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Neural Plasticity 2022Sound stimulation is generally used for tinnitus and hyperacusis treatment. Recent studies found that long-term noise exposure can change synaptic and firing properties...
Sound stimulation is generally used for tinnitus and hyperacusis treatment. Recent studies found that long-term noise exposure can change synaptic and firing properties in the central auditory system, which will be detected by the acoustic startle reflex. However, the perceptual consequences of long-term low-intensity sound exposure are indistinct. This study will detect the effects of moderate-level noise exposure (83 dB SPL) on auditory loudness, and temporal processing was evaluated using CBA/CaJ mice. C-Fos staining was used to detect neural activity changes in the central auditory pathway. With two weeks of 83 dB SPL noise exposure (8 hours per day), no persistent threshold shift of the auditory brainstem response (ABR) was identified. On the other hand, noise exposure enhanced the acoustic startle response (ASR) and gap-induced prepulse inhibition significantly (gap-PPI). Low-level noise exposure, according to the findings, can alter temporal acuity. Noise exposure increased the number of c-Fos labeled neurons in the dorsal cochlear nucleus (DCN) and caudal pontine reticular nucleus (PnC) but not at a higher level in the central auditory nuclei. Our results suggested that noise stimulation can change acoustical temporal processing presumably by increasing the excitability of auditory brainstem neurons.
Topics: Mice; Animals; Mice, Inbred CBA; Cochlear Nucleus; Time Perception; Reflex, Startle; Vestibular Nuclei; Proto-Oncogene Proteins c-fos
PubMed: 36452876
DOI: 10.1155/2022/6463355 -
Medical Hypotheses Oct 2020Prepulse inhibition (PPI) of acoustic startle reflex is a measure of sensorimotor gating that may reflect the biological processes underlying gaiting impairments in...
Prepulse inhibition (PPI) of acoustic startle reflex is a measure of sensorimotor gating that may reflect the biological processes underlying gaiting impairments in schizophrenia. Although PPI is clinically useful, why PPI is inhibited in schizophrenia is largely unknown. Prepulse inhibition is mediated by M2-like muscarinic acetylcholine receptor on neurons in the caudal pontine reticular nucleus (PnC), activation of this receptor induces Gαi dissociation, and inhibits adenylyl cyclase, resulting in the inhibition of the neurons. On the other hand, the symptoms of schizophrenia are mainly linked to hyperactive dopaminergic activity, mediated by dopamine D2-like receptor. Interestingly, D2-like receptor also uses Gαi. This means that both M2-like acetylcholine receptor and D2-like dopamine receptor use same Gαi-protein, competitively. Thus, chronic over-activation of D2-like receptor observed in schizophrenia may disrupt normal M2-like acetylcholine receptor functions due to their shared coupling to Gαi-proteins, i.e. by reducing the amount of Gαi-protein available for M2-like acetylcholine receptors, resulting in the impairment of PPI.
Topics: Acoustic Stimulation; Humans; Prepulse Inhibition; Receptors, Dopamine; Reflex, Startle; Schizophrenia
PubMed: 32502900
DOI: 10.1016/j.mehy.2020.109901 -
Psychophysiology Dec 2023The startle response is a cross-species defensive reflex that is considered a key tool for cross-species translational emotion research. While the neural pathway... (Review)
Review
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.
Topics: Humans; Reflex, Startle; Electromyography; Brain; Emotions
PubMed: 37402156
DOI: 10.1111/psyp.14364 -
Schizophrenia Research Oct 2020Latency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response, and provides an index of neural processing speed....
BACKGROUND
Latency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response, and provides an index of neural processing speed. Schizophrenia subjects exhibit slowed latency compared to healthy controls. One prior publication reported significant heritability of latency. The current study was undertaken to replicate and extend this solitary finding in a larger cohort.
