ABSTRACT
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.
Subject(s)
Emergency Medical Services , Prepulse Inhibition , Humans , Reflex, Startle/physiology , Acoustic Stimulation , ElectromyographyABSTRACT
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-â£/-) 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-â£/- rats had a dramatic increase in sound-evoked responses compared with wildtype counterparts, but male Cntnap2-â£/- rats showed only a modest increase in PnC activity that cannot fully explain the largely increased startle in male Cntnap2-â£/- rats. The present study therefore investigates activation and histological properties of PnC giant neurons in Cntnap2-â£/- 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-â£/- 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-â£/- 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-â£/- rats, particularly in males. These findings allow for a better understanding of increased reactivity to sound in Cntnap2-â£/- rats and in CNTNAP2-associated disorders such as ASD.
Subject(s)
Autism Spectrum Disorder , Reflex, Startle , Animals , Female , Male , Rats , Acoustic Stimulation , Neurons/physiology , Reflex, Startle/genetics , Reflex, Startle/physiology , Reticular Formation/physiology , Disease Models, AnimalABSTRACT
This review investigated which patterns of thyroid- and brain-related effects are seen in rats upon gestational/lactational exposure to 14 substances causing thyroid hormone imbalance by four different modes-of-action (inhibition of thyroid peroxidase, sodium-iodide symporter and deiodinase activities, enhancement of thyroid hormone clearance) or to dietary iodine deficiency. Brain-related parameters included motor activity, cognitive function, acoustic startle response, hearing function, periventricular heterotopia, electrophysiology and brain gene expression. Specific modes-of-action were not related to specific patterns of brain-related effects. Based upon the rat data reviewed, maternal serum thyroid hormone levels do not show a causal relationship with statistically significant neurodevelopmental effects. Offspring serum thyroxine together with offspring serum triiodothyronine and thyroid stimulating hormone appear relevant to predict the likelihood for neurodevelopmental effects. Based upon the collated database, thresholds of ≥60%/≥50% offspring serum thyroxine reduction and ≥20% and statistically significant offspring serum triiodothyronine reduction indicate an increased likelihood for statistically significant neurodevelopmental effects; accuracies: 83% and 67% when excluding electrophysiology (and gene expression). Measurements of brain thyroid hormone levels are likely relevant, too. The extent of substance-mediated thyroid hormone imbalance appears more important than substance mode-of-action to predict neurodevelopmental impairment in rats. Pertinent research needs were identified, e.g. to determine whether the phenomenological offspring thyroid hormone thresholds are relevant for regulatory toxicity testing. The insight from this review shall be used to suggest a tiered testing strategy to determine whether gestational/lactational substance exposure may elicit thyroid hormone imbalance and potentially also neurodevelopmental effects.
Subject(s)
Endocrine System Diseases , Thyroid Gland , Pregnancy , Female , Rats , Animals , Triiodothyronine/metabolism , Triiodothyronine/pharmacology , Thyroxine/metabolism , Thyroxine/pharmacology , Lactation , Reflex, Startle , Thyroid HormonesABSTRACT
Polychlorinated biphenyls (PCBs) are toxic environmental pollutants. Humans are exposed to PCB mixtures via contaminated food or water. PCB exposure causes adverse effects in adults and after exposure in utero. PCB toxicity depends on the congener mixture and CYP1A2 gene activity. For coplanar PCBs, toxicity depends on ligand affinity for the aryl hydrocarbon receptor (AHR). Previously, we found that perinatal exposure of mice to a three-coplanar/five-noncoplanar PCB mixture induced deficits in novel object recognition and trial failures in the Morris water maze in Cyp1a2-/- ::Ahrb1 C57BL6/J mice compared with wild-type mice (Ahrb1 = high AHR affinity). Here we exposed gravid Cyp1a2-/- ::Ahrb1 mice to a PCB mixture on embryonic day 10.5 by gavage and examined the F1 and F3 offspring (not F2 ). PCB-exposed F1 mice exhibited increased open-field central time, reduced acoustic startle, greater conditioned contextual freezing and reduced CA1 hippocampal long-term potentiation with no change in spatial learning or memory. F1 mice also had inhibited growth, decreased heart rate and cardiac output, and impaired fertility. F3 mice showed few effects. Gene expression changes were primarily in F1 PCB males compared with wild-type males. There were minimal RNA and DNA methylation changes in the hippocampus from F1 to F3 with no clear relevance to the functional effects. F0 PCB exposure during a period of rapid DNA de-/remethylation in a susceptible genotype produced clear F1 effects with little evidence of transgenerational effects in the F3 generation. While PCBs show clear developmental neurotoxicity, their effects do not persist across generations for effects assessed herein.
