Properties of the Caudal Pontine Reticular Nucleus Neurons Determine the Acoustic Startle Response in Cntnap2 KO Rats.

BACKGROUND: Rats with a loss-of-function mutation in the contactin-associated protein-like 2 (Cntnap2) gene have been validated as an animal model of autism spectrum disorder (ASD). Similar to many autistic individuals, Cntnap2 knock-out rats (Cntnap2-⁣/-) are hyperreactive to sound as measured through the acoustic startle response. The brainstem region that mediates the acoustic startle response is the caudal pontine reticular nucleus (PnC), specifically giant neurons in the PnC. We previously reported a sex-dependent genotypic effect in the sound-evoked neuronal activity recorded from the PnC, whereby female Cntnap2-⁣/- rats had a dramatic increase in sound-evoked responses compared with wildtype counterparts, but male Cntnap2-⁣/- rats showed only a modest increase in PnC activity that cannot fully explain the largely increased startle in male Cntnap2-⁣/- rats. The present study therefore investigates activation and histological properties of PnC giant neurons in Cntnap2-⁣/- rats and wildtype littermates. METHODS: The acoustic startle response was elicited by presenting rats with 95 dB startle pulses before rats were euthanized. PnC brain sections were stained and analyzed for the total number of PnC giant neurons and the percentage of giant neurons that expressed phosphorylated cAMP response element binding protein (pCREB) in response to startle stimuli. Additionally, in vitro electrophysiology was conducted to assess the resting state activity and intrinsic properties of PnC giant neurons. RESULTS: Wildtype and Cntnap2-⁣/- rats had similar total numbers of PnC giant neurons and similar levels of baseline pCREB expression, as well as similar numbers of giant neurons that were firing at rest. Increased startle magnitudes in Cntnap2-⁣/- rats were associated with increased percentages of pCREB-expressing PnC giant neurons in response to startle stimuli. Male rats had increased pCREB-expressing PnC giant neurons compared with female rats, and the recruited giant neurons in males were also larger in soma size. CONCLUSIONS: Recruitment and size of PnC giant neurons are important factors for regulating the magnitude of the acoustic startle response in Cntnap2-⁣/- rats, particularly in males. These findings allow for a better understanding of increased reactivity to sound in Cntnap2-⁣/- rats and in CNTNAP2-associated disorders such as ASD.

Affective processing in dysphoria: Evidence from startle probe modulation of ERPs.

The hypoactivation of the appetitive and defensive motivational systems in the brain is a feature of depression and might also represent a vulnerability factor for the disorder. A measure that can be employed to investigate both motivational systems is the electroencephalographic response to an acoustic startle probe during affective processing. Particularly, the amplitude of auditory event-related potentials (ERPs) components to the startle probe is smaller when the emotional context is more arousing. Neural responses to an unattended startle probe during an emotional passive viewing task of pleasant, neutral, and unpleasant pictures was employed to assess the activation of the approach and defensive motivational systems in a sample of individuals with (n = 24, 23 females) vs. without (n = 24, 23 females) dysphoria. The group without dysphoria showed a reduced startle-elicited N200 only in the context of pleasant relative to neutral pictures, indicating that the affective processing of the appetitive context might reduce the attentional resources needed to orient attention toward unattended non-salient stimuli. Conversely, the N200 amplitude was not attenuated for pleasant relative to neutral and unpleasant contexts in the group with dysphoria. Moreover, no within- or between-group differences emerged in the P300 amplitude. Taken together, the results of this study showed that depression vulnerability is characterized by reduced attention to pleasant contexts, suggesting a blunted affective processing of appetitive emotional stimuli.

Impact of handgun ownership and biological sex on startle reactivity to predictable and unpredictable threats.

