Prepulse Inhibition Research Articles

Hypoxic preconditioning in rats with low and high prepulse inhibition of acoustic startle is implemented through topographically different sensory inputs. Working hypothesis

Hypoxic preconditioning in rats with low and high prepulse inhibition of acoustic startle is implemented through topographically different sensory inputs. Working hypothesis

A Systematic Review on Sex Differences in Prepulse Inhibition of Startle

Abstract: Prepulse inhibition of the startle response is defined as the inhibition of the startle reflex to an intense contextual stimulus (named pulse) when a weaker stimulus (named prepulse) precedes it and is considered a measure of sensorimotor gating. Consistent with recent research, it has been observed that this measure might exhibit sex differences in studies of both humans and rodents, although the results in the literature appear to be inconsistent. Therefore, this systematic review aims to analyze the sexual differences observed in human and nonhuman animal studies from a comparative perspective. A comprehensive search was conducted from the inception to the present in the Web of Science, PubMed, and PsycInfo databases. Following the search, 58 studies were included in the review. The average age in human studies ( n = 32) was 31.45 years (range = 4–69), while among nonhuman animal studies ( n = 26), the average age was 75.5 postnatal days (range = 7–360). The results indicated no clear sexual differences in the startle response magnitude. However, consistent sex differences in prepulse inhibition were found, revealing that males exhibited higher levels of sensorimotor gating compared to females in both humans (78.79% of the studies) and nonhuman animal studies (69.23% of the studies). Therefore, the findings corroborate the sex differences of prepulse inhibition and underscore the value of this paradigm in comparative science, emphasizing the importance of considering sex as an independent variable when studying this phenomenon.

Tinnitus Generation and Behavioral Changes Caused by Chronic Stress: A Behavioral and Brain Study in a Rat Model.

This study explores the connection between chronic stress and tinnitus, a phantom auditory perception, using an animal model. Rats were subjected to 2 h of daily restraint stress for 10 days. Tinnitus was assessed on the last day of stress exposure using the gap response of pre-pulse inhibition acoustic reflex, measured at 60 dB background sound level at 8, 16, and 20 kHz. Chronic stress-exposed rats were categorized into two groups: tinnitus (RTG) and non-tinnitus (RNTG). Various tests, including hearing assessments (distortion product otoacoustic emissions and auditory brainstem response), behavioral evaluations (elevated plus maze test and forced swimming test), and immunohistochemical studies in the auditory and limbic brain regions, were conducted to understand the relationship between chronic stress, tinnitus, and behavioral changes. Following chronic restraint stress, 64.3% of the rats exhibited tinnitus with no audiometric changes. EPM and FST indicated an increase of anxiety- and depression-related behavior in RTG. Immunohistochemical analyses identified specific alterations in the expression of neurotransmitter receptors within brain regions implicated in tinnitus. Specifically, we observed a decrease in γ-aminobutyric acid A receptor α1 expression and an increase in glutamate receptor (N-methyl-D-aspartate receptor subunit 1 and receptor subunit 2B) expression in specific brain region. These changes suggest a reorganization of neural circuits associated with the tinnitus generation and behavioral changes of the rats after chronic stress exposure. Chronic stress alone can be a causal factor for the generation of tinnitus and behavioral changes through altered neural activities in tinnitus-related brain networks. NA Laryngoscope, 2024.

Investigating the Feasibility of Gap Prepulse Inhibition by Auditory Middle Latency Responses in Healthy Subjects

Background and Aim: Gap Prepulse Inhibition (GPI) is a type of Prepulse Inhibition (PPI) in which a gap is used as a prepulse. This study was conducted to investigate the silence gap effect on Auditory Middle Latency Response (AMLR) inhibition in normal subjects. Methods: In this study, 25 participants with normal hearing and no history of tinnitus were included. AMLR was recorded in response to stimuli with gap and without gap in two background noises of 2 and 8 kHz at two electrode locations Fz and Cz and then, gap prepulse inhibition for Na-Pa, Pa-Nb, Nb-Pb and Pb-Nc amplitude with Use of responses to stimuli with and without gap was calculated. Results: The results showed that the mean amplitudes of all four AMLR indices decreased in response to the stimuli with gap and this decrease was more and statistically significant in 8 kHz background noise (p≤0.001). Conclusion: According to the results of this study, it seems that in future studies, PPI of Na-Pa and Pb-Nc amplitudes can be used as main indicators and PPI of Pa-Nb and Nb-Pb amplitudes as alternative indicators in the PPI paradigm in tinnitus diagnosis. Keywords: Prepulse inhibition; tinnitus; auditory middle latency responses

Impact of 5-Lipoxygenase Deficiency on Dopamine-Mediated Behavioral Responses.