Subject(s)
Cytochrome P-450 CYP1A2/metabolism , Environmental Pollutants/toxicity , Fertility/drug effects , Long-Term Potentiation/drug effects , Polychlorinated Biphenyls/toxicity , Prenatal Exposure Delayed Effects/chemically induced , Reflex, Startle/drug effects , Spatial Memory/drug effects , Animals , CA1 Region, Hippocampal/drug effects , CA1 Region, Hippocampal/physiopathology , Conditioning, Classical , Cytochrome P-450 CYP1A2/genetics , Female , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/drug effects , Pregnancy , Prenatal Exposure Delayed Effects/enzymology , Prenatal Exposure Delayed Effects/physiopathology , Prenatal Exposure Delayed Effects/psychologyABSTRACT
Prepulse inhibition (PPI) and habituation of the acoustic startle response (ASR) are considered to be effective neurobiological measures of sensorimotor gating and information processing. The deficit of PPI and habituation of ASR has been proposed to be candidate endophenotypes of schizophrenia spectrum disorders. However, there has been little information on PPI and ASR measures in Chinese. The present study aimed to provide more information about the characteristics of PPI and ASR in young healthy Chinese and investigate their sensitivity to experimental parameters and characteristics of population. In this study, we examined the PPI and habituation of ASR in 41 young healthy adults (21 males and 20 females), using an acoustic startle stimulus of 115 dB and a prepulse of 75 dB at a lead interval (LI) of 60 ms and 120 ms, respectively. The behavioral performance demonstrated that the PPI and habituation of ASR in all the young participants were robust. The significant difference was not observed in PPI and habituation between male and female. The block effect on PPI was significant; PPI reduces with increasing training. Latency facilitation was observed under prepulse conditions, with a significant effect of LI. Compared to previous studies in Caucasians, Chinese in this study shows a higher habituation and PPI. In conclusion, this research provides more data of behavioral characteristics of PPI and ASR in young healthy Chinese. Chinese in this study shows a higher habituation and PPI than Caucasians in previous studies.
Subject(s)
Prepulse Inhibition , Schizophrenia , Acoustic Stimulation , Asian People , Female , Humans , Male , Reflex, StartleABSTRACT
Hearing is an essential sense for communication in animals and humans. Normal function of the cochlea of higher vertebrates relies on a fine-tuned interplay of afferent and efferent innervation of both inner and outer hair cells. Efferent inhibition is controlled via olivocochlear feedback loops, mediated mainly by acetylcholine, γ-aminobutyric acid (GABA) and glycine, and is one of the first sites affected by synapto- and neuropathy in the development of hearing loss. While the functions of acetylcholine, GABA and other inhibitory transmitters within these feedback loops are at least partially understood, especially the function of glycine still remains elusive. To address this question, we investigated hearing in glycine receptor (GlyR) α3 knockout (KO) and wildtype (WT) mice. We found no differences in pure tone hearing thresholds at 11.3 and 16 kHz between the two groups as assessed by auditory brainstem response (ABR) measurements. Detailed analysis of the ABR waves at 11.3 kHz, however, revealed a latency decrease of wave III and an amplitude increase of wave IV in KO compared to WT animals. GlyRα3 KO animals showed significantly impaired prepulse inhibition of the auditory startle response in a noisy environment, indicating that GlyRα3-mediated glycinergic inhibition is important for signal-in-noise detection.
