart. Results: We were able to confirm high test-retest reliability of the PPI with a mean intraclass correlation (ICC) of > 0.80 and significant positive correlation of PPI with n-back but not with CDT performance. Detailed analysis showed that PPI across all prepulse intensities significantly correlated with both the 2-back and 0-back conditions, suggesting regulation by cross-conditional processes (e.g. attention). However, when removing the 0-back component from the 2-back data, we found a specific and significant correlation with WM for the 76-dB PPI condition. Conclusion: With the present study, we were able to confirm the high test-retest reliability of the PPI in humans and could validate and expand on its correlation with WM performance. [ABSTRACT FROM AUTHOR]

• Olivocochlear and non-olivocochlear neurons in the VNTB lack a distinct topographic pattern, exhibiting a mixed arrangement. • A notable proportion of VNTB cholinergic neurons projecting to the cochlear root nucleus is concentrated at rostral levels. • The VNTB plays a role in the prepulse inhibition of acoustic startle reflex, particularly at short interstimulus intervals. • Non-olivocochlear VNTB neurons are involved in the rapid top-down cholinergic pathway of auditory prepulse inhibition. Cholinergic signaling is essential to mediate the auditory prepulse inhibition (PPI), an operational measure of sensorimotor gating, that refers to the reduction of the acoustic startle reflex (ASR) when a low-intensity, non-startling acoustic stimulus (the prepulse) is presented just before the onset of the acoustic startle stimulus. The cochlear root neurons (CRNs) are the first cells of the ASR circuit to receive cholinergic inputs from non-olivocochlear neurons of the ventral nucleus of the trapezoid body (VNTB) and subsequently decrease their neuronal activity in response to auditory prepulses. Yet, the contribution of the VNTB-CRNs pathway to the mediation of PPI has not been fully elucidated. In this study, we used the immunotoxin anti-choline acetyltransferase (ChAT)-saporin as well as electrolytic lesions of the medial olivocochlear bundle to selectively eliminate cholinergic VNTB neurons, and then assessed the ASR and PPI paradigms. Retrograde track-tracing experiments were conducted to precisely determine the site of lesioning VNTB neurons projecting to the CRNs. Additionally, the effects of VNTB lesions and the integrity of the auditory pathway were evaluated via auditory brain responses tests, ChAT- and FOS-immunohistochemistry. Consequently, we established three experimental groups: 1) intact control rats (non-lesioned), 2) rats with bilateral lesions of the olivocochlear bundle (OCB-lesioned), and 3) rats with bilateral immunolesions affecting both the olivocochlear bundle and the VNTB (OCB/VNTB-lesioned). All experimental groups underwent ASR and PPI tests at several interstimulus intervals before the lesion and 7, 14, and 21 days after it. Our results show that the ASR amplitude remained unaffected both before and after the lesion across all experimental groups, suggesting that the VNTB does not contribute to the ASR. The%PPI increased across the time points of evaluation in the control and OCB-lesioned groups but not in the OCB/VNTB-lesioned group. At the ISI of 50 ms, the OCB-lesioned group exhibited a significant increase in%PPI (p < 0.01), which did not occur in the OCB/VNTB-lesioned group. Therefore, the ablation of cholinergic non-olivocochlear neurons in the OCB/VNTB-lesioned group suggests that these neurons contribute to the mediation of auditory PPI at the 50 ms ISI through their cholinergic projections to CRNs. Our study strongly reinforces the notion that auditory PPI encompasses a complex mechanism of top-down cholinergic modulation, effectively attenuating the ASR across different interstimulus intervals within multiple pathways. [ABSTRACT FROM AUTHOR]