Extant literature suggests that many individuals obtain firearms because they perceive the world as unsafe and believe that firearm ownership increases physical protection. Converging evidence suggests that firearm owners are vulnerable to uncertainty and experience chronic anticipatory anxiety in daily life; however, biological sex is thought to potentially moderate this association. Studies have yet to examine this hypothesis using objective markers of anticipatory anxiety. The present study therefore examined the impact of handgun ownership and biological sex on psychophysiological reactivity to predictable (P-) and unpredictable (U-) threat (N = 133). Male and female adult participants were classified into two groups: a) individuals who do not currently own any handguns (n = 52), and b) individuals who currently own one or more handguns (n = 81). Startle eyeblink potentiation was recorded as an index of aversive reactivity during a well-validated threat-of-shock paradigm designed to probe anticipatory anxiety (during U-threat) and fear (during P-threat). Results revealed no main effect of group on startle reactivity to P- or U-threat. Females displayed greater startle reactivity to threat (P- and U-) compared with males. The main effect was qualified by a significant group x biological sex interaction. Male handgun owners exhibited greater startle to U-threat, but not P-threat, relative to non-handgun owners. There was no effect of group on startle reactivity in females. Findings revealed that biological sex and threat type influenced threat reactivity. Male handgun owners displayed increased sensitivity to stressors that are uncertain, which may reflect an objective mechanism related to firearm ownership.

Prepulse inhibition and the call alert in emergency medical services.

In emergency medical services, paramedics are informed of an emergency call by a high-intensity acoustic alarm called the "call alert." Sudden, loud sounds like the call alert may cause a startle response and be experienced as aversive. Studies have identified an association between the call alert and adverse health effects in first responders; conceivably, these adverse health effects might be reduced by modifying the call alert to blunt its startling and aversive properties. Here, we assessed whether the call alert causes a startle response and whether its startling and aversive properties are reduced when the call alert is preceded by a weak acoustic "prepulse," a process referred to as "prepulse inhibition" (PPI). Paramedics (n = 50; 34M:13F:3 not reported; ages 20-68) were exposed to four call alerts (two with and two without a prepulse) in counterbalanced order. Responses were measured using electromyography (measuring blink amplitude), visual analog scales (quantifying perceived call alert intensity and aversiveness), and an electrocardiogram (assessing heart rate). Paramedics responded to the call alert with a startle reflex blink and an increased heart rate. Acoustic prepulses significantly reduced the amplitude of the call alert-induced startle blink, the perceived sound intensity, and the perceived "dislike" of the call alert. These findings confirm that the call alert is associated with an acoustic startle response in paramedics; adding a prepulse to the call alert can reduce its startling and aversive properties. Conceivably, such reductions might also diminish adverse health effects associated with the call alert in first responders.

Unconditioned response to a naturally aversive stimulus is associated with sensitized defensive responding and self-reported fearful traits in a PTSD sample.

Unconditioned responding (UCR) to a naturally aversive stimulus is associated with defensive responding to a conditioned threat cue (CS+) and a conditioned safety cue (CS-) in trauma-exposed individuals during fear acquisition. However, the relationships of UCR with defensive responses during extinction training, posttraumatic stress disorder (PTSD) symptom severity, and fearful traits in trauma-exposed individuals are not known. In a sample of 100 trauma-exposed adults with a continuum of PTSD severity, we recorded startle responses and skin conductance responses (SCR) during fear acquisition and extinction training using a 140 psi, 250-ms air blast to the larynx as the unconditioned stimulus. We explored dimensional associations of two different measures of UCR (unconditioned startle and unconditioned SCR) with conditioned defensive responding to CS+ and CS-, conditioned fear (CS+ minus CS-), PTSD symptom severity, and a measure of fearful traits (composite of fear survey schedule, anxiety sensitivity index, and Connor-Davidson resilience scale). Unconditioned startle was positively associated with startle potentiation to the threat cue and the safety cue across both learning phases (CS+ Acquisition, CS- Acquisition, CS+ Extinction Training, CS- Extinction Training) and with fearful traits. Unconditioned SCR was positively associated with SCR to the CS+ and CS- and SCR difference score during Acquisition. Neither type of UCR was associated with PTSD symptom severity. Our findings suggest that UCR, particularly unconditioned startle to a naturally aversive stimulus, may inform research on biomarkers and treatment targets for symptoms of pervasive and persistent fear in trauma-exposed individuals.

Attenuation of Anxiety-Potentiated Startle After Treatment With Escitalopram or Mindfulness Meditation in Anxiety Disorders.