The 5-lipoxygenase/leukotriene system has been implicated in both physiological and pathological states within the central nervous system. Understanding how this system interacts with the dopaminergic system could provide valuable insights into dopamine-related pathologies. This study focused on examining both motor and non-motor dopamine-related responses in 5-lipoxygenase/leukotriene-deficient mice. We used pharmacological agents such as amphetamine, apomorphine, and reserpine to challenge the dopaminergic system, evaluating their effects on prepulse inhibition reaction (PPI), general motor activity, and oral involuntary movements. Additionally, we analyzed striatal glial marker expression (GFAP and Iba-1) in reserpine-treated mice. The 5-lipoxygenase/leukotriene-deficient mice exhibited increased spontaneous locomotor activity, including both horizontal and vertical exploration, along with stereotyped behavior compared to wild-type mice. This hyperactivity was reduced by acute apomorphine treatment. Although basal PPI responses were unchanged, 5-lipoxygenase/leukotriene-deficient mice displayed a significant reduction in susceptibility to amphetamine-induced PPI disruption. Conversely, these mice were more vulnerable to reserpine-induced involuntary movements. There were no significant differences in the basal expression of striatal GFAP and Iba-1 positive cells between 5-lipoxygenase/leukotriene-deficient and wild-type mice. However, reserpine treatment significantly increased GFAP immunoreactivity in wild-type mice, an effect not observed in 5-lipoxygenase-deficient mice. Additionally, the percentage of activated microglia was significantly higher in reserpine-treated wild-type mice, an effect absents in 5-lipoxygenase/leukotriene-deficient mice. Our findings suggest that 5-lipoxygenase/leukotriene deficiency leads to a distinctive dopaminergic phenotype, indicating that leukotrienes may influence the modulation of dopamine-mediated responses.

Partial chemogenetic inhibition of the locus coeruleus due to heterogeneous transduction of noradrenergic neurons preserved auditory salience processing in wild-type rats.

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; 1mg/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 (> 150μm) 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.

Stress-Induced Tinnitus in a Rat Model: Transcriptomics of the Prefrontal Cortex and Hippocampus.

The molecular mechanisms by which stress leads to the development of tinnitus are not yet well understood. This study aimed to identify brain changes in a stress-induced tinnitus (ST) animal model through transcriptome analysis of the prefrontal lobe and hippocampus. Twenty Sprague-Dawley rats were subjected to restraint stress for 2 h. Following the gap prepulse inhibition of the acoustic startle (GPIAS) reflex test to assess tinnitus development, the prefrontal lobes and hippocampi of the brains were harvested from 15 rats: five with evident tinnitus (ST), five with noticeable non-tinnitus (stress-induced non-tinnitus; SNT), and five without stress (control group). Comparative RNA-seq analysis was conducted to examine gene expression profiles. In comparison to the control group, the ST group exhibited 971 and 463 differentially expressed genes (DEGs) in the prefrontal lobe and hippocampus, respectively (FDR < 0.05). The SNT group showed a largely similar gene expression to the control group. Enrichment analysis of the prefrontal lobe revealed the downregulation of gene sets associated with neurotransmitter and synapse-related functions and the upregulation of cell cycle-related gene sets in the ST group. In the hippocampus, there were significantly downregulated gene sets associated with steroid production and upregulated gene sets related to the extracellular matrix in the ST group. Immune-related gene sets were upregulated in both the prefrontal lobe and hippocampus. Our research presents evidence that differences in genetic expression in the prefrontal lobe and hippocampus after exposure to stress play a significant role in the development of tinnitus. NA Laryngoscope, 2024.

Reduced multiscale complexity of daily behavioral dynamics in autism spectrum disorder.