Subject(s)
Auditory Threshold , Evoked Potentials, Auditory, Brain Stem , Receptors, Glycine/genetics , Animals , Hair Cells, Auditory, Outer/metabolism , Hair Cells, Auditory, Outer/physiology , Male , Mice , Mice, Inbred C57BL , Reaction Time , Receptors, Glycine/metabolism , Reflex, Acoustic , Reflex, StartleABSTRACT
Although a large portion of the population is exposed to a traumatic event at some point, only a small percentage of the population develops post-traumatic stress disorder (PTSD), suggesting the presence of predisposing factors. Abnormal acoustic startle response (ASR) has been shown to be associated with PTSD, implicating it as a potential predictor of the development of PTSD-like behavior. Since poor extinction and retention of extinction learning are characteristic of PTSD patients, it is of interest to determine if abnormal ASR is predictive of development of such deficits. To determine whether baseline ASR has utility in predicting the development of PTSD-like behavior, the relationship between baseline ASR and freezing behavior following Pavlovian fear conditioning was examined in a group of adult, male Sprague-Dawley rats. Baseline acoustic startle response (ASR) was assessed preceding exposure to a Pavlovian fear conditioning paradigm where freezing behavior was measured during fear conditioning, extinction training, and extinction testing. Although there was no relationship between baseline ASR and fear memory following conditioning, rats with low baseline ASR had significantly lower magnitude of retention of the extinction memory than rats with high baseline ASR. The results suggest that baseline ASR has value as a predictive index of the development of a PTSD-like phenotype.
Subject(s)
Conditioning, Classical/physiology , Extinction, Psychological/physiology , Fear/physiology , Individuality , Reflex, Startle/physiology , Acoustic Stimulation , Animals , Freezing Reaction, Cataleptic/physiology , Male , Rats , Rats, Sprague-DawleyABSTRACT
Toxoplasma gondii (TOXO) is a neuroinvasive protozoan parasite that induces the formation of persistent cysts in mammalian brains. It infects approximately 1.1million people in the United States annually. Latent TOXO infection is implicated in the etiology of psychiatric disorders, especially schizophrenia (SCZ), and has been correlated with modestly impaired cognition. The acoustic startle response (ASR) is a reflex seen in all mammals. It is mediated by a simple subcortical circuit, and provides an indicator of neural function. We previously reported the association of TOXO with slowed acoustic startle latency, an index of neural processing speed, in a sample of schizophrenia and healthy control subjects. The alterations in neurobiology with TOXO latent infection may not be specific to schizophrenia. Therefore we examined TOXO in relation to acoustic startle in an urban, predominately African American, population with mixed psychiatric diagnoses, and healthy controls. Physiological and diagnostic data along with blood samples were collected from 364 outpatients treated at an inner-city hospital. TOXO status was determined with an ELISA assay for TOXO-specific IgG. A discrete titer was calculated based on standard cut-points as an indicator of seropositivity, and the TOXO-specific IgG concentration served as serointensity. A series of linear regression models were used to assess the association of TOXO seropositivity and serointensity with ASR magnitude and latency in models adjusting for demographics and psychiatric diagnoses (PTSD, major depression, schizophrenia, psychosis, substance abuse). ASR magnitude was 11.5% higher in TOXO seropositive subjects compared to seronegative individuals (p=0.01). This effect was more pronounced in models with TOXO serointensity that adjusted for sociodemographic covariates (F=7.41, p=0.0068; F=10.05, p=0.0017), and remained significant when psychiatric diagnoses were stepped into the models. TOXO showed no association with startle latency (t=0.49, p=0.63) in an unadjusted model, nor was TOXO associated with latency in models that included demographic factors. After stepping in individual psychiatric disorders, we found a significant association of latency with a diagnosis of PTSD (F=5.15, p=0.024), but no other psychiatric diagnoses, such that subjects with PTSD had longer startle latency. The mechanism by which TOXO infection is associated with high startle magnitude is not known, but possible mechanisms include TOXO cyst burden in the brain, parasite recrudescence, or molecular mimicry of a host epitope by TOXO. Future studies will focus on the neurobiology underlying the effects of latent TOXO infection as a potential inroad to the development of novel treatment targets for psychiatric disease.