Imbalances in dopamine activity significantly contribute to the pathophysiology of several neuropsychiatric disorders, including addiction, ADHD, schizophrenia, impulse control disorders, and Parkinson's Disease. Neuro(active)steroids, comprising endogenous steroids that finely modulate neuronal activity, are considered crucial regulators of brain function and behavior, with implications in various physiological processes and pathological conditions. Specifically, subclasses of Neuro(active)steroids belonging to the 5 α reductase pathway are prominently involved in brain disorders characterized by dopaminergic signaling imbalances. This review highlights the neuromodulatory effects of Neuro(active)steroids on the dopamine system and related aberrant behavioral phenotypes. We critically appraise the role of pregnenolone, progesterone, and allopregnanolone on dopamine signaling. Additionally, we discuss the impact of pharmacological interventions targeting 5 α reductase activity in neuropsychiatric conditions characterized by excessive activation of the dopaminergic system, ranging from psychotic (endo)phenotypes and motor complications to decision-making problems and addiction. • Neuro(active)steroids modulate dopamine system. • Neuro(active) steroids contribute to the pathophysiology of dopamine-dependent disorders. • 5αR-neuro(active)steroids rescue hyperdopaminergic phenotypes. [ABSTRACT FROM AUTHOR]

Genetic and environmental models of neuropsychiatric disease have grown exponentially over the last 20years. One measure that is often used to evaluate the translational relevance of these models to human neuropsychiatric disease is prepulse inhibition of startle (PPI), an operational measure of sensorimotor gating. Deficient PPI characterizes several neuropsychiatric disorders but has been most extensively studied in schizophrenia. It has become a useful tool in translational neuropharmacological and molecular genetics studies because it can be measured across species using almost the same experimental parameters. Although initial studies of PPI in rodents were pharmacological because of the robust predictive validity of PPI for antipsychotic efficacy, more recently, PPI has become standard common behavioral measures used in genetic and neurodevelopmental models of schizophrenia. Here we review "two hit" models of schizophrenia and discuss the utility of PPI as a tool in phenotyping these models of relevant risk factors. In the review, we consider approaches to rodent models of genetic and neurodevelopmental risk factors and selectively review "two hit" models of gene×environment and environment×environment interactions in which PPI has been measured.

Tic related disorders affect 4–20% of the population, mostly idiopathic, can be grouped in a wide spectrum of severity, where the most severe end is Tourette Syndrome (TS). Tics are arrhythmic hyperkinesias to whom execution the subject is forced by a "premonitory urge" that can be classified as sensory tic, just-right experience or urge without obsession. If an intact volitional inhibition allows patients to temporarily suppress tics, a lack or deficit in automatic inhibition is involved in the genesis of the disorder. Studies have assessed the presence of intrinsic microscopic and macroscopic anomalies in striatal circuits and relative cortical areas in association with a hyperdopaminergic state in the basal forebrain. Prepulse inhibition (PPI) of the startle reflex is a measure of inhibitory functions by which a weak sensory stimulus inhibits the elicitation of a startle response determined by a sudden intense stimulus. It is considered an operation measure of sensorimotor gating, a neural process by which unnecessary stimuli are eliminated from awareness. Evidence points out that the limbic domain of the CSTC loops, dopamine and GABA receptors within the striatum play an important role in PPI modulation. It is conceivable that a sensorimotor gating deficit may be involved in the genesis of premonitory urge and symptoms. Therefore, correcting the sensorimotor gating deficit may be considered a target for tic-related disorders therapies; in such case PPI (as well as other indirect estimators of sensorimotor gating) could represent therapeutic impact predictors. [ABSTRACT FROM AUTHOR]

The maternal immune activation produced by the systemic administration of lipopolysaccharide (LPS) in rats provides valuable insights into the basis of behavioural schizophrenia-like disturbances and biochemical changes in the brains of the offspring, such as microglial activation. Regarding therapy, antipsychotics continually constitute the cornerstone of schizophrenia treatment. To their various efficacy and side effects, as well as not fully recognised mechanisms of action, further characteristics have been suggested, including an anti-inflammatory action via the impact on neuron–microglia axes responsible for inhibition of microglial activation. Therefore, in the present study, we sought to determine whether chronic treatment with chlorpromazine, quetiapine or aripiprazole could influence schizophrenia-like behavioural disturbances at the level of sensorimotor gating in male offspring prenatally exposed to LPS. Simultaneously, we wanted to explore if the chosen antipsychotics display a positive impact on the neuroimmunological parameters in the brains of these adult animals with a special focus on the ligand-receptor axes controlling neuron–microglia communication as well as pro- and anti-inflammatory factors related to the microglial activity. The results of our research revealed the beneficial effect of quetiapine on deficits in sensorimotor gating observed in prenatally LPS-exposed offspring. In terms of axes controlling neuron–microglia communication and markers of microglial reactivity, we observed a subtle impact of quetiapine on hippocampal Cx3cl1 and Cx3cr1 levels, as well as cortical Cd68 expression. Hence, further research is required to fully define and explain the involvement of quetiapine and other antipsychotics in Cx3cl1-Cx3cr1 and/or Cd200-Cd200r axes modulation and inflammatory processes in the LPS-based model of schizophrenia-like disturbances. [ABSTRACT FROM AUTHOR]

