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Journal of Visualized Experiments : JoVE Jan 2024We developed a simple screening system for the evaluation of neuromuscular and general toxicity in zebrafish embryos. The modular system consists of electrodynamic...
We developed a simple screening system for the evaluation of neuromuscular and general toxicity in zebrafish embryos. The modular system consists of electrodynamic transducers above which tissue culture dishes with embryos can be placed. Multiple such loudspeaker-tissue culture dish pairs can be combined. Vibrational stimuli generated by the electrodynamic transducers induce a characteristic startle and escape response in the embryos. A belt-driven linear drive sequentially positions a camera above each loudspeaker to record the movement of the embryos. In this way, alterations to the startle response due to lethality or neuromuscular toxicity of chemical compounds can be visualized and quantified. We present an example of the workflow for chemical compound screening using this system, including the preparation of embryos and treatment solutions, operation of the recording system, and data analysis to calculate benchmark concentration values of compounds active in the assay. The modular assembly based on commercially available simple components makes this system both economical and flexibly adaptable to the needs of particular laboratory setups and screening purposes.
Topics: Animals; Zebrafish; Reflex, Startle; Vibration; Movement; Biological Assay; Embryo, Nonmammalian
PubMed: 38284527
DOI: 10.3791/66153 -
Translational Psychiatry Jan 2024Pavlovian fear conditioning is widely used as a pre-clinical model to investigate methods for prevention and treatment of anxiety and stress-related disorders. In this... (Randomized Controlled Trial)
Randomized Controlled Trial
Pavlovian fear conditioning is widely used as a pre-clinical model to investigate methods for prevention and treatment of anxiety and stress-related disorders. In this model, fear memory consolidation is thought to require synaptic remodeling, which is induced by signaling cascades involving matrix metalloproteinase 9 (MMP-9). Here we investigated the effect of the tetracycline antibiotic minocycline, an inhibitor of MMP-9, on fear memory retention. We conducted a pre-registered, randomized, double-blind, placebo-controlled trial in N = 105 healthy humans (N = 70 female), using a configural fear conditioning paradigm. We administered a single dose of minocycline before configural fear memory acquisition and assessed fear memory retention seven days later in a recall test. To index memory retention, we pre-registered fear-potentially startle (FPS) as our primary outcome, and pupil dilation as the secondary outcome. As control indices of memory acquisition, we analyzed skin conductance responses (SCR) and pupil dilation. We observed attenuated retention of configural fear memory in individuals treated with minocycline compared to placebo, as measured by our primary outcome. In contrast, minocycline did not affect fear memory acquisition or declarative contingency memory. Our findings provide in-vivo evidence for the inhibition of fear memory consolidation by minocycline. This could motivate further research into primary prevention, and given the short uptake time of minocycline, potentially also secondary prevention of PTSD after trauma.
Topics: Humans; Female; Minocycline; Matrix Metalloproteinase 9; Memory; Fear; Mental Recall; Extinction, Psychological; Reflex, Startle
PubMed: 38233395
DOI: 10.1038/s41398-024-02732-2 -
Psychophysiology Mar 2024Individual differences in reactivity to unpredictable threat (U-threat) have repeatedly been linked to symptoms of anxiety and drinking behavior. An emerging theory is...
Individual differences in reactivity to unpredictable threat (U-threat) have repeatedly been linked to symptoms of anxiety and drinking behavior. An emerging theory is that individuals who are hyper-reactive to U-threat experience chronic anticipatory anxiety, hyperarousal, and are vulnerable to excessive alcohol use via negative reinforcement processes. Notably, anxiety and alcohol use commonly relate to disruptions in sleep behavior and recent findings suggest that sleep quality may impact the link between reactivity to U-threat and psychiatric symptoms and behaviors. The aim of the current study was to examine the unique and interactive effects of reactivity to U-threat and sleep quality on anxiety symptoms and drinking behavior in a cohort of youth, ages 16-19 years. Participants (N = 112) completed a well-validated threat-of-shock task designed to probe individual differences in reactivity to U-threat and predictable threat (P-threat). Startle eyeblink potentiation was recorded during the task as an index of aversive reactivity. Participants also completed well-validated self-report measures of anxiety and depression symptoms, lifetime alcohol use, and current sleep quality. Results revealed significant startle reactivity to U-threat by sleep quality interactions on anxiety symptoms and lifetime drinking behavior. At high levels of sleep disturbance (only), greater reactivity to U-threat was associated with greater anxiety symptoms and total number of lifetime alcoholic beverages. These results suggest that sensitivity to uncertainty and chronic hyperarousal increases anxiety symptoms and alcohol use behavior, particularly in the context of poor sleep quality.