Subject(s)
Reflex, Startle/immunology , Social Environment , Toxoplasma/immunology , Toxoplasmosis/immunology , Urban Population , Acoustic Stimulation , Adult , Black or African American , Female , Humans , Male , Middle AgedABSTRACT
INTRODUCTION: Understanding the extent to which murine models of traumatic brain injury (TBI) replicate clinically relevant neurologic outcomes is critical for mechanistic and therapeutic studies. We determined sensorimotor outcomes in a mouse model of TBI and validated the use of a standardized neurologic examination scoring system to quantify the extent of injury. MATERIALS AND METHODS: We used a lateral fluid percussion injury model of TBI and compared TBI animals to those that underwent sham surgery. We measured neurobehavioral deficits using a standardized 12-point neurologic examination, magnetic resonance imaging, a rotating rod test, and longitudinal acoustic startle testing. RESULTS: TBI animals had a significantly decreased ability to balance on a rotating rod and a marked reduction in the amplitude of acoustic startle response. The neurologic examination had a high inter-rater reliability (87% agreement) and correlated with latency to fall on a rotating rod (Rs = -0.809). CONCLUSIONS: TBI impairs sensorimotor function in mice, and the extent of impairment can be predicted by a standardized neurologic examination.
Subject(s)
Brain Injuries, Traumatic/physiopathology , Animals , Brain Injuries, Traumatic/diagnosis , Brain Injuries, Traumatic/psychology , Injury Severity Score , Magnetic Resonance Imaging , Male , Mice , Mice, Inbred C57BL , Neurologic Examination , Neuropsychological Tests , Observer Variation , Postural Balance , Random Allocation , Reflex, StartleABSTRACT
Previous studies suggest an inhibitory top-down control of the amygdala by the prefrontal cortex (PFC). Both brain regions play a role in the modulation of prepulse modification (PPM) of the acoustic startle response by a pre-stimulus. Repetitive transcranial magnetic stimulation (rTMS) can modulate the activity of the PFC and might thus affect PPM. This study tested the effect of inhibitory rTMS on PPM accounting for a genetic variant of the dopamine transporter gene (DAT1). Healthy participants (N = 102) were stimulated with continuous theta burst stimulation (cTBS, an intense form of inhibitory rTMS) or sham treatment over the right PFC. Afterwards, during continuous presentation of a background white noise a louder noise burst was presented either alone (control startle) or preceded by a prepulse. Participants were genotyped for a DAT1 variable number tandem repeat (VNTR) polymorphism. Two succeeding sessions of cTBS over the right PFC (2 × 600 stimuli with a time lag of 15 min) attenuated averaged prepulse inhibition (PPI) in participants with a high resting motor threshold. An attenuation of PPI induced by prepulses with great distances to the pulse (480, 2000 ms) was observed following active cTBS in participants that were homozygous carriers of the 10-repeat-allele of the DAT1 genotype and had a high resting motor threshold. Our results confirm the importance of the prefrontal cortex for the modulation of PPM. The effects were observed in participants with a high resting motor threshold only, probably because they received a higher dose of cTBS. The effects in homozygous carriers of the DAT1 10-repeat allele confirm the relevance of dopamine for PPM. Conducting an exploratory study we decided against the use of a correction for multiple testing.