Although individuals with schizophrenia typically present deficits in social interaction, little is known about the quality of their parent–infant interactions. In the present study, we assessed the behavioral effects of neonatal ventral hippocampus lesion (nVHL) in female rats (nVHL is known to induce schizophrenia‐like deficits in males). Sexually naïve adult nVHL or sham female rats received cognitive and social tests, and their maternal behavior was observed in independent groups of adult nVHL and sham rats on postpartum days 2, 6, and 12. Compared to Sham females, naïve nVHL rats displayed elevated locomotor activity, less social interaction, and disrupted habituation of the acoustic startle response (ASR), while dorsal immobility (a defensive behavioral response) and prepulse inhibition of ASR were not affected. Although all nVHL mothers retrieved their pups, adopted the crouching posture, and nursed them, they showed disturbances in the display of pup body licking and nest building. Furthermore, a high proportion of nVHL mothers displayed atypical retrieval of pups and re‐retrieving of pups, atypical nest‐building, excavation, and cannibalism, as well a high level of these behaviors. These data indicate that cognition, locomotor activity, and maternal care is disrupted in nVHL female, suggesting disturbances in mesocorticolimbic dopaminergic systems and/or in social cognition. [ABSTRACT FROM AUTHOR]

Rationale: Mescaline is a classical psychedelic compound with a phenylethylamine structure that primarily acts on serotonin 5-HT2A/C receptors, but also binds to 5-HT1A and 5-HT2B receptors. Despite being the first psychedelic ever isolated and synthesized, the precise role of different serotonin receptor subtypes in its behavioral pharmacology is not fully understood., Objectives: In this study, we aimed to investigate how selective antagonists of 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT1A receptors affect the behavioral changes induced by subcutaneous administration of mescaline (at doses of 10, 20, and 100 mg/kg) in rats., Methods: We used adult male Wistar rats in all our experiments. We evaluated locomotor activity using the open field test, and assessed sensorimotor gating deficits by measuring prepulse inhibition (PPI) of acoustic startle reaction (ASR)., Results: While the highest dose of mescaline induced hyperlocomotion (p < 0.001), which almost all the other antagonists reversed (p < 0.05-0.001), the PPI deficits were selectively normalized by the 5-HT2A antagonist (p < 0.05-0.01). The 5-HT2C antagonist partially reversed the small PPI deficit induced by lower doses of mescaline (p = 0.0017)., Conclusion: Our findings suggest that mescaline-induced changes in behavior are primarily mediated by the 5-HT2A receptor subtype, with less pronounced contributions from the 5-HT2C receptor. The other antagonists had limited effects., Competing Interests: Declaration of competing interest TP and JH declare to have shares in “Psyon s.r.o.”, and have founded “PSYRES - Psychedelic Research Foundation”. TP has shares in “Společnost pro podporu neurovědního výzkumu s.r.o.” and reports consulting fees from GH Research and CB21-Pharma outside the submitted work. TP and/or JH are/were involved in Compass Pathways, MAPS, GH-Research, Ketabon clinical trials with psilocybin, MDMA, 5-MeO-DMT, ketamine and MDMA outside the submitted work., (Copyright © 2024. Published by Elsevier Inc.)

