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Behavioural Pharmacology Oct 2023Sensorimotor gating disruptions have been noted in several psychiatric and neurodegenerative disorders. However, the involvement of sensorimotor gating processes in...
Sensorimotor gating disruptions have been noted in several psychiatric and neurodegenerative disorders. However, the involvement of sensorimotor gating processes in eating disorders has not been well characterized. Our objective was to examine the sensorimotor gating of the acoustic startle response following dietary-induced binge eating and high-fat diet (HFD) induced weight gain in male C57B/6J mice. Acute administration of the norepinephrine reuptake inhibitor, nisoxetine (0.5 and 5 mg/kg), and a dopamine reuptake inhibitor, GBR 12783 (1.6 and 16 mg/kg), were either given alone or in combination to assess norepinephrine and dopamine alterations, respectively. Male mice with repeated bouts of calorie restriction (Restrict) and with limited access to a sweetened fat food (Binge) demonstrated an escalation of intake over 2.5 weeks under standard chow conditions. Restrict Binge (RB) mice had a reduced startle response to the startle pulse (110 dB) compared with the Naive control group at 5 mg/kg nisoxetine. There was an overall effect of nisoxetine (0.5 and 5 mg/kg) to increase percent inhibition at pre-pulse (74 dB), %PP74. Under HFD conditions, the RB group did not demonstrate a binge-like eating phenotype. The RB group on HFD had a higher response to 74 dB with nisoxetine (5.0 mg/kg) compared with a combinational dose of nisoxetine (5.0 mg/kg) and GBR 12783 (1.6 mg/kg). These findings suggest that dietary conditions that promote binge-like eating can influence the central noradrenergic and dopaminergic controls of the acoustic startle response and potentially influence sensorimotor gating.
Topics: Mice; Male; Animals; Reflex, Startle; Dopamine; Norepinephrine; Acoustics; Eating
PubMed: 37578423
DOI: 10.1097/FBP.0000000000000748 -
Laryngoscope Investigative... Oct 2023Despite 6%-20% of the adult population suffering from tinnitus, there is no standard treatment for it. Placenta extract has been used for various therapeutic purposes,...
OBJECTIVE
Despite 6%-20% of the adult population suffering from tinnitus, there is no standard treatment for it. Placenta extract has been used for various therapeutic purposes, including hearing loss. Here, we evaluate the effect of a novel neuroprotective protein composition (NPPC) extract on electrophysiological and molecular changes in the medial geniculate body (MGB) of tinnitus-induced rats.
METHODS
To evaluate the protein analysis by western blot, the rats were divided into three groups: (1) saline group (intraperitoneal injection of 200 mg/kg saline twice a day for 28 consecutive days, (2) chronic Na-Sal group received sodium salicylate as in the first group, and (3) chronic treatment group (received salicylate 200 mg/kg twice daily for 2 weeks, followed by 0.4 mg NPPC daily from day 14 to day 28). Single-unit recordings were performed on a separate group that was treated as in group 4. Gap-prepulse inhibition of the acoustic startle (GPIAS) and pre-pulse inhibition (PPI) was performed to confirm tinnitus in all groups at the baseline, 14th and 28th days.
RESULTS
Western blot analysis showed that the expression of γ-Aminobutyric acid Aα1 subunit (GABA Aα1), N-methyl-d-aspartate receptor subtype 2B (NR2B or NMDAR2B), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors subunit GluR1 (GluR1), and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors subunit GluR2 (GluR2) decreased after Na-Sal injection, while NPPC upregulated their expression. MGB units in rats with tinnitus showed decreased spontaneous firing rate, burst per minute, and a spike in a burst. After NPPC administration, neural activity patterns showed a significant positive effect of NPPC on tinnitus.
CONCLUSION
NPPC can play an effective role in the treatment of tinnitus in salicylate-induced rats, and MGB is one of the brain areas involved in these processes.
LEVEL OF EVIDENCE
NA.
