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Journal of Integrative Neuroscience Mar 2024Rats with a loss-of-function mutation in the contactin-associated protein-like 2 () gene have been validated as an animal model of autism spectrum disorder (ASD)....
BACKGROUND
Rats with a loss-of-function mutation in the contactin-associated protein-like 2 () gene have been validated as an animal model of autism spectrum disorder (ASD). Similar to many autistic individuals, knock-out rats () 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 rats had a dramatic increase in sound-evoked responses compared with wildtype counterparts, but male rats showed only a modest increase in PnC activity that cannot fully explain the largely increased startle in male rats. The present study therefore investigates activation and histological properties of PnC giant neurons in 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, electrophysiology was conducted to assess the resting state activity and intrinsic properties of PnC giant neurons.
RESULTS
Wildtype and 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 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 rats, particularly in males. These findings allow for a better understanding of increased reactivity to sound in rats and in -associated disorders such as ASD.
Topics: Animals; Female; Male; Rats; Acoustic Stimulation; Autism Spectrum Disorder; Neurons; Reflex, Startle; Reticular Formation; Disease Models, Animal
PubMed: 38538232
DOI: 10.31083/j.jin2303063 -
Sleep and Biological Rhythms Apr 2024Sleep deprivation (SD) impairs pre-stimulus inhibition, but the effect of quetiapine (QET) remains largely unknown.
BACKGROUND
Sleep deprivation (SD) impairs pre-stimulus inhibition, but the effect of quetiapine (QET) remains largely unknown.
OBJECTIVE
This study aimed to investigate the behavioral and cognitive effects of QET in both naïve and sleep-deprived rats.
MATERIALS AND METHODS
Seven groups ( = 49) of male Wistar Albino rats were used in this study. SD was performed using the modified multiple platform technique in a water tank for 72 h. Our study consists of two experiments investigating the effect of QET on pre-pulse inhibition (PPI) of the acoustic startle reflex. The first experiment tested the effect of short- and long-term administration of QET on PPI response in non-sleeping (NSD) rats. The second experiment used 72 h REM sleep deprivation as a model for SD-induced impairment of the PPI response. Here, we tested the effect of QET on the % PPI of SD rats by short- and long-term intraperitoneal injection at the last 90 min of sleep SD and immediately subsequently tested for PPI.
RESULTS
72 h SD impaired PPI, reduced startle amplitude, and attenuated the PPI% at + 4 dB, + 8 dB, and + 16 dB prepulse intensities. 10 mg/kg short and long-term QET administration completely improved sensorimotor gating deficit, increased startle amplitude, and restored the impaired PPI% at + 4 dB, + 8 dB, and + 16 dB after 72 h SD in rats.
CONCLUSION
Our results showed short- and long-term administration of QET improved sensorimotor gating deficit in 72 h SD. Further research is required for the etiology of insomnia and the dose-related behavioral effects of QET.
PubMed: 38524169
DOI: 10.1007/s41105-023-00504-x -
Royal Society Open Science Mar 2024Individual variation in fearfulness can be modified during ontogeny, and high levels of fear can affect animal welfare. We asked whether early-life environmental...
Individual variation in fearfulness can be modified during ontogeny, and high levels of fear can affect animal welfare. We asked whether early-life environmental complexity and genetic strain affect fear behaviour in young laying hens (pullets). Four replicates of brown (B) and white (W) genetic strains (breeds) of layers were each raised in four environmental treatments (housing): conventional cages () and different rearing aviaries with increasing space and complexity ( < < ). We used a startle reflex test (weeks 4 and 14) to measure startle amplitude and autonomic response (i.e. comb temperature). A combination of novel arena (NA) and novel object (NO) tests was used (week 14) to assess NA exploration and alertness, latency to approach the centre and initial NO avoidance and investigation. Housing × strain affected startle amplitude (B-Conv, B-High < B-Low, B-Mid; B > W; no housing effect in W) but not autonomic response. Fear behaviour was affected by housing (NA exploration, investigation: Conv < Low, Mid, High; NO avoidance: Conv, High < Low, Mid), strain (NA alertness: B > W, NO avoidance: W > B) and their interaction (NA centre approach: B-Conv < all other groups). We present evidence for strain-specific fear responses depending on early experience.