Sensory thresholds enable animals to regulate their behavioral responses to environmental threats. Despite the importance of sensory thresholds for animal behavior and human health, we do not yet have a full appreciation of the underlying molecular-genetic and circuit mechanisms. The larval zebrafish acoustic startle response provides a powerful system to identify molecular mechanisms underlying establishment of sensory thresholds and plasticity of thresholds through mechanisms like habituation. Using this system, we identify Cadherin 16 as a previously undescribed regulator of sensory gating. We demonstrate that Cadherin 16 regulates sensory thresholds via an endocrine organ, the corpuscle of Stannius (CS), which is essential in zebrafish for regulating Ca 2+ homeostasis. We further show that Cadherin 16 regulates whole-body calcium and ultimately behavior through the hormone Stanniocalcin 1L, and the IGF-regulatory metalloprotease, Papp-aa. Finally, we demonstrate the importance of the CS through ablation experiments that reveal its role in promoting normal acoustic sensory gating. Together, our results uncover a previously undescribed brain non-autonomous pathway for the regulation of behavior and establish Ca 2+ homeostasis as a critical process underlying sensory gating in vivo.

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., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Doornaert et al.)

Background: Cordia myxa L. (Boraginaceae) is widely distributed in tropical regions and it's fruits, leaves and stem bark have been utilized in folk medicine for treating trypanosomiasis caused by Trypanosoma cruzi. A population-based study showed that T. cruzi infection is associated with cognitive impairments. Therefore, if C. myxa has ameliorating activities on cognitive function, it would be useful for both T. cruzi infection and cognitive impairments. Methods: In this study, we evaluated the effects of an ethanol extract of leaves of C. myxa (ELCM) on memory impairments and sensorimotor gating deficits in mice. The phosphorylation level of protein was observed by the Western blot analysis. Results: The administration of ELCM significantly attenuated scopolamine-induced cognitive dysfunction in mice, as measured by passive avoidance test and novel object recognition test. Additionally, in the acoustic startle response test, we observed that the administration of ELCM ameliorated MK-801-induced prepulse inhibition deficits. We found that these behavioral outcomes were related with increased levels of phosphorylation phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK-3β) in the cortex and extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in the hippocampus by western blot analysis. Conclusions: These results suggest that ELCM would be a potential candidate for treating cognitive dysfunction and sensorimotor gating deficits observed in individuals with neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Objectives Despite of strenuous research in the past decades, the etiology of schizophrenia (SCZ) still remains incredibly controversial. Previous genetic analysis has uncovered a close association of Unc-51 like kinase 4 (ULK4), a family member of Unc-51-like serine/threonine kinase, with SCZ. However, animal behavior data which may connect Ulk4 deficiency with psychiatric disorders, particularly SCZ are still missing. Methods We generated Emx1-Cre:Ulk4flox/flox conditional knockout (CKO) mice, in which Ulk4 was deleted in the excitatory neurons of cerebral cortex and hippocampus. Results The cerebral cellular architecture was maintained but the spine density of pyramidal neurons was reduced in Ulk4 CKO mice. CKO mice showed deficits in the spatial and working memories and sensorimotor gating. Levels of p-Akt and p-GSK-3α/β were markedly reduced in the CKO mice indicating an elevation of GSK-3 signaling. Mechanistically, Ulk4 may regulate the GSK-3 signaling via putative protein complex comprising of two phosphatases, protein phosphatase 2A (PP2A) and 1α (PP1α). Indeed, the reduction of p-Akt and p-GSK-3α/β was rescued by administration of inhibitor acting on PP2A and PP1α in CKO mice. Conclusions Our data identified potential downstream signaling pathway of Ulk4, which plays important roles in the cognitive functions and when defective, may promote SCZ-like pathogenesis and behavioral phenotypes in mice. [ABSTRACT FROM AUTHOR]

Sensory and sensorimotor gating provide the early processing of information under conditions of rapid presentation of multiple stimuli. Gating deficiency is observed in various psychopathologies, in particular, in schizophrenia. However, there is also a significant proportion of people in the general population with low filtration rates who do not show any noticeable cognitive decline. The review article presents a comparative analysis of existing data on the peculiarities of cholinergic and dopaminergic mechanisms associated with lowering gating in healthy individuals and in patients with schizophrenia. The differences in gating mechanisms in cohorts of healthy individuals and those with schizophrenia are discussed. [ABSTRACT FROM AUTHOR]