Subject(s)
Dopamine Plasma Membrane Transport Proteins/genetics , Evoked Potentials, Motor/physiology , Prefrontal Cortex/physiology , Prepulse Inhibition/physiology , Reflex, Startle/physiology , Theta Rhythm/physiology , Transcranial Magnetic Stimulation/methods , Adult , Female , Genotype , Humans , Male , Minisatellite Repeats , Polymorphism, Genetic , Young AdultABSTRACT
Repetitive transcranial magnetic stimulation (rTMS) enables the local and non-invasive modulation of cortical activity and has proved to achieve antidepressant effects. To a lesser extent, rTMS is investigated as a treatment option for anxiety disorders. As the prefrontal cortex and the amygdala represent key components of human emotion regulation, we investigated how prefrontally applied rTMS affects the responsiveness of the subcortical amygdala during a fear-relevant study paradigm to examine potential cortico-limbic effects. Sham-controlled, randomised inhibitory rTMS (continuous theta burst stimulation, TBS) was applied to 102 healthy subjects (female = 54) over the right dorsolateral prefrontal cortex. Subsequently, the emotion-potentiated (unpleasant, neutral, and pleasant International Affective Picture System pictures) acoustic startle response was investigated. Subjective anxiety ratings (anxiety sensitivity, trait and state anxiety) were considered. Picture category affected the startle magnitude as expected for both TBS intervention groups (highest startle response for unpleasant, lowest for pleasant pictures). However, no modulatory effects of TBS on startle potentiation were discerned. No significant interaction effects of TBS intervention, subjective anxiety ratings, and gender were identified. Interestingly, startle habituation was influenced by TBS intervention on a trend-level, with verum TBS leading to an accelerated habituation. We found no evidence for the hypothesis that prefrontal inhibitory TBS affects the responsiveness of the amygdala during the presentation of emotionally relevant stimuli in healthy subjects. Instead, we found accelerated habituation under verum TBS on a statistical trend-level. Hence, some preliminary hints for modulatory effects of inhibitory TBS on basic learning mechanisms could be found.
Subject(s)
Emotions/physiology , Prefrontal Cortex/physiology , Reflex, Startle/physiology , Theta Rhythm/physiology , Transcranial Magnetic Stimulation , Acoustic Stimulation , Adult , Analysis of Variance , Female , Healthy Volunteers , Humans , Male , Psychiatric Status Rating Scales , Sex Factors , Young AdultABSTRACT
We developed and tested a novel hardware-and-software system for recording the amplitude of the acoustic startle response in rodents. In our experiments, the baseline indexes of acoustic startle response in laboratory rats and pre-stimulation inhibition under the standard delivery of acoustic stimulation were similar to those evaluated by other investigators on foreign devices. The proposed system is relatively cheap and provides the possibility of performing experiments on freely moving specimens. It should be emphasized that the results of studies can be processed with free-access software.
Subject(s)
Acoustic Stimulation/methods , Action Potentials/physiology , Reflex, Startle/physiology , Animals , Male , Rats , Rats, Wistar , SoftwareABSTRACT
Perceptual abnormalities such as hyperacusis and tinnitus often occur after acoustic overexposure. Although such exposure can also result in permanent threshold elevation, some individuals with noise-induced hyperacusis or tinnitus show clinically normal thresholds. Recent work in animals has shown that a "neuropathic" noise exposure can cause immediate, permanent degeneration of the cochlear nerve despite complete threshold recovery and lack of hair cell damage (Kujawa SG, Liberman MC. J Neurosci 29: 14077-14085, 2009; Lin HW, Furman AC, Kujawa SG, Liberman MC. J Assoc Res Otolaryngol 12: 605-616, 2011). Here we ask whether this noise-induced primary neuronal degeneration results in abnormal auditory behavior, based on the acoustic startle response (ASR) and prepulse inhibition (PPI) of startle. Responses were measured in mice exposed either to a "neuropathic" noise or to a lower-intensity, "nonneuropathic" noise and in unexposed control mice. Mice with cochlear neuropathy displayed hyperresponsivity to sound, evidenced by enhanced ASR and PPI, while exposed mice without neuronal loss showed control-like responses. Gap PPI tests, often used to assess tinnitus, revealed limited gap detection deficits in mice with cochlear neuropathy only for certain gap-startle latencies, inconsistent with the presence of tinnitus "filling in the gap." Despite significantly reduced wave 1 of the auditory brainstem response, representing cochlear nerve activity, later peaks were unchanged or enhanced, suggesting compensatory neural hyperactivity in the auditory brainstem. Considering the rapid postexposure onset of both cochlear neuropathy and exaggerated startle-based behavior, the results suggest a role for cochlear primary neuronal degeneration, per se, in the central neural excitability that could underlie the generation of hyperacusis.