METHODS
Schizophrenia probands, their relatives, and control subjects from the Consortium on the Genetics of Schizophrenia (COGS-1) were tested in a paradigm to ascertain magnitude, latency, and prepulse inhibition of startle. Trial types in the paradigm were: pulse-alone, and trials with 30, 60, or 120 ms between the prepulse and pulse. Comparisons of subject groups were conducted with ANCOVAs to assess startle latency and magnitude. Heritability of startle magnitude and latency was analyzed with a variance component method implemented in SOLAR v.4.3.1.
RESULTS
980 subjects had analyzable startle results: 199 schizophrenia probands, 456 of their relatives, and 325 controls. A mixed-design ANCOVA on startle latency in the four trial types was significant for subject group (F(2,973) = 4.45, p = 0.012) such that probands were slowest, relatives were intermediate and controls were fastest. Magnitude to pulse-alone trials differed significantly between groups by ANCOVA (F(2,974) = 3.92, p = 0.020) such that controls were lowest, probands highest, and relatives intermediate. Heritability was significant (p < 0.0001), with heritability of 34-41% for latency and 45-59% for magnitude.
CONCLUSION
Both startle latency and magnitude are significantly heritable in the COGS-1 cohort. Startle latency is a strong candidate for being an endophenotype in schizophrenia.
Topics: Acoustic Stimulation; Acoustics; Humans; Prepulse Inhibition; Reflex, Startle; Schizophrenia
PubMed: 33189519
DOI: 10.1016/j.schres.2020.11.003 -
Journal of Anxiety Disorders Jan 2022The clinical presentation of anxiety may differ between Hispanics/Latinx (H/L) and non-H/L, although findings on ethnic differences in self-reported anxiety symptoms...
The clinical presentation of anxiety may differ between Hispanics/Latinx (H/L) and non-H/L, although findings on ethnic differences in self-reported anxiety symptoms have been mixed. Fewer studies have focused on ethnic differences in quick and relatively automatic laboratory-assessed indicators of anxiety symptoms, which have the potential to be more objective indicators than self-report. Therefore, the present study examined ethnic differences in two laboratory-assessed indicators of threat sensitivity (an important transdiagnostic mechanism of anxiety): attentional bias to threat and electromyography startle reactivity to threat. White H/L (n = 117) and White non-H/L (n = 168) adults who were matched on demographics and lifetime psychopathology (including anxiety) completed a dot-probe task to assess attentional bias to threat and the No-Predictable-Unpredictable threat (NPU) task to assess startle reactivity to threat. Results indicated that H/L displayed less Slow Orientation (β = -0.27, p = 0.032, R = 0.02), and increased Slow Disengagement (β = 0.31, p = 0.016, R = 0.02) compared to non-H/L. H/L exhibited blunted overall startle compared to non-H/L (β = -0.30, p = 0.014, R = 0.02), but groups did not differ in startle reactivity to either predictable or unpredictable threat. In summary, H/L and non-H/L may differ in their experience and presentation of anxiety symptoms and such differences may vary across indicators of sensitivity to threat.
Topics: Adult; Anxiety; Anxiety Disorders; Fear; Humans; Reflex, Startle; Self Report
PubMed: 34864540
DOI: 10.1016/j.janxdis.2021.102508 -
Behavioural Brain Research Jan 2021Deficits in safety signal learning are well-established in fear-related disorders (e.g., PTSD, phobias). The current study used a fear conditioning paradigm to test...
BACKGROUND
Deficits in safety signal learning are well-established in fear-related disorders (e.g., PTSD, phobias). The current study used a fear conditioning paradigm to test associations among eye blink startle and event-related brain potential (ERP) latency measures of safety signal learning, as well as the role of cardiac vagal control (a measure of top-down inhibition necessary for safety learning).
METHODS
Participants were 49 trauma-exposed women ages 17 to 28 years. Eyeblink startle response and ERP amplitudes/latencies were derived for conditioned stimuli associated (CS+) and not associated (CS-) with an aversive unconditioned stimulus. ERPs included the P100 and late positive potential (LPP), which index early visual processing and sustained emotional encoding, respectively. Cardiac vagal control was assessed with resting heart rate variability (HRV).