PubMed: 37899856
DOI: 10.1002/lio2.1156 -
Translational Psychiatry Oct 2023Many neurodevelopmental disorders, including autism spectrum disorder (ASD), are associated with changes in sensory processing and sensorimotor gating. The acoustic...
Many neurodevelopmental disorders, including autism spectrum disorder (ASD), are associated with changes in sensory processing and sensorimotor gating. The acoustic startle response and prepulse inhibition (PPI) of startle are widely used translational measures for assessing sensory processing and sensorimotor gating, respectively. The Cntnap2 knockout (KO) rat has proven to be a valid model for ASD, displaying core symptoms, including sensory processing perturbations. Here, we used a novel method to assess startle and PPI in Cntnap2 KO rats that allows for the identification of separate scaling components: startle scaling, which is a change in startle amplitude to a given sound, and sound scaling, which reflects a change in sound processing. Cntnap2 KO rats show increased startle due to both an increased overall response (startle scaling) and a left shift of the sound/response curve (sound scaling). In the presence of a prepulse, wildtype rats show a reduction of startle due to both startle scaling and sound scaling, whereas Cntnap2 KO rats show normal startle scaling, but disrupted sound scaling, resulting in the reported PPI deficit. These results validate that startle and sound scaling by a prepulse are indeed two independent processes, with only the latter being impaired in Cntnap2 KO rats. As startle scaling is likely related to motor output and sound scaling to sound processing, this novel approach reveals additional information on the possible cause of PPI disruptions in preclinical models.
Topics: Animals; Rats; Acoustic Stimulation; Autism Spectrum Disorder; Prepulse Inhibition; Reflex, Startle; Sensory Gating
PubMed: 37852987
DOI: 10.1038/s41398-023-02629-6 -
Journal of Medical Genetics Jan 2024Otosclerosis is a common cause of adult-onset progressive hearing loss, affecting 0.3%-0.4% of the population. It results from dysregulation of bone homeostasis in the...
BACKGROUND
Otosclerosis is a common cause of adult-onset progressive hearing loss, affecting 0.3%-0.4% of the population. It results from dysregulation of bone homeostasis in the otic capsule, most commonly leading to fixation of the stapes bone, impairing sound conduction through the middle ear. Otosclerosis has a well-known genetic predisposition including familial cases with apparent autosomal dominant mode of inheritance. While linkage analysis and genome-wide association studies suggested an association with several genomic loci and with genes encoding structural proteins involved in bone formation or metabolism, the molecular genetic pathophysiology of human otosclerosis is yet mostly unknown.
METHODS
Whole-exome sequencing, linkage analysis, generation of CRISPR mutant mice, hearing tests and micro-CT.
RESULTS
Through genetic studies of kindred with seven individuals affected by apparent autosomal dominant otosclerosis, we identified a disease-causing variant in , encoding a key component of the PBAF chromatin remodelling complex. We generated CRISPR-Cas9 transgenic mice carrying the human mutation in the mouse orthologue. Mutant mice exhibited marked hearing impairment demonstrated through acoustic startle response and auditory brainstem response tests. Isolated ossicles of the auditory bullae of mutant mice exhibited a highly irregular structure of the incus bone, and their in situ micro-CT studies demonstrated the anomalous structure of the incus bone, causing disruption in the ossicular chain.
CONCLUSION
We demonstrate that otosclerosis can be caused by a variant in , with a similar phenotype of hearing impairment and abnormal bone formation in the auditory bullae in transgenic mice carrying the human mutation in the mouse orthologue.
Topics: Adult; Humans; Mice; Animals; Otosclerosis; Blister; Genome-Wide Association Study; Reflex, Startle; Hearing Loss; Phenotype; Mice, Transgenic; Mutation; DNA Helicases; Nuclear Proteins; Transcription Factors
PubMed: 37399313
DOI: 10.1136/jmg-2023-109264 -
Scientific Reports Sep 2023
PubMed: 37739990
DOI: 10.1038/s41598-023-42343-3 -
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 -
Biological Psychiatry Jan 2024Biological markers for anxiety disorders may further understanding of disorder pathophysiology and suggest potential targeted treatments. The fear-potentiated startle...