Autism spectrum disorder (ASD) is difficult to diagnose objectively due to its heterogeneous and complex manifestations. This study aimed to objectively characterize the behavioral phenotypes of ASD children by exploring the multiscale behavioral dynamics. We applied behavioral organization (BO) and multiscale sample entropy (MSE) analyses to physical activity data collected from ASD and typically developing children, using wearable monitors in their daily life. We also examined their correlation with auditory startle response measures and clinical questionnaires, including the Social Responsiveness Scale (SRS) and the Strengths and Difficulties Questionnaire (SDQ). A significant decrease in MSE at timescales longer than 6 min was observed in ASD children, suggesting decreased irregularity or unpredictability, potentially linked to repetitive behaviors or stereotyped patterns commonly observed in ASD. Additionally, an increase in MSE positively correlated with prepulse inhibition levels, indicating its relationship with sensorimotor gating. Moreover, the observed significant negative correlation with the total difficulty score of SDQ substantiates MSE's potential as an objective metric for assessing general mental health problems associated with ASD. Multiscale analysis enhances the understanding of ASD's behavioral dynamics, providing valuable metrics for real-world assessments.

Cannabidiol attenuates prepulse inhibition disruption by facilitating TRPV1 and 5-HT1A receptor-mediated neurotransmission

Individuals with schizophrenia (SCZ) often present sensorimotor gating impairments that can be investigated by the prepulse inhibition test (PPI). PPI disruption can be mimicked experimentally with psychostimulants such as amphetamine and attenuated/reversed by antipsychotics. Cannabidiol (CBD), the main non-psychotomimetic component of the Cannabis sativa plant, produces antipsychotic-like effects in clinical and preclinical studies. CBD can interact with many pharmacological targets, but the mechanisms involved in its antipsychotic activity are unclear. Using amphetamine-induced PPI disruption in mice, we investigated the involvement of four CBD potential pharmacological targets (CB1, CB2 TRPV1, and 5-HT1A receptors) in its antipsychotic properties. CBD effects were blocked by the TRPV1 antagonist capsazepine and, to a greater extent, by the 5-HT1A receptor antagonist WAY100635. No effect was observed with the CB1 (AM251) or CB2 (AM630) receptor antagonists. These results corroborate findings showing the antipsychotic effects of CBD in the PPI model and indicate that they involve the participation of TRPV1 and 5-HT1A receptors.

DCC in the cerebral cortex is required for cognitive functions in mouse.

Schizophrenia (SZ) is a highly heritable mental disorder, and genome-wide association studies have identified the association between deleted in colorectal cancer (DCC) and SZ. Previous study has shown a lowered expression of DCC in the cerebral cortex of SZ patient. In this study, we identified novel single nucleotide polymorphisms (SNPs) of DCC statistically correlated with SZ. Based on these, we generated DCC conditional knockout (CKO) mice and explored behavioral phenotypes in these mice. We observed that deletion of DCC in cortical layer VI but not layer V led to deficits in fear and spatial memory, as well as defective sensorimotor gating revealed by the prepulse inhibition test (PPI). Critically, the defective sensorimotor gating could be restored by olanzapine, an antipsychotic drug. Furthermore, we found that the levels of p-AKT and p-GSK3α/β were decreased, which was responsible for impaired PPI in the DCC-deficient mice. Finally, the DCC-deficient mice also displayed reduced spine density of pyramidal neurons and disturbed delta-oscillations. Our data, for the first time, identified and explored downstream substrates and signaling pathway of DCC which supports the hypothesis that DCC is a SZ-related risky gene and when defective, may promote SZ-like pathogenesis and behavioral phenotypes in mice.

PDE4B Missense Variant Increases Susceptibility to Post-traumatic Stress Disorder-Relevant Phenotypes in Mice.

Large-scale genome-wide association studies (GWASs) have associated intronic variants in PDE4B, encoding cAMP-specific phosphodiesterase-4B (PDE4B), with increased risk for post-traumatic stress disorder (PTSD), as well as schizophrenia and substance use disorders that are often comorbid with it. However, the pathophysiological mechanisms of genetic risk involving PDE4B are poorly understood. To examine the effects of PDE4B variation on phenotypes with translational relevance to psychiatric disorders, we focused on PDE4B missense variant M220T, which is present in the human genome as rare coding variant rs775201287. When expressed in HEK-293 cells, PDE4B1-M220T exhibited an attenuated response to a forskolin-elicited increase in the intracellular cAMP concentration. In behavioral tests, homozygous Pde4b M220T male mice with a C57BL/6JJcl background exhibited increased reactivity to novel environments, startle hyperreactivity, prepulse inhibition deficits, altered cued fear conditioning, and enhanced spatial memory, accompanied by an increase in cAMP signaling pathway-regulated expression of BDNF in the hippocampus. In response to a traumatic event (10 tone-shock pairings), neuronal activity was decreased in the cortex but enhanced in the amygdala and hippocampus of Pde4b M220T mice. At 24 h post-trauma, Pde4b M220T mice exhibited increased startle hyperreactivity and decreased plasma corticosterone levels, similar to phenotypes exhibited by PTSD patients. Trauma-exposed Pde4b M220T mice also exhibited a slower decay in freezing at 15 and 30 d post-trauma, demonstrating enhanced persistence of traumatic memories, similar to that exhibited by PTSD patients. These findings provide substantive mouse model evidence linking PDE4B variation to PTSD-relevant phenotypes and thus highlight how genetic variation of PDE4B may contribute to PTSD risk.