RESULTS
P100 and LPP latencies for the CS- (safety signal stimulus) were significantly negatively associated with startle to the CS-, but not the CS + . LPP CS- latencies were significantly negatively associated with PTSD Intrusion scores, and this relationship was moderated by vagal control, such that the effect was only present among those with low HRV.
CONCLUSIONS
ERP-based markers of safety signal learning were associated with startle response to the CS- (but not CS+) and PTSD symptoms, indicating that these markers may have relevance for fear-related disorders. Cardiac vagal control indexed by HRV is a moderating factor in these associations and may be relevant to safety signal learning.
Topics: Adolescent; Adult; Autonomic Nervous System; Blinking; Conditioning, Classical; Evoked Potentials; Female; Heart Rate; Humans; Psychological Trauma; Reflex, Startle; Vagus Nerve; Young Adult
PubMed: 32976862
DOI: 10.1016/j.bbr.2020.112914 -
Psychoneuroendocrinology Aug 2019During pregnancy, the hypothalamic-pituitary-adrenal (HPA) axis, the main regulator of the stress response, undergoes dramatic changes. The acoustic startle response...
During pregnancy, the hypothalamic-pituitary-adrenal (HPA) axis, the main regulator of the stress response, undergoes dramatic changes. The acoustic startle response (ASR) and the prepulse inhibition (PPI) of the startle response are neurophysiological research tools and objective measures of an individual's response to an emotional context or stressor. The ASR and PPI are influenced by psychiatric diseases characterized by anxiety symptoms and are sensitive to cortisol. Hence, the ASR and the PPI can be used to investigate the effects of pregnancy-induced endocrine changes and their contribution to affective disorders. The present study sought to investigate the association between measures of HPA-axis responsiveness, startle reactivity and sensorimotor gating during pregnancy that to date remains unknown. The eye-blink component of the ASR, and its prepulse inhibition, were measured in 107 late third trimester pregnant women. Saliva samples were collected to assess the cortisol awakening response (CAR), a measure of HPA-axis activity. Blood was sampled to measure serum levels of cortisol, cortisone and the cortisone to cortisol ratio. Ongoing anxiety disorders, sleep duration, smoking, and age were considered as potential confounders in the statistical analyses. CAR reactivity, measured as area under the curve (AUC) increase and above baseline, was positively associated with baseline startle magnitude [Cohen's d = 0.27; F (1, 105) = 4.99; p = 0.028, and Cohen's d = 0.30; F (1, 105) = 6.25; p = 0.014, respectively] as well as PPI at 86 dB [Cohen's d = 0.29; F (1, 105) = 5.93; p = 0.017; and Cohen's d = 0.34; F (1, 105) = 8.38; p = 0.005, respectively]. The observed positive correlation between startle magnitude in pregnant women and greater increase in cortisol during the awakening response may be interpreted as heightened neurophysiological reactivity, likely associated with dysregulation of the stress system.
Topics: Acoustic Stimulation; Adult; Cortisone; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Pregnancy; Pregnancy Trimester, Third; Pregnant Women; Prepulse Inhibition; Reflex, Startle; Saliva; Sensorimotor Cortex; Sensory Gating
PubMed: 30927623
DOI: 10.1016/j.psyneuen.2019.03.008 -
Epilepsy & Behavior : E&B Feb 2020Dravet syndrome is an intractable pediatric epilepsy associated with SCN1A mutations. In addition to having a large seizure burden and a reduced lifespan, patients with...
