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Ideggyogyaszati Szemle Sep 2023
Ciprofloxacin (CIP) is a broad-spectrum antibiotic widely used in clinical practice to treat musculoskeletal infections. Fluoroquinolone-induced neurotoxic adverse...
BACKGROUND AND PURPOSE
Ciprofloxacin (CIP) is a broad-spectrum antibiotic widely used in clinical practice to treat musculoskeletal infections. Fluoroquinolone-induced neurotoxic adverse events have been reported in a few case reports, all the preclinical studies on its neuropsychiatric side effects involved only healthy animals. This study firstly investigated the behavioral effects of CIP in an osteoarthritis rat model with joint destruction and pain, which can simulate inflammation-associated musculoskeletal pain. Furthermore, effects of CIP on regional brain-derived neurotrophic factor (BDNF) expression were examined given its major contributions to the neuromodulation and plasticity underlying behavior and cognition.
.METHODS
Fourteen days after induction of chronic osteoarthritis, animals were administered vehicle, 33 mg/kg or 100 mg/kg CIP for five days intraperitoneally. Motor activity, behavioral motivation, and psychomotor learning were examined in a reward-based behavioral test (Ambitus) on Day 4 and sensorimotor gating by the prepulse inhibition test on Day 5. Thereafter, the prolonged BDNF mRNA and protein expression levels were measured in the hippocampus and the prefrontal cortex.
.RESULTS
CIP dose-dependently reduced both locomotion and reward-motivated exploratory activity, accompanied with impaired learning ability. In contrast, there were no significant differences in startle reflex and sensory gating among treatment groups; however, CIP treatment reduced motor activity of the animals in this test, too. These alterations were associated with reduced BDNF mRNA and protein expression levels in the hippocampus but not the prefrontal cortex.
.CONCLUSION
This study revealed the detrimental effects of CIP treatment on locomotor activity and motivation/learning ability during osteoarthritic condition, which might be due to, at least partially, deficient hippocampal BDNF expression and ensuing impairments in neural and synaptic plasticity.
.Topics: Humans; Rats; Animals; Brain-Derived Neurotrophic Factor; Ciprofloxacin; Reflex, Startle; Learning; RNA, Messenger; Hippocampus
PubMed: 37782061
DOI: 10.18071/isz.76.0327 -
Medicina (Kaunas, Lithuania) Sep 2023: Epidemiological data indicate that blast exposure is the most common morbidity responsible for mild TBI among Service Members (SMs) during recent military operations....
: Epidemiological data indicate that blast exposure is the most common morbidity responsible for mild TBI among Service Members (SMs) during recent military operations. Blast-induced tinnitus is a comorbidity frequently reported by veterans, and despite its wide prevalence, it is also one of the least understood. Tinnitus arising from blast exposure is usually associated with direct structural damage that results in a conductive and sensorineural impairment in the auditory system. Tinnitus is also believed to be initiated by abnormal neuronal activities and temporal changes in neuroplasticity. Clinically, it is observed that tinnitus is frequently accompanied by sleep disruption as well as increased anxiety. In this study, we elucidated some of the mechanistic aspects of sensorineural injury caused by exposure to both shock waves and impulsive noise. The isolated conductive auditory damage hypothesis was minimized by employing an animal model wherein both ears were protected. : After the exposure, the animals' hearing circuitry status was evaluated via acoustic startle response (ASR) to distinguish between hearing loss and tinnitus. We also compared the blast-induced tinnitus against the well-established sodium salicylate-induced tinnitus model as the positive control. The state of the sensorineural auditory system was evaluated by auditory brainstem response (ABR), and this test helped examine the neuronal circuits between the cochlea and inferior colliculus. We then further evaluated the role of the excitatory and inhibitory neurotransmitter receptors and neuronal synapses in the auditory cortex (AC) injury after blast exposure. : We observed sustained elevated ABR thresholds in animals exposed to blast shock waves, while only transient ABR threshold shifts were observed in the impulsive noise group solely at the acute time point. These changes were in concert with the increased expression of ribbon synapses, which is suggestive of neuroinflammation and cellular energy metabolic disorder. It was also found that the onset of tinnitus was accompanied by anxiety, depression-like symptoms, and altered sleep patterns. By comparing the effects of shock wave exposure and impulsive noise exposure, we unveiled that the shock wave exerted more significant effects on tinnitus induction and sensorineural impairments when compared to impulsive noise. : In this study, we systematically studied the auditory system structural and functional changes after blast injury, providing more significant insights into the pathophysiology of blast-induced tinnitus.
Topics: Animals; Tinnitus; Reflex, Startle; Deafness; Anxiety; Anxiety Disorders
PubMed: 37763802
DOI: 10.3390/medicina59091683 -
European Journal of Applied Physiology Mar 2024For whole-body sway patterns, a compound motor response following an external stimulus may comprise reflexes, postural adjustments (anticipatory or compensatory), and...