Subject(s)
Cochlear Nerve/physiopathology , Hyperacusis/physiopathology , Noise/adverse effects , Sensory Gating , Tinnitus/physiopathology , Vestibulocochlear Nerve Diseases/physiopathology , Animals , Cell Death , Cochlear Nerve/pathology , Hyperacusis/etiology , Male , Mice , Mice, Inbred C57BL , Neurons/pathology , Neurons/physiology , Tinnitus/etiology , Vestibulocochlear Nerve Diseases/etiologyABSTRACT
Anabolic androgenic steroids (AAS) are taken by both sexes to enhance athletic performance and body image, nearly always in conjunction with an exercise regime. Although taken to improve physical attributes, chronic AAS use can promote negative behavior, including anxiety. Few studies have directly compared the impact of AAS use in males versus females or assessed the interaction of exercise and AAS. We show that AAS increase anxiety-like behaviors in female but not male mice and that voluntary exercise accentuates these sex-specific differences. We also show that levels of the anxiogenic peptide corticotrophin releasing factor (CRF) are significantly greater in males, but that AAS selectively increase CRF levels in females, thus abrogating this sex-specific difference. Exercise did not ameliorate AAS-induced anxiety or alter CRF levels in females. Exercise was anxiolytic in males, but this behavioral outcome did not correlate with CRF levels. Brain-derived neurotrophic factor (BDNF) has also been implicated in the expression of anxiety. As with CRF, levels of hippocampal BDNF mRNA were significantly greater in males than females. AAS and exercise were without effect on BDNF mRNA in females. In males, anxiolytic effects of exercise correlated with increased BDNF mRNA, however AAS-induced changes in BDNF mRNA and anxiety did not. In sum, we find that AAS elicit sex-specific differences in anxiety and that voluntary exercise accentuates these differences. In addition, our data suggest that these behavioral outcomes may reflect convergent actions of AAS and exercise on a sexually differentiated CRF signaling system within the extended amygdala.
Subject(s)
Anabolic Agents/toxicity , Androgens/toxicity , Anxiety/chemically induced , Anxiety/psychology , Physical Conditioning, Animal/physiology , Sexual Behavior, Animal/physiology , Steroids/toxicity , Animals , Body Weight/drug effects , Choice Behavior , Corticotropin-Releasing Hormone/metabolism , Female , Male , Mice , Mice, Inbred C57BL , Reflex, Startle/drug effects , Sex Characteristics , Social BehaviorABSTRACT
The sensorimotor gating is a nervous system function that modulates the acoustic startle response (ASR). Prepulse inhibition (PPI) phenomenon is an operational measure of sensorimotor gating, defined as the reduction of ASR when a high intensity sound (pulse) is preceded in milliseconds by a weaker stimulus (prepulse). Brainstem nuclei are associated with the mediation of ASR and PPI, whereas cortical and subcortical regions are associated with their modulation. However, it is still unclear how the modulatory units can influence PPI. In the present work, we developed a computational model of a neural circuit involved in the mediation (brainstem units) and modulation (cortical and subcortical units) of ASR and PPI. The activities of all units were modeled by the leaky-integrator formalism for neural population. The model reproduces basic features of PPI observed in experiments, such as the effects of changes in interstimulus interval, prepulse intensity, and habituation of ASR. The simulation of GABAergic and dopaminergic drugs impaired PPI by their effects over subcortical units activity. The results show that subcortical units constitute a central hub for PPI modulation. The presented computational model offers a valuable tool to investigate the neurobiology associated with disorder-related impairments in PPI.