BACKGROUND: Biological markers for anxiety disorders may further understanding of disorder pathophysiology and suggest potential targeted treatments. The fear-potentiated startle (FPS) (a measure of startle to predictable threat) and anxiety-potentiated startle (APS) (startle to unpredictable threat) laboratory paradigm has been used to detect physiological differences in individuals with anxiety disorders compared with nonanxious control individuals, and in pharmacological challenge studies in healthy adults. However, little is known about how startle may change with treatment for anxiety disorders, and no data are available regarding alterations due to mindfulness meditation training. METHODS: Ninety-three individuals with anxiety disorders and 66 healthy individuals completed 2 sessions of the neutral, predictable, and unpredictable threat task, which employs a startle probe and the threat of shock to assess moment-by-moment fear and anxiety. Between the two testing sessions, patients received randomized 8-week treatment with either escitalopram or mindfulness-based stress reduction. RESULTS: APS, but not FPS, was higher in participants with anxiety disorders compared with healthy control individuals at baseline. Further, there was a significantly greater decrease in APS for both treatment groups compared with the control group, with the patient groups showing reductions bringing them into the range of control individuals at the end of the treatment. CONCLUSIONS: Both anxiety treatments (escitalopram and mindfulness-based stress reduction) reduced startle potentiation during unpredictable (APS) but not predictable (FPS) threat. These findings further validate APS as a biological correlate of pathological anxiety and provide physiological evidence for the impact of mindfulness-based stress reduction on anxiety disorders, suggesting that there may be comparable effects of the two treatments on anxiety neurocircuitry.

Long-term impacts of prenatal maternal immune activation and postnatal maternal separation on maternal behavior in adult female rats: Relevance to postpartum mental disorders.

Early life adversities are known to exert long-term negative impacts on psychological and brain functions in adulthood. The present work examined how a prenatal brain insult and a postnatal stressor independently or interactively influence the quality of maternal care of postpartum female rats and their cognitive and emotional functions, as a way to identify the behavioral dysfunctions underlying childhood trauma-induced postpartum mental disorders (as indexed by impaired maternal care). Sprague-Dawley female offspring born from mother rats exposed to polyinosinic:polycytidylic acid (PolyI:C, 4.0-6.0 mg/kg) intended to cause gestational maternal immune activation (MIA) or saline were subjected to a repeated maternal separation stress (RMS, 3 h/day) or no separation for 9 days in the first two weeks of life (a 2 × 2 design). When these offspring became mothers, their attentional filtering ability (as measured in the prepulse inhibition of acoustic startle reflex test), positive hedonic response (as measured in the sucrose preference test), and negative emotional response (as measured in the startle reflex and fear-potentiated startle test) were examined, along with their home-cage maternal behavior. Virgin littermates served as controls in all the behavioral tests except in maternal behavior. Results showed that mother rats who experienced RMS displayed impaired nest building and crouching/nursing activities. RMS also interacted with MIA to alter pup retrieval latency and startle reactivity, such that MIA-RMS dams demonstrated significantly slower pup retrieval latency and higher startle magnitude compared to either RMS-only and MIA-only mothers. MIA also disrupted attentional filtering ability, with significantly lower prepulse inhibition. However, neither prenatal MIA nor postnatal RMS impaired sucrose preference or the acquisition of fear-potentiated startle. These results indicate that prenatal stress and postnatal adversity could impair maternal behavior individually, and interact with each other, causing impairments in attention, emotion and maternal motivation.

Testing Prepulse Inhibition of Acoustic Startle in Rodents.

Prepulse inhibition (PPI) is a measure of sensorimotor gating which is widely used in rodents to study information processing and attention dysfunction. PPI is commonly measured in rats and mice using automated equipment. Here, we present details of a PPI testing protocol extensively used in previous studies. The protocol includes a set pulse-alone startle level and prepulse-pulse combinations with varying interval and intensity. Variations of this protocol can be used depending on the experimental aim or equipment and software version.

Accessible and reliable neurometric testing in humans using a smartphone platform.

Tests of human brain circuit function typically require fixed equipment in lab environments. We have developed a smartphone-based platform for neurometric testing. This platform, which uses AI models like computer vision, is optimized for at-home use and produces reproducible, robust results on a battery of tests, including eyeblink conditioning, prepulse inhibition of acoustic startle response, and startle habituation. This approach provides a scalable, universal resource for quantitative assays of central nervous system function.