Dravet syndrome is an intractable pediatric epilepsy associated with SCN1A mutations. In addition to having a large seizure burden and a reduced lifespan, patients with Dravet syndrome also exhibit delays in reaching normal developmental milestones in attentional, emotional, and cognitive function. These developmental delays manifest in autistic-like social withdrawal and compulsive behavior. Additionally, cognitive impairments including deficits in sensorimotor processing and memory function are present. Several mouse models utilizing heterozygous deletion of Scn1a (Scn1a mice) have been generated that recapitulate many aspects of Dravet syndrome. Studies in these mouse models of Dravet syndrome have characterized behavioral phenotypes in adult mice. In the present study, we characterized the behavioral phenotype of Scn1a mice generated by targeted deletion of Scn1a exon 1 (Scn1a) during adolescence. Identifying behavioral deficits in adolescent mice would more closely model the early onset of attentional, emotional, and cognitive delays observed in patients with Dravet syndrome. The behaviors of adolescent Scn1a and wildtype (WT) mice were compared across several behavioral domains. We assessed motor function (open-field test), sociability and social recognition memory (three-chambered social preference and social interaction tests), memory function (novel object recognition, Barnes maze, fear conditioning paradigm), anxiety-related behavior (elevated plus maze and open-field thigmotaxis), startle reflex and sensorimotor gating (prepulse inhibition of startle (PPI) tests), and repetitive compulsive behavior (marble burying test). Adolescent Scn1a mice exhibited normal locomotor activity, marble burying behavior, sociability, and sensorimotor gating. However, adolescent Scn1a mice displayed increased anxiety-related thigmotactic behavior, atypical fear expression, blunted acoustic startle responses, and impaired social recognition and spatial memory. Our results show that Scn1a mice display various behavioral impairments during adolescence, which provides a foundation for testing early intervention therapies targeting developmental delays modeled in Dravet syndrome mice.
Topics: Age Factors; Animals; Disease Models, Animal; Epilepsies, Myoclonic; Humans; Male; Maze Learning; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; NAV1.1 Voltage-Gated Sodium Channel; Reflex, Startle; Seizures; Spatial Memory
PubMed: 31870807
DOI: 10.1016/j.yebeh.2019.106842 -
Psychophysiology Jan 2020Overgeneralization (i.e., the transfer of fear to stimuli not related to an aversive event) is part of alterations in associative fear learning in mental disorders. In...
Overgeneralization (i.e., the transfer of fear to stimuli not related to an aversive event) is part of alterations in associative fear learning in mental disorders. In the present experimental study, we investigated whether this holds true for post-traumatic stress disorder (PTSD) related to childhood abuse. We expected that fear generalization under experimental conditions reflects generalization of aversive stimuli to different social domains in real life. Sixty-four women with PTSD after childhood abuse and 30 healthy participants (HC) underwent a differential fear conditioning and generalization paradigm. Online risk ratings, reaction time, and fear-potentiated startle served as dependent variables. Based on the subjectively assessed generalization of triggered intrusions across different domains of life, PTSD participants were split into two groups reporting low (low-GEN) and high (high-GEN) generalization. PTSD patients reported a higher expectation of an aversive event. During fear conditioning, they assessed the risk of danger related to a safety cue slower and showed a blunted fear-potentiated startle toward the danger cue. During generalization testing, reaction time increased in the high-GEN patients and decreased in the HC group with increasing similarity of a stimulus with the conditioned safety cue. Alterations of fear learning in PTSD suggest impaired defensive responses in case of a high threat probability. Moreover, our findings bridge the gap between the generalization of aversive cues during everyday life and laboratory-based experimental parameters: impairments in the processing of cues signaling safety generalize particularly in those patients who report a spreading of PTSD symptoms across different domains of everyday life.
Topics: Adult; Adult Survivors of Child Abuse; Adverse Childhood Experiences; Conditioning, Classical; Cues; Fear; Female; Generalization, Psychological; Humans; Middle Aged; Reflex, Startle; Stress Disorders, Post-Traumatic; Young Adult
PubMed: 31206738
DOI: 10.1111/psyp.13422 -
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