ABSTRACT
Rodent models of behavior used in the fields of neuroscience and psychology generate a wealth of multimodal data. For instance, as a rodent moves and behaves in its environment, muscle contractions apply subtle forces to any surface the animal contacts. These forces generate acoustic waves that propagate through the waveguide as Lamb and shear horizontal (SH) waves and contain information about the rodent's physiology, behavior, and underlying psychological state. If the information in these waves were to be tapped, it would provide a novel, non-invasive way to study rodent behavior. This article lays the foundations for using guided ultrasonic waves generated by a mouse's movement on an aluminum plate for detecting behavior and drawing inferences about acoustic startle responses. The experimental setup involves piezoelectric sensors capturing the waves generated by the rodent's movement, which are then stored as discrete acoustic emission (AE) hits using an amplitude threshold-based data acquisition system. This method of data acquisition ensures that data collection occurs only when the animal moves or behaves, and each movement/behavior is represented by values of features within the generated wavepackets (AE hits). Through open field tests with C57BL/6J mice, utilizing piezoelectric sensors and the DAQ system, it was observed that every movement/behavior of the animal generated Lamb wavepackets within the frequency range of 20 kHz to 100 kHz. Furthermore, rearing behavior in the animals also led to the generation of SH wavepackets in the frequency range of 75 kHz to 230 kHz. This criterion was subsequently employed to detect rearing behavior. In the acoustic startle response test, where the animals' responses to intense sound pulse were recorded, AE hits' features proved useful in quantifying the response. These experimental findings validate the proposed technology's practicality and demonstrate its capability to enhance studies of rodent behavior.
Subject(s)
Reflex, Startle , Rodentia , Animals , Mice , Acoustics , Mice, Inbred C57BL , SoundABSTRACT
BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is one of the most robust genetic predictors of psychosis and other psychiatric illnesses. In this study, we examined 22q11DS subjects' acoustic startle responses (ASRs), which putatively index psychosis risk. Latency of the ASR is a presumptive marker of neural processing speed and is prolonged (slower) in schizophrenia. ASR measures correlate with increased psychosis risk, depend on glutamate and dopamine receptor signaling, and could serve as translational biomarkers in interventions for groups at high psychosis risk. METHODS: Startle magnitude, latency, and prepulse inhibition were assessed with a standard acoustic startle paradigm in 31 individuals with 22q11.2DS and 32 healthy comparison (HC) subjects. Surface electrodes placed on participants' orbicularis oculi recorded the electromyographic signal in ASR eyeblinks. Individuals without measurable startle blinks in the initial habituation block were classified as non-startlers. RESULTS: Across the startle session, the ASR magnitude was significantly lower in 22q11DS subjects than HCs because a significantly higher proportion of 22q11DS subjects were non-startlers. Latency of the ASR to pulse-alone stimuli was significantly slower in 22q11DS than HC subjects. Due to the overall lower 22q11DS startle response frequency and magnitudes prepulse inhibition could not be analyzed. CONCLUSIONS: Reduced magnitude and slow latency of 22q11DS subjects' responses suggest reduced central nervous system and neuronal responsiveness. These findings are consistent with significant cognitive impairments observed in 22q11DS subjects. Further research is needed to untangle the connections among basic neurotransmission dysfunction, psychophysiological responsiveness, and cognitive impairment.
Subject(s)
Blinking , DiGeorge Syndrome , Prepulse Inhibition , Reflex, Startle , Humans , Male , Female , Reflex, Startle/physiology , Adult , Adolescent , Young Adult , DiGeorge Syndrome/physiopathology , Prepulse Inhibition/physiology , Blinking/physiology , Reaction Time/physiology , Electromyography , Acoustic StimulationABSTRACT
BACKGROUND: Prenatal alcohol exposure can contribute to a wide range of neurodevelopmental impairments in children and adults including behavioral and neuropsychiatric disorders. In rhesus monkeys, we examined whether moderate-level prenatal alcohol exposure would alter acoustic startle responses and prepulse inhibition (PPI) of the acoustic startle. PPI is a highly quantifiable measure of inhibitory neural processes or sensorimotor gating associated with neuropsychiatric disorders. METHODS: Acoustic startle and PPI of the acoustic startle were tested in 37 adult rhesus monkeys (Macaca mulatta) from 4 experimental conditions: (i) moderate-level prenatal alcohol-exposed, (ii) prenatally stressed, (iii) moderate-level prenatal alcohol-exposed + prenatally stressed, and (iv) sucrose controls. RESULTS: Prenatal alcohol-exposed monkeys showed a higher magnitude of acoustic startle response and disrupted PPI compared with monkeys not exposed to alcohol prenatally. Monkeys in all conditions showed higher hypothalamic-pituitary-adrenocortical (HPA) axis responses after undergoing the startle procedure, but HPA responses were unrelated to startle response magnitude, latency, or PPI. CONCLUSIONS: Finding altered PPI in monkeys prenatally exposed to a moderate dose of alcohol suggests that reduced sensorimotor gating is 1 effect of prenatal alcohol exposure. Because reduced sensorimotor gating is observed in many neuropsychiatric disorders, sensorimotor gating deficits could be an aspect of the comorbidity between fetal alcohol spectrum disorder and mental health conditions.