Muscarinic receptor agonists in animal models of psychosis: protocol for a systematic review and meta-analysis

Background Muscarinic receptor agonism is a promising mechanism of action for treating psychosis, not present in most D2R-blocking antipsychotics. Xanomeline, an M1/M4-preferring agonist, has shown efficacy in late-stage clinical trials, with more compounds being investigated. Therefore, we aim to synthesize evidence on the preclinical efficacy of muscarinic receptor agonists in animal models of psychosis to provide unique insights and evidence-based information to guide drug development. Methods We plan a systematic review and meta-analysis of in vivo animal studies comparing muscarinic receptor agonists or positive allosteric modulators with control conditions and existing D2R-blocking antipsychotics in animals subjected to any method that induces behavioural changes of relevance for psychosis. We will identify eligible studies by searching multiple electronic databases. At least two independent reviewers will conduct the study selection and data extraction using prespecified forms and assess the risk of bias with the SYRCLE’s tool. Our primary outcomes include locomotor activity and prepulse inhibition measured with standardized mean differences. We will examine other behavioural readouts of relevance for psychosis as secondary outcomes, such as social interaction and cognitive function. We will synthesize the data using multi-level meta-analysis with a predefined random-effects structure, considering the non-independence of the data. In meta-regressions we will explore potential sources of heterogeneity from a predefined list of characteristics of the animal population, model, and intervention. We will assess the confidence in the evidence considering a self-developed instrument thatconsiders the internal and external validity of the evidence. Protocol registration PROSPERO-ID: CRD42024520914

An increased copy number of glycine decarboxylase (GLDC) associated with psychosis reduces extracellular glycine and impairs NMDA receptor function.

Glycine is an obligatory co-agonist at excitatory NMDA receptors in the brain, especially in the dentate gyrus, which has been postulated to be crucial for the development of psychotic associations and memories with psychotic content. Drugs modulating glycine levels are in clinical development for improving cognition in schizophrenia. However, the functional relevance of the regulation of glycine metabolism by endogenous enzymes is unclear. Using a chromosome-engineered allelic series in mice, we report that a triplication of the gene encoding the glycine-catabolizing enzyme glycine decarboxylase (GLDC) - as found on a small supernumerary marker chromosome in patients with psychosis - reduces extracellular glycine levels as determined by optical fluorescence resonance energy transfer (FRET) in dentate gyrus (DG) and suppresses long-term potentiation (LTP) in mPP-DG synapses but not in CA3-CA1 synapses, reduces the activity of biochemical pathways implicated in schizophrenia and mitochondrial bioenergetics, and displays deficits in schizophrenia-like behaviors which are in part known to be dependent on the activity of the dentate gyrus, e.g., prepulse inhibition, startle habituation, latent inhibition, working memory, sociability and social preference. Our results demonstrate that Gldc negatively regulates long-term synaptic plasticity in the dentate gyrus in mice, suggesting that an increase in GLDC copy number possibly contributes to the development of psychosis in humans.

Accumulation of mitochondrial DNA with a point mutation in tRNALeu(UUR) gene induces brain dysfunction in mice

Brain functions are mediated via the complex interplay between several complex factors, and hence, identifying the underlying cause of an abnormality within a certain brain region can be challenging. In mitochondrial disease, abnormalities in brain function are thought to be attributed to accumulation of mitochondrial DNA (mtDNA) with pathogenic mutations; however, only few previous studies have directly demonstrated that accumulation of mutant mtDNA induced abnormalities in brain function. Herein, we examined the effects of mtDNA mutations on brain function via behavioral analyses using a mouse model with an A2748G point mutation in mtDNA tRNALeu(UUR). Our results revealed that mice with a high percentage of mutant mtDNA showed a characteristic trend toward reduced prepulse inhibition and memory-dependent test performance, similar to that observed in psychiatric disorders, such as schizophrenia; however, muscle strength and motor coordination were not markedly affected. Upon examining the hippocampus and frontal lobes of the brain, mitochondrial morphology was abnormal, and the brain weight was slightly reduced. These results indicate that the predominant accumulation of a point mutation in the tRNALeu(UUR) gene may affect brain functions, particularly the coordination of sensory and motor functions and memory processes. These abnormalities probably caused by both direct effects of accumulation of the mutant mtDNA in neuronal cells and indirect effects via changes of systemic extracellular environments. Overall, these findings will lead to a better understanding of the pathogenic mechanism underlying this complex disease and facilitate the development of optimal treatment methods.