The current study investigated whether lower sensory and sensorimotor gating were related to higher levels of creativity and/or attentional difficulties in a natural population of primary school children (9-to 13-year-old). Gating abilities were measured with P50 suppression and prepulse inhibition of the startle reflex (PPI). The final sample included 65 participants in the P50 analyses and 37 participants in the PPI analyses. Our results showed that children with a high P50 amplitude to testing stimuli scored significantly higher on the divergent outcome measures of fluency and flexibility but not originality compared to children with a lower amplitude. No significant differences were found on any of the creativity measures when the sample was split on average PPI parameters. No significant differences in attention, as measured with a parent questionnaire, were found between children with low or high levels of sensory or sensorimotor gating. The data suggest that quantitative, but not qualitative measures of divergent thinking benefit from lower psychophysiological gating and that attentional difficulties stem from specific instead of general gating deficits. Future studies should take the effect of controlled attention into consideration. [ABSTRACT FROM AUTHOR]

Abstract Background Sensorimotor 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. Results Using 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. Conclusions Our 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.

BackgroundPrepulse inhibition (PPI) of startle, an operational measure of sensorimotor gating, is used to study normal and pathological brain function. From 2001 to 2016, we screened healthy subjects (HS) to establish their suitability for tests of drug effects on PPI. Because of the size and systematic characterization of this sample across variables of relevance to PPI, we now report these screening results.MethodsAcoustic startle and PPI were assessed in HS to identify those eligible for studies of drug effects on PPI from 2001 to 2016, yielding 457 "eligible" subjects.ResultsData confirmed the consistency of PPI across this 15-year period, and supported the role of several variables previously reported to moderate either startle or PPI.ConclusionsStartle and PPI are robust physiological measures that are predictably moderated by specific physiological variables in healthy adults. As such, these measures serve as robust markers of neurobiological processes in healthy and patient populations.

The current study investigated whether lower sensory and sensorimotor gating were related to higher levels of creativity and/or attentional difficulties in a natural population of primary school children (9- to 13-year-old). Gating abilities were measured with P50 suppression and prepulse inhibition of the startle reflex (PPI). The final sample included 65 participants in the P50 analyses and 37 participants in the PPI analyses. Our results showed that children with a high P50 amplitude to testing stimuli scored significantly higher on the divergent outcome measures of fluency and flexibility but not originality compared to children with a lower amplitude. No significant differences were found on any of the creativity measures when the sample was split on average PPI parameters. No significant differences in attention, as measured with a parent questionnaire, were found between children with low or high levels of sensory or sensorimotor gating. The data suggest that quantitative, but not qualitative measures of divergent thinking benefit from lower psychophysiological gating and that attentional difficulties stem from specific instead of general gating deficits. Future studies should take the effect of controlled attention into consideration.

Sensory and sensorimotor gating provide the early processing of information under conditions of rapid presentation of multiple stimuli. Gating deficiency is observed in various psychopathologies, in particular, in schizophrenia. However, there is also a significant proportion of people in the general population with low filtration rates who do not show any noticeable cognitive decline. The review article presents a comparative analysis of existing data on the peculiarities of cholinergic and dopaminergic mechanisms associated with lowering gating in healthy individuals and in patients with schizophrenia. The differences in gating mechanisms in cohorts of healthy individuals and those with schizophrenia are discussed.