PubMed: 38511084
DOI: 10.1098/rsos.231075 -
PloS One 2024Behavioral thresholds define the lowest stimulus intensities sufficient to elicit a behavioral response. Establishment of baseline behavioral thresholds during...
Behavioral thresholds define the lowest stimulus intensities sufficient to elicit a behavioral response. Establishment of baseline behavioral thresholds during development is critical for proper responses throughout the animal's life. Despite the relevance of such innate thresholds, the molecular mechanisms critical to establishing behavioral thresholds during development are not well understood. The acoustic startle response is a conserved behavior whose threshold is established during development yet is subsequently acutely regulated. We have previously identified a zebrafish mutant line (escapist) that displays a decreased baseline or innate acoustic startle threshold. Here, we identify a single base pair substitution on Chromosome 25 located within the coding sequence of the synaptotagmin 7a (syt7a) gene that is tightly linked to the escapist acoustic hypersensitivity phenotype. By generating animals in which we deleted the syt7a open reading frame, and subsequent complementation testing with the escapist line, we demonstrate that loss of syt7a function is not the cause of the escapist behavioral phenotype. Nonetheless, escapist mutants provide a powerful tool to decipher the overlap between acute and developmental regulation of behavioral thresholds. Extensive behavioral analyses reveal that in escapist mutants the establishment of the innate acoustic startle threshold is impaired, while regulation of its acute threshold remains intact. Moreover, our behavioral analyses reveal a deficit in baseline responses to visual stimuli, but not in the acute regulation of responses to visual stimuli. Together, this work eliminates loss of syt7a as causative for the escapist phenotype and suggests that mechanisms that regulate the establishment of behavioral thresholds in escapist larvae can operate independently from those regulating acute threshold regulation.
Topics: Animals; Reflex, Startle; Zebrafish; Base Pairing; Acoustic Stimulation; Behavior, Animal
PubMed: 38498506
DOI: 10.1371/journal.pone.0300529 -
Current Biology : CB Apr 2024Sound elicits rapid movements of muscles in the face, ears, and eyes that protect the body from injury and trigger brain-wide internal state changes. Here, we performed...
Sound elicits rapid movements of muscles in the face, ears, and eyes that protect the body from injury and trigger brain-wide internal state changes. Here, we performed quantitative facial videography from mice resting atop a piezoelectric force plate and observed that broadband sounds elicited rapid and stereotyped facial twitches. Facial motion energy (FME) adjacent to the whisker array was 30 dB more sensitive than the acoustic startle reflex and offered greater inter-trial and inter-animal reliability than sound-evoked pupil dilations or movement of other facial and body regions. FME tracked the low-frequency envelope of broadband sounds, providing a means to study behavioral discrimination of complex auditory stimuli, such as speech phonemes in noise. Approximately 25% of layer 5-6 units in the auditory cortex (ACtx) exhibited firing rate changes during facial movements. However, FME facilitation during ACtx photoinhibition indicated that sound-evoked facial movements were mediated by a midbrain pathway and modulated by descending corticofugal input. FME and auditory brainstem response (ABR) thresholds were closely aligned after noise-induced sensorineural hearing loss, yet FME growth slopes were disproportionately steep at spared frequencies, reflecting a central plasticity that matched commensurate changes in ABR wave 4. Sound-evoked facial movements were also hypersensitive in Ptchd1 knockout mice, highlighting the use of FME for identifying sensory hyper-reactivity phenotypes after adult-onset hyperacusis and inherited deficiencies in autism risk genes. These findings present a sensitive and integrative measure of hearing while also highlighting that even low-intensity broadband sounds can elicit a complex mixture of auditory, motor, and reafferent somatosensory neural activity.
Topics: Animals; Mice; Male; Hearing; Sound; Acoustic Stimulation; Female; Auditory Cortex; Mice, Inbred C57BL; Movement; Evoked Potentials, Auditory, Brain Stem
PubMed: 38492568
DOI: 10.1016/j.cub.2024.02.057 -
Somatosensory & Motor Research Mar 2024The application of a noxious stimulus reduces the perception and responsiveness to other pain stimuli. This inhibition can be experimentally assessed with a method...