BACKGROUND
Biological markers for anxiety disorders may further understanding of disorder pathophysiology and suggest potential targeted treatments. The fear-potentiated startle (FPS) (a measure of startle to predictable threat) and anxiety-potentiated startle (APS) (startle to unpredictable threat) laboratory paradigm has been used to detect physiological differences in individuals with anxiety disorders compared with nonanxious control individuals, and in pharmacological challenge studies in healthy adults. However, little is known about how startle may change with treatment for anxiety disorders, and no data are available regarding alterations due to mindfulness meditation training.
METHODS
Ninety-three individuals with anxiety disorders and 66 healthy individuals completed 2 sessions of the neutral, predictable, and unpredictable threat task, which employs a startle probe and the threat of shock to assess moment-by-moment fear and anxiety. Between the two testing sessions, patients received randomized 8-week treatment with either escitalopram or mindfulness-based stress reduction.
RESULTS
APS, but not FPS, was higher in participants with anxiety disorders compared with healthy control individuals at baseline. Further, there was a significantly greater decrease in APS for both treatment groups compared with the control group, with the patient groups showing reductions bringing them into the range of control individuals at the end of the treatment.
CONCLUSIONS
Both anxiety treatments (escitalopram and mindfulness-based stress reduction) reduced startle potentiation during unpredictable (APS) but not predictable (FPS) threat. These findings further validate APS as a biological correlate of pathological anxiety and provide physiological evidence for the impact of mindfulness-based stress reduction on anxiety disorders, suggesting that there may be comparable effects of the two treatments on anxiety neurocircuitry.
Topics: Adult; Humans; Anxiety; Anxiety Disorders; Escitalopram; Meditation; Mindfulness; Reflex, Startle; Case-Control Studies
PubMed: 37331547
DOI: 10.1016/j.biopsych.2023.06.003 -
Journal of Neurochemistry Oct 2023There is much interest in identifying novel pharmacotherapeutic targets that improve clinical outcomes for the treatment of alcohol use disorder (AUD). One promising...
There is much interest in identifying novel pharmacotherapeutic targets that improve clinical outcomes for the treatment of alcohol use disorder (AUD). One promising target for therapeutic intervention is the relaxin family peptide 3 (RXFP3) receptor, a cognate receptor for neuropeptide relaxin-3, which has previously been implicated in regulating alcohol drinking behavior. Recently, we developed the first small-molecule RXFP3-selective negative allosteric modulator (NAM) RLX-33. Therefore, the goal of the present work was to characterize the impact of this novel NAM on affective-related behaviors and alcohol self-administration in rats. First, the effects of RLX-33 were tested on alcohol and sucrose self-administration in Wistar and alcohol-preferring P rats to determine the dose-response profile and specificity for alcohol. Then, we assessed the effects of systemic RLX-33 injection in Wistar rats in a battery of behavioral assays (open-field test, elevated zero maze, acoustic startle response test, and prepulse inhibition) and tested for alcohol clearance. We found that the lowest effective dose (5 mg/kg) reduced alcohol self-administration in both male and female Wistar rats, while in alcohol-preferring P rats, this effect was restricted to males, and there were no effects on sucrose self-administration or general locomotor activity. The characterization of affective and metabolic effects in Wistar rats generally found few locomotor, affective, or alcohol clearance changes, particularly at the 5 mg/kg dose. Overall, these findings are promising and suggest that RXFP3 NAM has potential as a pharmacological target for treating AUD.