Nicotine's Effects on Schizophrenia-like Symptoms in a Mice Model: Time Matters.

Tobacco consumption in schizophrenia (SCHZ) patients is highly prevalent. Data support the occurrence of sequential events during comorbidity establishment, and both smoking first, SCHZ second and SCHZ first, smoking second sequences have been proposed. To investigate whether these two possibilities lead to distinct outcomes of comorbidity, we used a phencyclidine-induced SCHZ model and nicotine exposure as a surrogate of smoking. C57Bl/6 mice were submitted to a protocol that either began with 4 days of phencyclidine exposure or 4 days of nicotine exposure. This period was followed by 5 days of combined phencyclidine + nicotine exposure. Locomotor sensitization and pre-pulse inhibition (PPI) were assessed due to their well-known associations with SCHZ as opposed to rearing, an unrelated behavior. Nicotine priming potentiated phencyclidine-evoked sensitization. However, nicotine exposure after SCHZ modeling did not interfere with phencyclidine's effects. In the PPI test, nicotine after SCHZ modeling worsened the phencyclidine-evoked deficiency in males. In contrast, nicotine priming had no effects. Regarding rearing, nicotine priming failed to interfere with phencyclidine-mediated inhibition. Similarly, phencyclidine priming did not modify nicotine-mediated inhibition. The present results indicate that the sequence, either SCHZ-first or nicotine-first, differentially impacts comorbidity outcomes, a finding that is relevant for the identification of mechanisms of nicotine interference in the neurobiology of SCHZ.

Not a Deficit, Just Different: Prepulse Inhibition Disruptions in Autism Depend on Startle Stimulus Intensities.

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.

Inhibitory effects of prepulse stimuli on the electrophysiological responses to startle stimuli in the deep layers of the superior colliculus.

Prepulse inhibition (PPI) is a phenomenon where a weak prepulse stimulus inhibits the startle reflex to a subsequent stronger stimulus, which can be induced by various sensory stimulus modalities such as visual, tactile, and auditory stimuli. This study investigates the neural mechanisms underlying auditory PPI by focusing on the deep layers of the superior colliculus (deepSC) and the inferior colliculus (IC) in rats. Nineteen male Sprague-Dawley rats were implanted with electrodes in the left deepSC and the right IC, and electrophysiological recordings were conducted under anesthesia to observe the frequency following responses (FFRs) to startle stimuli with and without prepulse stimuli. Our results showed that in the deepSC, narrowband noise as a prepulse stimulus significantly inhibited the envelope component of the startle response, while the fine structure component remained unaffected. However, this inhibitory effect was not observed in the IC or when the prepulse stimulus was a gap. These findings suggest that the deepSC plays a crucial role in the neural circuitry of PPI, particularly in the modulation of the envelope component of the startle response. The differential effects of narrowband noise and gap as prepulse stimuli also indicate distinct neural pathways for sound-induced PPI and Gap-PPI. Understanding these mechanisms could provide insights into sensory processing and potential therapeutic targets for disorders involving impaired PPI, such as tinnitus.

Vestibular prepulse inhibition of the human blink reflex

ObjectiveAuditory and somatosensory prepulses are commonly used to assess prepulse inhibition (PPI). The effect of a vestibular prepulse upon blink reflex excitability has not been hitherto assessed. MethodsTwenty-two healthy subjects and two patients with bilateral peripheral vestibular failure took part in the study. Whole body yaw rotation in the dark provided a vestibular inertial prepulse. Blink reflex was electrically evoked after the end of the rotation. The amplitude of R1 and the area-under-the-curve (area) of the blink reflex R2 and R2c responses were recorded and analysed. ResultsA vestibular prepulse inhibited the R2 (p < 0.001) and R2c area (p < 0.05). Increasing the angular acceleration did not increase the R2 and R2c inhibition (p > 0.05). Voluntary suppression of the vestibulo-ocular reflex did not affect the magnitude of inhibition (p > 0.05). Patients with peripheral vestibular failure did not show any inhibition. ConclusionsOur data support a vestibular gating mechanism in humans. SignificanceThe main brainstem nucleus mediating PPI – the pedunculopontine nucleus (PPN) – is heavily vestibular responsive, which is consistent with our findings of a vestibular-mediated PPI. Our technique may be used to interrogate the fidelity of brain circuits mediating vestibular-related PPN functions. Given the PPN’s importance in human postural control, our technique may also provide a neurophysiological biomarker of balance.