AIM OF THE STUDY
The application of a noxious stimulus reduces the perception and responsiveness to other pain stimuli. This inhibition can be experimentally assessed with a method called 'counterirritation'. The question arises if counterirritation acts also on the perception and responsiveness to aversive but non-nociceptive stimuli (e.g., loud tones). Since aversive stimulation is often associated with state anxiety or state fear, we investigated in addition the modulatory effects of these emotions on counterirritation.
MATERIAL AND METHODS
51 subjects participated in our study. We presented tones with aversive loudness (105 dB), first alone then during counterirritation (immersion of the hand in a hot water bath of 46 °C) to assess inhibition of loudness perception and responsiveness. Influences of state anxiety and state fear on counterirritation were investigated by using the Neutral-Predictable(fear)- Unpredictable(anxiety) Paradigm (NPU), which is based on classical conditioning. Loudness ratings (perception of the aversive tones) and startle reflex (defensive reaction to aversive tones) were assessed.
RESULTS
Counterirritation reduced startle reflex amplitudes, but not the loudness ratings. Although state anxiety and state fear were successfully induced, counterirritation remained unaffected.
CONCLUSIONS
Our study showed that pain inhibits the responsiveness to aversive stimuli (loud tones). Thus, the postulate that 'pain inhibits pain' might be better changed to 'pain inhibits aversiveness'. Consequently, our findings may also question the assumption of a clear pain specificity in inhibitory action as assumed by theoretical approaches like 'conditioned pain modulation' (CPM). Furthermore, counterirritation appeared one more time resistant to the influence of negative emotions.
PubMed: 38459928
DOI: 10.1080/08990220.2024.2322499 -
JAMA Psychiatry Jun 2024Current interventions for posttraumatic stress disorder (PTSD) are efficacious, yet effectiveness may be limited by adverse effects and high withdrawal rates.... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Current interventions for posttraumatic stress disorder (PTSD) are efficacious, yet effectiveness may be limited by adverse effects and high withdrawal rates. Acupuncture is an emerging intervention with positive preliminary data for PTSD.
OBJECTIVE
To compare verum acupuncture with sham acupuncture (minimal needling) on clinical and physiological outcomes.
DESIGN, SETTING, AND PARTICIPANTS
This was a 2-arm, parallel-group, prospective blinded randomized clinical trial hypothesizing superiority of verum to sham acupuncture. The study was conducted at a single outpatient-based site, the Tibor Rubin VA Medical Center in Long Beach, California, with recruitment from April 2018 to May 2022, followed by a 15-week treatment period. Following exclusion for characteristics that are known PTSD treatment confounds, might affect biological assessment, indicate past nonadherence or treatment resistance, or indicate risk of harm, 93 treatment-seeking combat veterans with PTSD aged 18 to 55 years were allocated to group by adaptive randomization and 71 participants completed the intervention protocols.
INTERVENTIONS
Verum and sham were provided as 1-hour sessions, twice weekly, and participants were given 15 weeks to complete up to 24 sessions.
MAIN OUTCOMES AND MEASURES
The primary outcome was pretreatment to posttreatment change in PTSD symptom severity on the Clinician-Administered PTSD Scale-5 (CAPS-5). The secondary outcome was pretreatment to posttreatment change in fear-conditioned extinction, assessed by fear-potentiated startle response. Outcomes were assessed at pretreatment, midtreatment, and posttreatment. General linear models comparing within- and between-group were analyzed in both intention-to-treat (ITT) and treatment-completed models.
RESULTS
A total of 85 male and 8 female veterans (mean [SD] age, 39.2 [8.5] years) were randomized. There was a large treatment effect of verum (Cohen d, 1.17), a moderate effect of sham (d, 0.67), and a moderate between-group effect favoring verum (mean [SD] Δ, 7.1 [11.8]; t90 = 2.87, d, 0.63; P = .005) in the intention-to-treat analysis. The effect pattern was similar in the treatment-completed analysis: verum d, 1.53; sham d, 0.86; between-group mean (SD) Δ, 7.4 (11.7); t69 = 2.64; d, 0.63; P = .01). There was a significant pretreatment to posttreatment reduction of fear-potentiated startle during extinction (ie, better fear extinction) in the verum but not the sham group and a significant correlation (r = 0.31) between symptom reduction and fear extinction. Withdrawal rates were low.