Assessing the Cntnap2 knockout rat prepulse inhibition deficit through prepulse scaling of the baseline startle response curve.

Many neurodevelopmental disorders, including autism spectrum disorder (ASD), are associated with changes in sensory processing and sensorimotor gating. The acoustic startle response and prepulse inhibition (PPI) of startle are widely used translational measures for assessing sensory processing and sensorimotor gating, respectively. The Cntnap2 knockout (KO) rat has proven to be a valid model for ASD, displaying core symptoms, including sensory processing perturbations. Here, we used a novel method to assess startle and PPI in Cntnap2 KO rats that allows for the identification of separate scaling components: startle scaling, which is a change in startle amplitude to a given sound, and sound scaling, which reflects a change in sound processing. Cntnap2 KO rats show increased startle due to both an increased overall response (startle scaling) and a left shift of the sound/response curve (sound scaling). In the presence of a prepulse, wildtype rats show a reduction of startle due to both startle scaling and sound scaling, whereas Cntnap2 KO rats show normal startle scaling, but disrupted sound scaling, resulting in the reported PPI deficit. These results validate that startle and sound scaling by a prepulse are indeed two independent processes, with only the latter being impaired in Cntnap2 KO rats. As startle scaling is likely related to motor output and sound scaling to sound processing, this novel approach reveals additional information on the possible cause of PPI disruptions in preclinical models.

Neurobehavioral impairments in ciprofloxacin- treated osteoarthritic adult rats.

Background and purpose:

Ciprofloxacin (CIP) is a broad-spectrum antibiotic widely used in clinical practice to treat musculoskeletal infections. Fluoroquinolone-induced neurotoxic adverse events have been reported in a few case reports, all the preclinical studies on its neuropsychiatric side effects involved only healthy animals. This study firstly investigated the behavioral effects of CIP in an osteoarthritis rat model with joint destruction and pain, which can simulate inflammation-associated musculoskeletal pain. Furthermore, effects of CIP on regional brain-derived neurotrophic factor (BDNF) expression were examined given its major contributions to the neuromodulation and plasticity underlying behavior and cognition. 

Fourteen days after induction of chronic osteoarthritis, animals were administered vehicle, 33 mg/kg or 100 mg/kg CIP for five days intraperitoneally. Motor activity, behavioral motivation, and psychomotor learning were examined in a reward-based behavioral test (Ambitus) on Day 4 and sensorimotor gating by the prepulse inhibition test on Day 5. Thereafter, the prolonged BDNF mRNA and protein expression levels were measured in the hippocampus and the prefrontal cortex. 

CIP dose-dependently reduced both locomotion and reward-motivated exploratory activity, accompanied with impaired learning ability. In contrast, there were no significant differences in startle reflex and sensory gating among treatment groups; however, CIP treatment reduced motor activity of the animals in this test, too. These alterations were associated with reduced BDNF mRNA and protein expression levels in the hippocampus but not the prefrontal cortex. 

This study revealed the detrimental effects of CIP treatment on locomotor activity and motivation/learning ability during osteoarthritic condition, which might be due to, at least partially, deficient hippocampal BDNF expression and ensuing impairments in neural and synaptic plasticity.

Facial EMG startle response and self-report reactions after exposure to severely underweight and severely obese body images in individuals with disordered eating: An examination of motivational responses.

Examining appetitive and aversive responses toward body image stimuli of those with disordered eating may illuminate motivational systems unique to eating pathology. The current study extended previous literature by examining self-report and startle responses to a range of body sizes. In this cross-sectional design, female, adult participants (n = 45) were sorted into disordered eating (DE; n = 22) and healthy control (HC; n = 23) groups based on Eating Disorder Examination Questionnaire global scores that were one standard deviation above or below normative values. Participants viewed eight computer-generated female body pictures from each group: severely underweight (BMI < 16.0), average (BMI 18.5-24.99), and severely obese (BMI > 40.0). Startle responses and self-reported valence and anxiety scores were collected to assess implicit and explicit reactions. 2 × 3 ANCOVA/ANOVAs were used to examine startle responses and self-report differences between groups, in response to image types. Results indicated startle responses did not differ between groups. There was a significant main effect for body picture type (p < .001), after controlling for psychotropic medication. Startle responses were higher for severely underweight body images compared to severely obese body images, although non-significant at post-hoc. The DE group reported higher levels of anxiety and sadness when viewing body images compared to the HC group. Average bodies were rated as less anxiety provoking and more positive than severely underweight and obese bodies. Group differences in anxiety and valence scores could be due to more maladaptive cognitions related to fear of weight gain among people with disordered eating.