[Display omitted] • Amygdala glutamatergic neurons suppress auditory neurotransmission in vitro. • Amygdala glutamatergic neurons likely act on GlyT2+ neurons not auditory afferents. • Activation of brainstem GlyT2+ neurons is sufficient to induce acoustic PPI in vivo. • The contribution of brainstem GlyT2+ neurons to acoustic PPI decreases with aging. Prepulse inhibition (PPI) of the auditory startle response, a key measure of sensorimotor gating, diminishes with age and is impaired in various neurological conditions. While PPI deficits are often associated with cognitive impairments, their reversal is routinely used in experimental systems for antipsychotic drug screening. Yet, the cellular and circuit-level mechanisms of PPI remain unclear, even under non-pathological conditions. We recently showed that brainstem neurons located in the caudal pontine reticular nucleus (PnC) expressing the glycine transporter type 2 (GlyT2±) receive inputs from the central nucleus of the amygdala (CeA) and contribute to PPI but via an uncharted pathway. Here, using tract-tracing, immunohistochemistry and in vitro optogenetic manipulations coupled to field electrophysiological recordings, we reveal the neuroanatomical distribution of GlyT2± PnC neurons and PnC-projecting CeA glutamatergic neurons and we provide mechanistic insights on how these glutamatergic inputs suppress auditory neurotransmission in PnC sections. Additionally, in vivo experiments using GlyT2-Cre mice confirm that optogenetic activation of GlyT2± PnC neurons enhances PPI and is sufficient to induce PPI in young mice, emphasizing their role. However, in older mice, PPI decline is not further influenced by inhibiting GlyT2± neurons. This study highlights the importance of GlyT2± PnC neurons in PPI and underscores their diminished activity in age-related PPI decline. [ABSTRACT FROM AUTHOR]

Acoustic startle reflex (ASR) constitutes a reliable, cross-species indicator of sensorimotor and inhibitory mechanisms, showing distinct signature in cognitive aging, sex, and psychopathological characterization. ASR can be modulated by the prepulse inhibition (PPI) paradigm, which comprises the suppression of reactivity to a startling stimulus (pulse) following a weak prepulse (30- to 500-ms time difference), being widely linked to inhibitory capabilities of the sensorimotor system. If the prepulse–pulse tones are more clearly separated (500–2,000 ms), ASR amplitude is enhanced, termed as prepulse facilitation (PPF), reflecting sustained or selective attention. Our study aimed to investigate early-life sensorimotor sex/age differences using Electroencephalographic recordings to measure muscular and neural ASR in a healthy young population. Sixty-three children and adolescents aged 6.2–16.7 years (31 females) took part in the experiment. Neural ASR was assessed by two different analyses, namely, event-related potentials (ERPs) and first-derivative potentials (FDPs). As expected, PPF showed enhanced responses compared with PPI, as indicated by eyeblink, ERP and FDP measures, confirming the gating effect hypothesis. Sex-related differences were reflected in FDPs, with females showing higher ASR than males, suggesting increased levels of poststartle excitability. Intragroup age effects were evaluated via multipredictor regression models, noticing positive correlation between age versus eyeblink and ERP responses. Attention-related ERPs (N100 and P200) showed distinct patterns in PPI versus PPF, potentially indicative for alternative attentional allocation and block-out of sensory overload. Screening measures of participants' neurodevelopmental (assessed by Wechsler Intelligence Scale for Children) and behavioral (assessed by Child Behavior Checklist) markers were also associated with increased N100/P200 responses, presumably indexing synergy between perceptual consistency, personality profiling, and inhibitory performance. Conclusively, modulation of ASR by PPI and PPF is associated with biological sex and internal/external personality traits in childhood and adolescence, potentially useful to guide symptomatology and prevention of psychopathology. [ABSTRACT FROM AUTHOR]

Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD‐93 protein reduction) a novel clinically relevant Dlg2+/− rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N‐Methyl‐D‐aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD‐93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2+/− rats show a potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, and partially dissimilar to behavioural deficits previously reported in Dlg2+/− mouse models demonstrating issues surrounding the comparison of models with different aetiology and species. Intact performance on many of the behavioural domains assessed here, such as anxiety and reward processing, will remove these as confounds when continuing investigation into this model using more complex cognitive tasks. [ABSTRACT FROM AUTHOR]