For whole-body sway patterns, a compound motor response following an external stimulus may comprise reflexes, postural adjustments (anticipatory or compensatory), and voluntary muscular activity. Responses to equilibrium destabilization may depend on both motor set and a subject`s expectation of the disturbing stimulus. To disentangle these influences on lower limb responses, we studied a model in which subjects (n = 14) were suspended in the air, without foot support, and performed a fast unilateral wrist extension (WE) in response to a passive knee flexion (KF) delivered by a robot. To characterize the responses, electromyographic activity of rectus femoris and reactive leg torque was obtained bilaterally in a series of trials, with or without the requirement of WE (motor set), and/or beforehand information about the upcoming velocity of KF (subject`s expectation). Some fast-velocity trials resulted in StartReact responses, which were used to subclassify leg responses. When subjects were uninformed about the upcoming KF, large rectus femoris responses concurred with a postural reaction in conditions without motor task, and with both postural reaction and postural adjustment when WE was required. WE in response to a low-volume acoustic signal elicited no postural adjustments. When subjects were informed about KF velocity and had to perform WE, large rectus femoris responses corresponded to anticipatory postural adjustment rather than postural reaction. In conclusion, when subjects are suspended in the air and have to respond with WE, the prepared motor set includes anticipatory postural adjustments if KF velocity is known, and additional postural reactions if KF velocity is unknown.
Topics: Humans; Posture; Electromyography; Wrist; Reflex; Lower Extremity; Postural Balance; Movement; Muscle, Skeletal
PubMed: 37755580
DOI: 10.1007/s00421-023-05323-z -
Scientific Reports Sep 2023
PubMed: 37739990
DOI: 10.1038/s41598-023-42343-3 -
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 -
Phytotherapy Research : PTR Dec 2023Schizophrenia is a chronic brain disorder characterized by positive symptoms (delusions or hallucinations), negative symptoms (impaired motivation or social withdrawal),...
Schizophrenia is a chronic brain disorder characterized by positive symptoms (delusions or hallucinations), negative symptoms (impaired motivation or social withdrawal), and cognitive impairment. In the present study, we explored whether D-pinitol could ameliorate schizophrenia-like behaviors induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Acoustic startle response test was conducted to evaluate the effects of D-pinitol on sensorimotor gating function. Social interaction and novel object recognition tests were employed to measure the impact of D-pinitol on social behavior and cognitive function, respectively. Additionally, we examined whether D-pinitol affects motor coordination. Western blotting was conducted to investigate the mechanism of action of D-pinitol. Single administration of D-pinitol at 30, 100, or 300 mg/kg improved the sensorimotor gating deficit induced by MK801 in the acoustic startle response test. D-Pinitol also reversed social behavior deficits and cognitive impairments induced by MK-801 without causing any motor coordination deficits. Furthermore, D-pinitol reversed increased expression levels of pNF-kB induced by MK-801 treatment and consequently increased expression levels of TNF-α and IL-6 in the prefrontal cortex. These results suggest that D-pinitol could be a potential candidate for treating sensorimotor gating deficits and cognitive impairment observed in schizophrenia by down-regulating transcription factor NF-κB and pro-inflammatory cytokines in the prefrontal cortex.
Topics: Mice; Animals; Dizocilpine Maleate; Reflex, Startle; Schizophrenia; Cognitive Dysfunction
PubMed: 37654104
DOI: 10.1002/ptr.8002 -
Molecular Neurobiology Feb 2024Numerous pathogenic variants of SCN2A gene, encoding voltage-gated sodium channel α2 subunit Nav1.2 protein, have been identified in a wide spectrum of neuropsychiatric...
Numerous pathogenic variants of SCN2A gene, encoding voltage-gated sodium channel α2 subunit Nav1.2 protein, have been identified in a wide spectrum of neuropsychiatric disorders including schizophrenia. However, pathological mechanisms for the schizophrenia-relevant behavioral abnormalities caused by the variants remain poorly understood. Here in this study, we characterized mouse lines with selective Scn2a deletion at schizophrenia-related brain regions, medial prefrontal cortex (mPFC) or ventral tegmental area (VTA), obtained by injecting adeno-associated viruses (AAV) expressing Cre recombinase into homozygous Scn2a-floxed (Scn2a) mice, in which expression of the Scn2a was locally deleted in the presence of Cre recombinase. The mice lacking Scn2a in the mPFC exhibited a tendency for a reduction in prepulse inhibition (PPI) in acoustic startle response. Conversely, the mice lacking Scn2a in the VTA showed a significant increase in PPI. We also found that the mice lacking Scn2a in the mPFC displayed increased sociability, decreased locomotor activity, and increased anxiety-like behavior, while the mice lacking Scn2a in the VTA did not show any other abnormalities in these parameters except for vertical activity which is one of locomotor activities. These results suggest that Scn2a-deficiencies in mPFC and VTA are inversely relevant for the schizophrenic phenotypes in patients with SCN2A variants.