Incidental learning of faces during threat: No evidence for enhanced physiological responses to former threat identities.

Remembering an unfamiliar person and the contextual conditions of that encounter is important for adaptive future behavior, especially in a potentially dangerous situation. Initiating defensive behavior in the presence of former dangerous circumstances can be crucial. Recent studies showed selective electrocortical processing of faces that were previously seen in a threat context compared to a safety context, however, this was not reflected in conscious recognition performance. Here, we investigated whether previously seen threat-faces, that could not be remembered, were capable to activate defensive psychophysiological response systems. During an encoding phase, 50 participants with low to moderate levels of anxiety viewed 40 face pictures with neutral expressions (6 s each), without an explicit learning instruction (incidental learning task). Each half of the faces were presented with contextual background colors that signaled either threat-of-shock or safety. In the recognition phase, all old and additional new faces (total of 60) were presented intermixed without context information. Participants had to decide whether a face was new or had been presented previously in a threatening or a safe context. Results show moderate face recognition independent of context conditions. Startle reflex and skin conductance responses (SCR) were more pronounced for threat compared to safety during encoding. For SCR, this differentiation was enhanced with higher levels of depression and anxiety. There were no differential startle reflex or SCR effects during recognition. From a clinical perspective, these findings do not support the notion that perceptual biases and physiological arousal directly relate to threat-associated identity recognition deficits in healthy and clinical participants with anxiety and trauma-related disorders.

N1-P2 event-related potentials and perceived intensity are associated: The effects of a weak pre-stimulus and attentional load on processing of a subsequent intense stimulus.

A weak stimulus presented immediately before a more intense one reduces both the N1-P2 cortical response and the perceived intensity of the intense stimulus. The former effect is referred to as cortical prepulse inhibition (PPI), the latter as prepulse inhibition of perceived stimulus intensity (PPIPSI). Both phenomena are used to study sensory gating in clinical and non-clinical populations, however little is known about their relationship. Here, we investigated 1) the possibility that cortical PPI and PPIPSI are associated, and 2) how they are affected by attentional load. Participants were tasked with comparing the intensity of an electric pulse presented alone versus one preceded 200 ms by a weaker electric prepulse (Experiment 1), or an acoustic pulse presented alone with one preceded 170 ms by a weaker acoustic prepulse (Experiment 2). A counting task (easy vs. hard) manipulating attentional load was included in Experiment 2. In both experiments, we observed a relationship between N1-P2 amplitude and perceived intensity, where greater cortical PPI was associated with a higher probability of perceiving the 'pulse with prepulse' as less intense. Moreover, higher attentional load decreased observations of PPIPSI but had no effect on N1-P2 amplitude. Based on the findings we propose that PPIPSI partially relies on the allocation of attentional resources towards monitoring cortical channels that process stimulus intensity characteristics such as the N1-P2 complex.

Effect of D-pinitol on MK-801-induced schizophrenia-like behaviors in mice.

Schizophrenia is a chronic brain disorder characterized by positive symptoms (delusions or hallucinations), negative symptoms (impaired motivation or social withdrawal), and cognitive impairment. In the present study, we explored whether D-pinitol could ameliorate schizophrenia-like behaviors induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Acoustic startle response test was conducted to evaluate the effects of D-pinitol on sensorimotor gating function. Social interaction and novel object recognition tests were employed to measure the impact of D-pinitol on social behavior and cognitive function, respectively. Additionally, we examined whether D-pinitol affects motor coordination. Western blotting was conducted to investigate the mechanism of action of D-pinitol. Single administration of D-pinitol at 30, 100, or 300 mg/kg improved the sensorimotor gating deficit induced by MK801 in the acoustic startle response test. D-Pinitol also reversed social behavior deficits and cognitive impairments induced by MK-801 without causing any motor coordination deficits. Furthermore, D-pinitol reversed increased expression levels of pNF-kB induced by MK-801 treatment and consequently increased expression levels of TNF-α and IL-6 in the prefrontal cortex. These results suggest that D-pinitol could be a potential candidate for treating sensorimotor gating deficits and cognitive impairment observed in schizophrenia by down-regulating transcription factor NF-κB and pro-inflammatory cytokines in the prefrontal cortex.