Acoustic startle reflex (ASR) constitutes a reliable, cross-species indicator of sensorimotor and inhibitory mechanisms, showing distinct signature in cognitive aging, sex, and psychopathological characterization. ASR can be modulated by the prepulse inhibition (PPI) paradigm, which comprises the suppression of reactivity to a startling stimulus (pulse) following a weak prepulse (30- to 500-ms time difference), being widely linked to inhibitory capabilities of the sensorimotor system. If the prepulse–pulse tones are more clearly separated (500–2,000 ms), ASR amplitude is enhanced, termed as prepulse facilitation (PPF), reflecting sustained or selective attention. Our study aimed to investigate early-life sensorimotor sex/age differences using Electroencephalographic recordings to measure muscular and neural ASR in a healthy young population. Sixty-three children and adolescents aged 6.2–16.7 years (31 females) took part in the experiment. Neural ASR was assessed by two different analyses, namely, event-related potentials (ERPs) and first-derivative potentials (FDPs). As expected, PPF showed enhanced responses compared with PPI, as indicated by eyeblink, ERP and FDP measures, confirming the gating effect hypothesis. Sex-related differences were reflected in FDPs, with females showing higher ASR than males, suggesting increased levels of poststartle excitability. Intragroup age effects were evaluated via multipredictor regression models, noticing positive correlation between age versus eyeblink and ERP responses. Attention-related ERPs (N100 and P200) showed distinct patterns in PPI versus PPF, potentially indicative for alternative attentional allocation and block-out of sensory overload. Screening measures of participants’ neurodevelopmental (assessed by Wechsler Intelligence Scale for Children) and behavioral (assessed by Child Behavior Checklist) markers were also associated with increased N100/P200 responses, presumably indexing synergy between perceptual consistency, personality profiling, and inhibitory performance. Conclusively, modulation of ASR by PPI and PPF is associated with biological sex and internal/external personality traits in childhood and adolescence, potentially useful to guide symptomatology and prevention of psychopathology.

Our 1992 paper, 'The neural substrates of sensorimotor gating of the startle reflex: a review of recent findings and their implications', reviewed a series of (then) new and preliminary findings from cross-species studies of prepulse inhibition of the startle reflex, and commented on their implications. At the time that the report was composed, PubMed listed about 40 citations for studies using the search term 'prepulse inhibition'. In the ensuing 25 years, the field has added about 2700 such reports, reflecting the substantial growth in interest in prepulse inhibition and its utility across a number of different experimental applications. The 30th anniversary of the Journal of Psychopharmacology provides an opportunity to comment briefly on what was described in that 1992 report, how the field has progressed in the subsequent decades, and the paths forward for studies of prepulse inhibition and its use as an operational measure of sensorimotor gating. Among these future paths, we highlight the use of prepulse inhibition as: an endophenotype for genomic studies, and a biomarker for healthy brain circuitry, which may predict sensitivity to psychotherapeutics. Our 1992 report was highly speculative and based on paper-thin empirical data, yet viewed in a certain light, it appears to have contained a basic roadmap for a journey spanning the next 25 years of prepulse inhibition research… and 'what a long, strange trip it's been'.

Mutations in the disrupted in schizophrenia‐1 (DISC1) gene are associated with an increased risk of developing psychological disorders including schizophrenia, bipolar disorder, and depression. Assessing the impact of knocking out genes, like DISC1, in animal models provides valuable insights into the relationship between the gene and behavioral outcomes. Previous research has relied on mouse models to assess these impacts, however these may not yield as reliable or rich a behavioral analysis as can be obtained using rats. Thus, the goal of the present study was to characterize the behavioral effects of a biallelic functional deletion of the DISC1 gene in the Sprague Dawley rat. Female and male wild type and DISC1 knockout rats were assessed beginning just prior to weaning and during the post‐weaning periadolescent period. The primary outcomes evaluated were activity, anxiety, responses to novel objects and conspecifics, and prepulse inhibition. These behaviors were selected as analogous indices of psychological dysfunction in humans. The DISC1 knockout had significant effects on behavior, although the kind and magnitude of deficits was different for females and males: in females, effects included hyperactivity, aversion to novelty, and a modest prepulse inhibition deficit; in males, effects in anxiety and neophobia were mild but their prepulse inhibition deficit was large. These data confirm that the DISC1 knockout rat model is an excellent way to reproduce and study symptoms of psychological disorders and provides compelling evidence for differential consequences of its dysfunction for females and males in the progression and emergence of specific behavioral deficits. [ABSTRACT FROM AUTHOR]