Topics: Mice; Humans; Animals; Reflex, Startle; Prepulse Inhibition; Ventral Tegmental Area; Prefrontal Cortex; Acoustics
PubMed: 37650965
DOI: 10.1007/s12035-023-03610-6 -
Scientific Reports Aug 2023Two studies examined the amplitude of the startle response as a function of the Dark Tetrad of personality (narcissism, Machiavellianism, psychopathy, and sadism). We...
Two studies examined the amplitude of the startle response as a function of the Dark Tetrad of personality (narcissism, Machiavellianism, psychopathy, and sadism). We measured electromyographic activity of the orbicularis oculi muscle evoked by a startle stimulus while participants viewed images on a computer screen. Both studies revealed a negative correlation between general startle reactivity (averaged across positive, negative, and neutral images) and sadistic tendencies. In Study 2, all four dark traits were negative correlates of general startle reactivity. Study 2 also examined the personality correlates of aversive startle potentiation (ASP; indexed by greater reactivity while viewing negatively-valenced images than positive or neutral images). ASP correlated negatively with a variety of personality measures of psychopathy and sadism, their facets, and related personality tendencies (callousness, risk-taking, and restricted affect). These findings suggest that ordinary people with high levels of callousness and antagonism display physiological evidence of non-reactivity (i.e., blunted acoustic startle in general), whereas psychopathy and sadism are preferentially associated with reduced ASP.
Topics: Humans; Reflex, Startle; Sadism; Antisocial Personality Disorder; Personality Disorders; Personality
PubMed: 37648765
DOI: 10.1038/s41598-023-41043-2 -
Neuroscience Oct 2023Fear-potentiated startle (FPS) has been widely used to study fear processing in humans and rodents. Human studies showed higher startle amplitudes and exaggerated fear...
Fear-potentiated startle (FPS) has been widely used to study fear processing in humans and rodents. Human studies showed higher startle amplitudes and exaggerated fear reactivity to unpredictable vs. predictable threats in individuals suffering from post-traumatic stress disorder (PTSD). Although human FPS studies use both sexes, a surprisingly limited number of rodent FPS studies use females. Here we investigate the effects of signal-threat contingency, signal-threat order and threat predictability on FPS in both sexes. We use a classic fear-conditioning protocol (100% contingency of cue and shock pairings, with forward conditioning such that the cue co-terminates with the shock) and compare it to modified fear-conditioning protocols (70% contingency; backward conditioning; or cue and shock un-paired). Although there are no sex differences in the startle amplitudes when corrected for body weight, females consistently demonstrate higher shock reactivity during fear-conditioning. Both sexes and strains demonstrate comparable levels of cued, non-cued, and contextual fear in the classic FPS and FPS following fear-conditioning with 70% contingency or backward order (cue co-starts with shock). However, in the classic FPS, Sprague-Dawley females show reduced proportion between cued fear and cue-elicited vigilant state than males. Lastly, a prominent sex difference is uncovered following unpredictable fear-conditioning (cue and shock un-paired), with Wistar, but not Sprague-Dawley, females showing significantly higher startle overall during the FPS recall, regardless of trial type, and higher contextual fear than males. This striking sex difference in processing unpredictable threats in rodent FPS might help to understand the mechanisms underlying higher incidence of PTSD in women.
Topics: Rats; Humans; Female; Male; Animals; Rats, Sprague-Dawley; Conditioning, Classical; Reflex, Startle; Rats, Wistar; Fear
PubMed: 37640137
DOI: 10.1016/j.neuroscience.2023.08.030 -
Experimental Brain Research Oct 2023Movement goals are an essential component of motor planning, altering voluntary and involuntary motor actions. While there have been many studies of motor planning, it...
Movement goals are an essential component of motor planning, altering voluntary and involuntary motor actions. While there have been many studies of motor planning, it is unclear if motor goals influence voluntary and involuntary movements at similar latencies. The objectives of this study were to determine how long it takes to prepare a motor action and to compare this time for voluntary and involuntary movements. We hypothesized a prepared motor action would influence voluntarily and involuntarily initiated movements at the same latency. We trained subjects to reach with a forced reaction time paradigm and used a startling acoustic stimulus (SAS) to trigger involuntary initiation of the same reaches. The time available to prepare was controlled by varying when one of four reach targets was presented. Reach direction was used to evaluate accuracy. We quantified the time between target presentation and the cue or trigger for movement initiation. We found that reaches were accurately initiated when the target was presented 48 ms before the SAS and 162 ms before the cue to voluntarily initiate movement. While the SAS precisely controlled the latency of movement onset, voluntary reach onset was more variable. We, therefore, quantified the time between target presentation and movement onset and found no significant difference in the time required to plan reaches initiated voluntarily or involuntarily (∆ = 8 ms, p = 0.2). These results demonstrate that the time required to plan accurate reaches is similar regardless of if they are initiated voluntarily or triggered involuntarily. This finding may inform the understanding of neural pathways governing storage and access of motor plans.
Topics: Humans; Reflex, Startle; Movement; Reaction Time; Cognition; Acoustic Stimulation; Dyskinesias; Electromyography
PubMed: 37634132
DOI: 10.1007/s00221-023-06666-x