Sex-dependent effects of Setd1a haploinsufficiency on development and adult behaviour.

Loss of function (LoF) mutations affecting the histone methyl transferase SETD1A are implicated in the aetiology of a range of neurodevelopmental disorders including schizophrenia. We examined indices of development and adult behaviour in a mouse model of Setd1a haploinsufficiency, revealing a complex pattern of sex-related differences spanning the pre- and post-natal period. Specifically, male Setd1a+/- mice had smaller placentae at E11.5 and females at E18.5 without any apparent changes in foetal size. In contrast, young male Setd1a+/- mice had lower body weight and showed enhanced growth, leading to equivalent weights by adulthood. Embryonic whole brain RNA-seq analysis revealed expression changes that were significantly enriched for mitochondria-related genes in Setd1a+/ samples. In adulthood, we found enhanced acoustic startle responding in male Setd1a+/- mice which was insentitive to the effects of risperidone, but not haloperidol, both commonly used antipsychotic drugs. We also observed reduced pre-pulse inhibition of acoustic startle, a schizophrenia-relevant phenotype, in both male and female Setd1a+/- mice which could not be rescued by either drug. In the open field and elevated plus maze tests of anxiety, Setd1a haplosufficiency led to more anxiogenic behaviour in both sexes, whereas there were no differences in general motoric ability and memory. Thus, we find evidence for changes in a number of phenotypes which strengthen the support for the use of Setd1a haploinsufficient mice as a model for the biological basis of schizophrenia. Furthermore, our data point towards possible underpinning neural and developmental mechanisms that may be subtly different between the sexes.

Investigating acoustic startle habituation and prepulse inhibition with silent functional MRI and electromyography in young, healthy adults.

Startle habituation and prepulse inhibition (PPI) are distinct measures of different sensory information processes, yet both result in the attenuation of the startle reflex. Identifying startle habituation and PPI neural mechanisms in humans has mostly evolved from acoustic-focused rodent models. Human functional magnetic resonance imaging (fMRI) studies have used tactile startle paradigms to avoid the confounding effects of gradient-related acoustic noise on auditory paradigms and blood-oxygen-level-dependent (BOLD) measures. This study aimed to examine the neurofunctional basis of acoustic startle habituation and PPI in humans with silent fMRI. Using silent fMRI and simultaneous electromyography (EMG) to measure startle, the neural correlates of acoustic short-term startle habituation and PPI [stimulus onset asynchronies (SOA) of 60 ms and 120 ms] were investigated in 42 healthy adults (28 females). To derive stronger inferences about brain-behaviour correlations at the group-level, models included EMG-assessed measures of startle habituation (regression slope) or PPI (percentage) as a covariate. A linear temporal modulator was modelled at the individual-level to characterise functional changes in neural activity during startle habituation. Over time, participants showed a decrease in startle response (habituation), accompanied by decreasing thalamic, striatal, insula, and brainstem activity. Startle habituation was associated with the linear temporal modulation of BOLD response amplitude in several regions, with thalamus, insula, and parietal lobe activity decreasing over time, and frontal lobe, dorsal striatum, and posterior cingulate activity increasing over time. The paradigm yielded a small amount of PPI (9-13%). No significant neural activity for PPI was detected. Startle habituation was associated with the thalamus, putamen, insula, and brainstem, and with linear BOLD response modulation in thalamic, striatal, insula, parietal, frontal, and posterior cingulate regions. These findings provide insight into the mediation and functional basis of the acoustic primary startle circuit. Instead, whilst reduced compared to conventional MRI, scanner noise may have disrupted prepulse detection and processing, resulting in low PPI and impacting our ability to map its neural signatures. Our findings encourage optimisation of the MRI environment for acoustic PPI-based investigations in humans. Combining EMG and functional neuroimaging methods shows promise for mapping short-term startle habituation in healthy and clinical populations.