CONCLUSIONS AND RELEVANCE
The acupuncture intervention used in this study was clinically efficacious and favorably affected the psychobiology of PTSD in combat veterans. These data build on extant literature and suggest that clinical implementation of acupuncture for PTSD, along with further research about comparative efficacy, durability, and mechanisms of effects, is warranted.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02869646.
Topics: Humans; Adult; Male; Stress Disorders, Post-Traumatic; Female; Middle Aged; Combat Disorders; Veterans; Young Adult; Treatment Outcome; Acupuncture Therapy; Reflex, Startle; Prospective Studies; Acupuncture, Ear
PubMed: 38381417
DOI: 10.1001/jamapsychiatry.2023.5651 -
Neuroscience Letters Feb 2024The 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...
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.
Topics: Female; Humans; Reflex, Startle; Emotions; Evoked Potentials; Brain; Electroencephalography
PubMed: 38346533
DOI: 10.1016/j.neulet.2024.137673 -
The Science of the Total Environment Mar 2024Plastic additives are widely used in plastic production and are found in the environment owing to their widespread applications. Among these additives, N-butyl...
Plastic additives are widely used in plastic production and are found in the environment owing to their widespread applications. Among these additives, N-butyl benzenesulfonamide (NBBS) and triphenyl phosphate (TPHP) are under international watchlist for evaluation, with limited studies on amphipods. Di-ethylhexyl phthalate (DEHP) and dibutyl phthalate (DBP) are banned in some countries and categorised as substances of very high concern. This study aimed to investigate the effects of NBBS, TPHP, DEHP and DBP on the swimming activity of a coastal intertidal marine amphipod, Echinogammarus marinus. Furthermore, this study is the first to quantify startle response in E. marinus in response to light stimuli. Amphipods were exposed to 0, 0.5, 5, 50 and 500 μg/l concentrations of all test compounds. Swimming activity and startle responses were assessed by video tracking and analysis using an 8-min alternating dark and light protocol after exposure on days 7 and 14. We observed an overall compound and light effect on the swimming activity of E. marinus. A significant decrease in swimming distance was found in 500 μg/l NBBS and TPHP. We observed that the startle response in E. marinus had a latency period of >2 s and animals were assessed at 1 s and the sum of the first 5 s. There was a clear startle response in E. marinus during dark to light transition, evident with increased swimming distance. NBBS exposure significantly increased startle response at environmental concentrations, while significant effects were only seen in 500 μg/l TPHP at 5 s. We found no significant effects of DEHP and DBP on swimming behaviour at the concentrations assessed. The findings of this study affirm the necessity for a continuous review of plastic additives to combat adverse behavioural effects that may be transferable to the population levels.
Topics: Animals; Swimming; Diethylhexyl Phthalate; Amphipoda; Reflex, Startle; Dibutyl Phthalate; Phthalic Acids; Benzenesulfonamides
PubMed: 38336051
DOI: 10.1016/j.scitotenv.2024.170793 -
Methods in Molecular Biology (Clifton,... 2024Apart from morphological, biochemical, and genetic alterations induced by teratogen compounds, there is an increased interest in characterizing behavioral alterations....
Apart from morphological, biochemical, and genetic alterations induced by teratogen compounds, there is an increased interest in characterizing behavioral alterations. Behavior is a sensitive parameter that can provide information regarding developmental disruptions non-invasively. Behavioral disturbances interfere with animals' capacity to cope with the environment, having an impact on the organism's life. Hereby, behavioral assays consisting of recording larvae in multi-well plates, Petri dishes, or cuvettes and video analysis using adequate software, allowing teratogen screening of behavior, are proposed. Examples of how to evaluate locomotor, anxiety-like and avoidance-like behaviors, and the integrity of sensory-motor functions and learning are discussed in this chapter.
Topics: Animals; Zebrafish; Reflex, Startle; Teratogens; Anxiety; Perciformes; Larva
PubMed: 38285357
DOI: 10.1007/978-1-0716-3625-1_26