Topics: Rats; Male; Female; Animals; Rats, Wistar; Reflex, Startle; Relaxin; Receptors, G-Protein-Coupled; Ethanol; Alcoholism; Sucrose; Receptors, Peptide
PubMed: 37674350
DOI: 10.1111/jnc.15949 -
Frontiers in Psychology 2024Bilateral stimulation is a core element of Eye Movement Desensitization and Reprocessing Therapy, a psychotherapeutic intervention for the treatment of Posttraumatic...
Apples and oranges: PTSD patients and healthy individuals are not comparable in their subjective and physiological responding to emotion induction and bilateral stimulation.
OBJECTIVES
Bilateral stimulation is a core element of Eye Movement Desensitization and Reprocessing Therapy, a psychotherapeutic intervention for the treatment of Posttraumatic Stress Disorder (PTSD). Promising previous findings showed measurable physiological effects of bilateral stimulation in healthy individuals, but studies that replicated these findings in PTSD patients are sparse.
METHODS
23 patients with PTSD and 30 healthy controls were confronted with affective standard scripts (pleasant, neutral, unpleasant) while bilateral tactile stimulation was applied. Monolateral and no stimulation served as control conditions. Noise-induced startle reflex response (valence measure) and galvanic skin response (arousal measure) were used for physiological responses and the valence and arousal scale of the Self-Assessment-Manikin for subjective responses.
RESULTS
Both groups showed a subjective distress reduction for unpleasant scripts and a subjective attention increase for positive scripts under bilateral stimulation. In healthy individuals, this was also for physiological measures, and a general startle-reducing effect of bilateral stimulation in the absence of affective stimuli was found. In PTSD patients, however, the effects were restricted on the subjective level, and no concomitant physiological effects were observed.
CONCLUSIONS AND SIGNIFICANCE
The findings indicate, that generalizing the effects of BLS in healthy individuals to PTSD patients may be problematic. The herein-reported group differences can be explained by PTSD-specific peculiarities in emotion processing and cognitive processing style.
PubMed: 38933577
DOI: 10.3389/fpsyg.2024.1406180 -
Behavioural Brain Research Aug 2023Synaptic dysfunction underlies many neurodevelopmental disorders (NDDs). The membrane-associated mucin domain-containing glycosylphosphatidylinositol anchor proteins...
Synaptic dysfunction underlies many neurodevelopmental disorders (NDDs). The membrane-associated mucin domain-containing glycosylphosphatidylinositol anchor proteins (MDGAs) regulate synaptic development by modulating neurexin-neuroligin complex formation. Since understanding the neurodevelopmental profile and the sex-based differences in the manifestation of the symptoms of NDDs is important for their early diagnosis, we tested a mouse model haploinsufficient for MDGA2 (MDGA2) on a neurodevelopmental test battery, containing sensory, motor, and cognitive measures, as well as ultrasonic vocalizations. When male and female MDGA2 and wildtype (WT) C57BL/6 J mice were examined from 2 to 23 days of age using this test battery, genotype and sex differences in body weight, sensory-motor processes, and ultrasonic vocalizations were observed. The auditory startle reflex appeared earlier in the MDGA2 than in WT mice and the MDGA2 mice produced fewer ultrasonic vocalizations. The MDGA2 mice showed reduced locomotion and rearing than WT mice in the open field after 17 days of age and spent less time investigating a novel object than WT mice at 21 days of age. Female MDGA2 mice weighed less than WT females and showed lower grip strength, indicating a delay in sensory-motor development in MDGA2 mice, which appears to be more pronounced in females than males. The behavioural phenotypes resulting from MDGA2 haploinsufficiency suggests that it shows delayed development of motor behaviour, grip strength and exploratory behaviour, non-social phenotypes of NDDs.
Topics: Mice; Female; Male; Animals; Mice, Inbred C57BL; Disease Models, Animal; Neurodevelopmental Disorders; Membrane Proteins; Reflex, Startle; Neural Cell Adhesion Molecules; GPI-Linked Proteins
PubMed: 37499910
DOI: 10.1016/j.bbr.2023.114590