Subject(s)
Acoustic Stimulation/methods , Alcohol Drinking/physiopathology , Neural Inhibition/physiology , Prenatal Exposure Delayed Effects/physiopathology , Reflex, Startle/physiology , Sensory Gating/physiology , Age Factors , Alcohol Drinking/psychology , Animals , Female , Macaca mulatta , Pregnancy , Prenatal Exposure Delayed Effects/psychologyABSTRACT
The startle reflex (SR), a robust, motor response elicited by an intense auditory, visual, or somatosensory stimulus has been widely used as a tool to assess psychophysiology in humans and animals for almost a century in diverse fields such as schizophrenia, bipolar disorder, hearing loss, and tinnitus. Previously, SR waveforms have been ignored, or assessed with basic statistical techniques and/or simple template matching paradigms. This has led to considerable variability in SR studies from different laboratories, and species. In an effort to standardize SR assessment methods, we developed a machine learning algorithm and workflow to automatically classify SR waveforms in virtually any animal model including mice, rats, guinea pigs, and gerbils obtained with various paradigms and modalities from several laboratories. The universal features common to SR waveforms of various species and paradigms are examined and discussed in the context of each animal model. The procedure describes common results using the SR across species and how to fully implement the open-source R implementation. Since SR is widely used to investigate toxicological or pharmaceutical efficacy, a detailed and universal SR waveform classification protocol should be developed to aid in standardizing SR assessment procedures across different laboratories and species. This machine learning-based method will improve data reliability and translatability between labs that use the startle reflex paradigm.
Subject(s)
Reflex, Startle , Tinnitus , Humans , Rats , Mice , Animals , Guinea Pigs , Reflex, Startle/physiology , Acoustic Stimulation/methods , Reproducibility of Results , Disease Models, Animal , GerbillinaeABSTRACT
BACKGROUND: Women with a history of adverse childhood experiences (ACEs) enter pregnancy and the postpartum with a physiologic system programmed by early life stress, potentially reflected in psychophysiologic reactivity. METHODS: We enrolled pregnant, psychiatrically healthy women ≥18 years old. Using the ACE Questionnaire, women were categorized as high (≥2 ACEs; n = 77) or low ACE (<2 ACEs; n = 72). Participants completed an affective modulation of acoustic startle response (ASR) task during pregnancy and postpartum, in which ASR magnitude was measured while participants viewed pleasant, unpleasant, and neutral pictures. Two types of control trials were included (habituation trials presented at baseline and intertrial interval trials presented when no picture was present). RESULTS: Among high ACE women, ASR was significantly higher postpartum compared with pregnancy in the unpleasant (p = 0.002, ß = 0.46, 95% CI [0.18, 0.74], χ2 = 10.12, z = 3.18) and intertrial interval trials (p = 0.002, ß = 0.44, 95% CI [0.16, 0.73], χ2 = 9.25, z = 3.04), accounting for multiple comparisons using a Bonferroni correction at p < 0.005. Among low ACE women, ASR was similar in pregnancy and postpartum. CONCLUSIONS: Physiological reactivity increased in high ACE women from pregnancy to postpartum, but no change was observed in low ACE women.