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Autonomic Neuroscience : Basic &... Jun 2024Unilateral nociceptive stimulation is associated with subtle signs of pupil asymmetry that may reflect lateralized activity in the locus coeruleus. To explore drivers of...
Unilateral nociceptive stimulation is associated with subtle signs of pupil asymmetry that may reflect lateralized activity in the locus coeruleus. To explore drivers of this pupil asymmetry, electrical stimuli, delivered alone or 200 ms before or after an acoustic startle stimulus, were administered to one ankle under four experimental conditions: with or without a 1.6 s anticipatory period, or while the forearm ipsilateral or contralateral to the electrical stimulus was heated tonically to induce moderate pain (15 healthy participants in each condition). Pupil diameter was measured at the start of each trial, at stimulus delivery, and each second for 5 s after stimulus delivery. At the start of the first trial, the pupil ipsilateral to the side on which electric shocks were later delivered was larger than the contralateral pupil. Both pupils dilated robustly during the anticipatory period and dilated further during single- and dual-stimulus trials. However, pupil asymmetry persisted throughout the experiment. Tonically-applied forearm heat-pain modulated the pupillary response to phasic electrical stimuli, with a slight trend for dilatation to be greater contralateral to the forearm being heated. Together, these findings suggest that focusing anxiously on the expected site of noxious stimulation was associated with dilatation of the ipsilateral pupil whereas phasic nociceptive stimuli and psychological arousal triggered bilateral pupillary dilatation. It was concluded that preparatory cognitive activity rather than phasic afferent nociceptive input is associated with pupillary signs of lateralized activity in the locus coeruleus.
Topics: Humans; Male; Pupil; Female; Young Adult; Adult; Electric Stimulation; Nociception; Reflex, Startle; Anticipation, Psychological; Functional Laterality; Pain; Hot Temperature
PubMed: 38677128
DOI: 10.1016/j.autneu.2024.103179 -
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 -
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 -
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 -
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 -
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 -
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 -
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 -
Iranian Journal of Child Neurology 2023The objective assessment tests overcome the variability of subjective methods. Cortical recordings with gap pre-pulse inhibition of the acoustic startle reflex stimulus...
OBJECTIVES
The objective assessment tests overcome the variability of subjective methods. Cortical recordings with gap pre-pulse inhibition of the acoustic startle reflex stimulus have been used as objective tinnitus assessments in humans. This study aims to investigate this possible objective tinnitus test and compare gap-induced inhibition in different stimulus parameters and brain regions.
MATERIALS & METHODS
Twenty People (18-50 years old) without hearing loss and tinnitus were included. The sound stimuli consisted of continuous background noise with a loud startle tone preceded by a silent gap (20 and 40 ms duration, 120 and 150 ms distance from the startle). The N1-P2 complex amplitude and topoplot maps were extracted in 27-channel cortical response recording after signal processing. Four brain regions of interest (ROI) of anterior-frontal, centro-frontal, right, and left temporal were investigated.
RESULTS
The results showed that the maximum inhibition occurred in a 40 ms gap duration and 150 ms distance in all 4 ROIs. In comparing ROIs, the centro-frontal and left temporal regions revealed the most inhibition (p<0.05). The decrease in the amplitude of the N1 and P2 in that region could also be traced in the 100 and 200 ms topoplots.
CONCLUSION
Gap-induced inhibition was observed in all gap-embedded stimuli and all ROIs. However, the 40-150 mode and centro-frontal and left temporal regions had maximum inhibition in normal subjects. It provides a promising tool for objectively assessing tinnitus in humans with particular implications in children.
PubMed: 38074929
DOI: 10.22037/ijcn.v17i4.42300