Topics: Humans; Adolescent; Sleep Quality; Uncertainty; Anxiety; Anxiety Disorders; Alcohol Drinking; Reflex, Startle
PubMed: 38217499
DOI: 10.1111/psyp.14490 -
ELife Jan 2024No preclinical experimental approach enables the study of voluntary oral consumption of high-concentration Δ-tetrahydrocannabinol (THC) and its intoxicating effects,...
No preclinical experimental approach enables the study of voluntary oral consumption of high-concentration Δ-tetrahydrocannabinol (THC) and its intoxicating effects, mainly owing to the aversive response of rodents to THC that limits intake. Here, we developed a palatable THC formulation and an optimized access paradigm in mice to drive voluntary consumption. THC was formulated in chocolate gelatin (THC-E-gel). Adult male and female mice were allowed ad libitum access for 1 and 2 hr. Cannabimimetic responses (hypolocomotion, analgesia, and hypothermia) were measured following access. Levels of THC and its metabolites were measured in blood and brain tissue. Acute acoustic startle responses were measured to investigate THC-induced psychotomimetic behavior. When allowed access for 2 hr to THC-E-gel on the second day of a 3-day exposure paradigm, adult mice consumed up to ≈30 mg/kg over 2 hr, which resulted in robust cannabimimetic behavioral responses (hypolocomotion, analgesia, and hypothermia). Consumption of the same gelatin decreased on the following third day of exposure. Pharmacokinetic analysis shows that THC-E-gel consumption led to parallel accumulation of THC and its psychoactive metabolite, 11-OH-THC, in the brain, a profile that contrasts with the known rapid decline in brain 11-OH-THC levels following THC intraperitoneal (i.p.) injections. THC-E-gel consumption increased the acoustic startle response in males but not in females, demonstrating a sex-dependent effect of consumption. Thus, while voluntary consumption of THC-E-gel triggered equivalent cannabimimetic responses in male and female mice, it potentiated acoustic startle responses preferentially in males. We built a dose-prediction model that included cannabimimetic behavioral responses elicited by i.p. versus THC-E-gel to test the accuracy and generalizability of this experimental approach and found that it closely predicted the measured acoustic startle results in males and females. In summary, THC-E-gel offers a robust preclinical experimental approach to study cannabimimetic responses triggered by voluntary consumption in mice, including sex-dependent psychotomimetic responses.
Topics: Mice; Male; Female; Animals; Dronabinol; Reflex, Startle; Hypothermia; Gelatin; Behavior, Animal
PubMed: 38214701
DOI: 10.7554/eLife.89867 -
International Journal of... Mar 2024Extant literature suggests that many individuals obtain firearms because they perceive the world as unsafe and believe that firearm ownership increases physical...
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.
Topics: Adult; Humans; Male; Female; Ownership; Anxiety; Fear; Mental Disorders; Reflex, Startle
PubMed: 38185419
DOI: 10.1016/j.ijpsycho.2024.112297 -
The Journal of Physiology Jan 2024Bilateral hand movements are assumed to be coordinated by a neural coupling mechanism. Neural coupling is experimentally reflected in complex electromyographic (EMG)...