Understanding Human Fear Extinction: Insights from Psychophysiology.

The study of fear extinction has been driven largely by Pavlovian fear conditioning methods across the translational spectrum. The primary methods used to study these processes in humans have been recordings of skin conductance (historically termed galvanic skin response) and fear-potentiation of the acoustic startle reflex. As outlined in the following chapter, the combined corpus of this work has demonstrated the value of psychophysiology in better understanding the underlying neurobiology of extinction learning in healthy humans as well as those with psychopathologies. In addition, psychophysiological approaches, which allow for the preservation of methods between species, have shown their applicability to the assessment of wide-ranging treatment effects. The chapter concludes with potential trajectories for future study in this area.

The interactive effects of different facets of threat uncertainty and cognitive load in shaping fear and anxiety responses.

A large body of research indicates that exaggerated response to uncertainty of a future threat is at the core of anxiety and related disorders, underscoring the need for a better understanding of the underlying mechanisms. Although behavioral and neuroimaging studies have suggested a close relationship between uncertainty responses and cognitive control, little is known about what elements of uncertainty are more or less vulnerable to cognitive modulation in shaping aversive responses. Leveraging a novel paradigm, an n-back working memory task embedded within a modified threat-of-shock paradigm, we examined how the influences of different facets of uncertainty (i.e., occurrence and timing) on psychophysiological responses were modulated by cognitive load. Psychophysiological responses were assessed using the acoustic startle reflex. Replicating prior work, the effects of cognitive load and temporal unpredictability of threat on startle responses were evident. The effect of occurrence unpredictability appears to depend on other factors. Under low cognitive load, startle response was potentiated when both the occurrence and the timing of threat were predictable. Under high cognitive load, startle response was significantly reduced, especially when a threat context involves uncertainty in both temporal and probability domains. These observations provide a framework for refining the model of fear and anxiety and for understanding the etiology of psychological disorders characterized by maladaptive uncertainty responses.

Prepulse inhibition deficit as a transdiagnostic process in neuropsychiatric disorders: a systematic review.

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.

Recent advances in studying brain-behavior interactions using functional imaging: The primary startle response pathway and its affective modulation in humans.

The startle response is a cross-species defensive reflex that is considered a key tool for cross-species translational emotion research. While the neural pathway mediating (affective) startle modulation has been extensively studied in rodents, human work on brain-behavior interactions has lagged in the past due to technical challenges, which have only recently been overcome through non-invasive simultaneous EMG-fMRI assessments. We illustrate key paradigms and methodological tools for startle response assessment in rodents and humans and review evidence for primary and modulatory neural circuits underlying startle responses and their affective modulation in humans. Based on this, we suggest a refined and integrative model for primary and modulatory startle response pathways in humans concluding that there is strong evidence from human work on the neurobiological pathway underlying the primary startle response while evidence for the modulatory pathway is still sparse. In addition, we provide methodological considerations to guide future work and provide an outlook on new and exciting perspectives enabled through technical and theoretical advances outlined in this work.

Evaluation of Sensorimotor Gating Deficits in Mice Through Prepulse Inhibition (PPI) of the Startle Response.

Prepulse inhibition of the startle response enables measuring animal behavior and helps us understand core aspects of neuropsychiatric diseases. Prepulse inhibition is considered a translational indicator of sensorimotor gating deficits present in schizophrenia patients and is crucial in the characterization of animal models of schizophrenia-like behaviors. Hallucinogenic drugs acting through 5-HT2A receptors, such as psilocybin, lysergic acid diethylamide (LSD), and dimethoxyiodoamphetamine (DOI), produce symptoms in healthy subjects comparable to those seen in schizophrenia and can be used in rodent models for mimicking some of these behaviors. Here we describe a protocol for the evaluation of prepulse inhibition of the startle response in CD1-Swiss male mice after a single dose of the hallucinogenic drug DOI.