Bilateral hand movements are assumed to be coordinated by a neural coupling mechanism. Neural coupling is experimentally reflected in complex electromyographic (EMG) responses in the forearm muscles of both sides to unilateral electrical arm nerve stimulation (ES). The aim of this study was to examine a potential involvement of the reticulospinal system in neural coupling by the application of loud acoustic stimuli (LAS) known to activate neurons of this system. LAS, ES and combined LAS/ES were applied to healthy subjects during visually guided bilateral hand flexion-extension movements. Muscle responses to the different stimuli were evaluated by electrophysiological recordings. Unilateral electrical ulnar nerve stimulation resulted in neural coupling responses in the forearm extensors (FE) of both sides. Interestingly, LAS evoked bilateral EMG responses that were similar in their configuration to those induced by ES. The presence of startles was associated with a shift of the onset and enhanced amplitude of LAS-induced coupling-like responses. Upon combined LAS/ES application, ES facilitated ipsilateral startles and coupling-like responses. Modulation of coupling-like responses by startles, the similarity of the responses to ES and LAS, and their interaction following combined stimulation suggests that both responses are mediated by the reticulospinal system. Our findings provide novel indirect evidence that the reticulospinal system is involved in the neural coupling of hand movements. This becomes clinically relevant in subjects with a damaged corticospinal system where a dominant reticulospinal system leads to involuntary limb coupling, referred to as associated movements. KEY POINTS: Automatic coordination of hand movements is assumed to be mediated by a neural coupling mechanism reflected by bilateral reflex responses in forearm muscles to unilateral electrical arm nerve stimulation (ES). Loud acoustic stimuli (LAS) were applied to assess a potential involvement of the reticulospinal system in the neural coupling mechanism. LAS evoked a bilateral reflex response in the forearm extensors that was similar to the neural coupling response to ES, and which could be separated from the acoustic startle response. Combined application of LAS and ES resulted in a facilitation of startle and coupling-like responses ipsilateral to ES, thus indicating an interaction of afferences from both stimuli. These novel findings provide indirect evidence that the reticulospinal system is a key motor structure for the coupling of bilateral hand movements.
Topics: Humans; Reflex, Startle; Electromyography; Movement; Muscle, Skeletal; Brain Stem
PubMed: 38178603
DOI: 10.1113/JP285403 -
Psychophysiology May 2024In 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...
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.
Topics: Humans; Prepulse Inhibition; Reflex, Startle; Acoustic Stimulation; Electromyography; Emergency Medical Services
PubMed: 38164815
DOI: 10.1111/psyp.14508 -
Frontiers in Behavioral Neuroscience 2023Noise-induced tinnitus is generally associated with hearing impairment caused by traumatic acoustic overexposure. Previous studies in laboratory animals and human...
Noise-induced tinnitus is generally associated with hearing impairment caused by traumatic acoustic overexposure. Previous studies in laboratory animals and human subjects, however, have observed differences in tinnitus susceptibility, even among individuals with similar hearing loss. The mechanisms underlying increased sensitivity or, conversely, resistance to tinnitus are still incompletely understood. Here, we used behavioral tests and ABR audiometry to compare the sound-evoked responses of mice that differed in the presence of noise-induced tinnitus. The aim was to find a specific pre-exposure neurophysiological marker that would predict the development of tinnitus after acoustic trauma. Noise-exposed mice were screened for tinnitus-like behavior with the GPIAS paradigm and subsequently divided into tinnitus (+T) and non-tinnitus (-T) groups. Both groups showed hearing loss after exposure, manifested by elevated audiometric thresholds along with reduced amplitudes and prolonged latencies of ABR waves. Prior to exposure, except for a slightly increased slope of growth function for ABR amplitudes in +T mice, the two groups did not show significant audiometric differences. Behavioral measures, such as the magnitude of the acoustic startle response and its inhibition by gap pre-pulse, were also similar before exposure in both groups. However, +T mice showed significantly increased suppression of the acoustic startle response in the presence of background noise of moderate intensity. Thus, increased modulation of startle by background sounds may represent a behavioral correlate of susceptibility to noise-induced tinnitus, and its measurement may form the basis of a simple non-invasive method for predicting tinnitus development in laboratory rodents.
PubMed: 38144362
DOI: 10.3389/fnbeh.2023.1321277 -
Behavioural Brain Research Mar 2024Early 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...
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.
Topics: Humans; Pregnancy; Rats; Animals; Female; Rats, Sprague-Dawley; Maternal Deprivation; Mental Disorders; Reflex, Startle; Postpartum Period; Maternal Behavior; Sucrose; Prenatal Exposure Delayed Effects; Behavior, Animal
PubMed: 38142861
DOI: 10.1016/j.bbr.2023.114831 -
Scientific Reports Dec 2023Tests of human brain circuit function typically require fixed equipment in lab environments. We have developed a smartphone-based platform for neurometric testing. This...
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.
Topics: Humans; Reflex, Startle; Smartphone; Acoustic Stimulation; Prepulse Inhibition; Habituation, Psychophysiologic
PubMed: 38129487
DOI: 10.1038/s41598-023-49568-2