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Beijing Da Xue Xue Bao. Yi Xue Ban =... Jun 2024To unveil the pathological changes associated with demyelination in schizophrenia (SZ) and its consequential impact on interstitial fluid (ISF) drainage, and to...
OBJECTIVE
To unveil the pathological changes associated with demyelination in schizophrenia (SZ) and its consequential impact on interstitial fluid (ISF) drainage, and to investigate the therapeutic efficacy of ursolic acid (UA) in treating demyelination and the ensuing abnormalities in ISF drainage in SZ.
METHODS
Female C57BL/6J mice, aged 6-8 weeks and weighing (20±2) g, were randomly divided into three groups: control, SZ model, and UA treatment. The control group received intraperitoneal injection (ip) of physiological saline and intragastric administration (ig) of 1% carboxymethylcellulose sodium (CMC-Na). The SZ model group was subjected to ip injection of 2 mg/kg dizocilpine maleate (MK-801) and ig administration of 1% CMC-Na. The UA treatment group underwent ig administration of 25 mg/kg UA and ip injection of 2 mg/kg MK-801. The treatment group received UA pretreatment via ig administration for one week, followed by a two-week drug intervention for all the three groups. Behavioral assessments, including the open field test and prepulse inhibition experiment, were conducted post-modeling. Subsequently, changes in the ISF partition drainage were investigated through fluorescent tracer injection into specific brain regions. Immunofluorescence analysis was employed to examine alterations in aquaporin 4 (AQP4) polarity distribution in the brain and changes in protein expression. Myelin reflex imaging using Laser Scanning Confocal Microscopy (LSCM) was utilized to study modifications in myelin within the mouse brain. Quantitative data underwent one-way ANOVA, followed by TukeyHSD for post hoc pairwise comparisons between the groups.
RESULTS
The open field test revealed a significantly longer total distance [(7 949.39±1 140.55) cm . (2 831.01±1 212.72) cm, < 0.001] and increased central area duration [(88.43±22.06) s . (56.85±18.58) s, =0.011] for the SZ model group compared with the controls. The UA treatment group exhibited signifi-cantly reduced total distance [(2 415.80±646.95) cm . (7 949.39±1 140.55) cm, < 0.001] and increased central area duration [(54.78±11.66) s . (88.43±22.06) s, =0.007] compared with the model group. Prepulse inhibition test results demonstrated a markedly lower inhibition rate of the startle reflex in the model group relative to the controls ( < 0.001 for both), with the treatment group displaying significant improvement ( < 0.001 for both). Myelin sheath analysis indicated significant demyelination in the model group, while UA treatment reversed this effect. Fluorescence tracing exhibited a significantly larger tracer diffusion area towards the rostral cortex and reflux area towards the caudal thalamus in the model group relative to the controls [(13.93±3.35) mm . (2.79±0.94) mm, < 0.001 for diffusion area; (2.48±0.38) mm . (0.05±0.12) mm, < 0.001 for reflux area], with significant impairment of drainage in brain regions. The treatment group demonstrated significantly reduced tracer diffusion and reflux areas [(7.93±2.48) mm . (13.93±3.35) mm, < 0.001 for diffusion area; (0.50±0.30) mm . (2.48±0.38) mm, < 0.001 for reflux area]. Immunofluorescence staining revealed disrupted AQP4 polarity distribution and reduced AQP4 protein expression in the model group compared with the controls [(3 663.88±733.77) μm . (13 354.92±4 054.05) μm, < 0.001]. The treatment group exhibited restored AQP4 polarity distribution and elevated AQP4 protein expression [(11 104.68±3 200.04) μm . (3 663.88±733.77) μm, < 0.001].
CONCLUSION
UA intervention ameliorates behavioral performance in SZ mice, Thus alleviating hyperactivity and anxiety symptoms and restoring sensorimotor gating function. The underlying mechanism may involve the improvement of demyelination and ISF drainage dysregulation in SZ mice.
Topics: Animals; Mice; Triterpenes; Schizophrenia; Mice, Inbred C57BL; Female; Disease Models, Animal; Demyelinating Diseases; Extracellular Fluid; Ursolic Acid; Dizocilpine Maleate; Aquaporin 4
PubMed: 38864135
DOI: 10.19723/j.issn.1671-167X.2024.03.016 -
Frontiers in Neuroscience 2024Prepulse inhibition (PPI) is a well-established phenomenon wherein a weak sensory stimulus attenuates the startle reflex triggered by a subsequent strong stimulus....
Prepulse inhibition (PPI) is a well-established phenomenon wherein a weak sensory stimulus attenuates the startle reflex triggered by a subsequent strong stimulus. Within the circuit, variations in target responses observed for PPI paradigms represent prepulse-induced excitability changes. However, little is known about the mechanism of PPI. Here, we focused on short-latency PPI of the trigeminal blink reflex R1 signal with an oligosynaptic reflex arc through the principal sensory trigeminal nucleus and the facial nucleus. As the facial nucleus is facilitatory to any input, R1 PPI is the phenomenon in the former nucleus. Considering that GABAergic modulation may be involved in PPI, this study investigated whether the PPI mechanism includes GABA-A equivalent inhibition, which peaks at approximately 30 ms in humans. In 12 healthy volunteers, the reflex was elicited by electrical stimulation of the supraorbital nerve, and recorded at the ipsilateral lower eyelid by accelerometer. Stimulus intensity was 1.5 times the R1 threshold for test stimulus and 0.9 times for the prepulse. The prepulse-test interval (PTI) was 5-150 ms. Results showed significant inhibition at 40-and 80-150-ms PTIs but not at 20-, 30-, 50-, 60-, and 70-ms PTIs, yielding two distinct inhibitions of different time scales. This corresponds well to the early and late components of inhibitory post synaptic potentials by GABA-A and GABA-B receptor activation. Thus, the data support the contribution of inhibitory post synaptic potentials elicited by the prepulse to the observed PPI. As inhibitory function-related diseases may impair the different inhibition components to varying degrees, methods deconvoluting each inhibitory component contribution are of clinical importance.
PubMed: 38841093
DOI: 10.3389/fnins.2024.1357368 -
Social Cognitive and Affective... Jun 2024Elevated arousal in anxiety is thought to affect attention control. To test this, we designed a visual short-term memory (VSTM) task to examine distractor suppression...
Elevated arousal in anxiety is thought to affect attention control. To test this, we designed a visual short-term memory (VSTM) task to examine distractor suppression during periods of threat and no-threat. We hypothesized that threat would impair performance when subjects had to filter out large numbers of distractors. The VSTM task required subjects to attend to one array of squares while ignoring a separate array. The number of target and distractor squares varied systematically, with high (four squares) and low (two squares) target and distractor conditions. This study comprised two separate experiments. Experiment 1 used startle responses and white noise as to directly measure threat-induced anxiety. Experiment 2 used BOLD to measure brain responses. For Experiment 1, subjects showed significantly larger startle responses during threat compared to safe period, supporting the validity of the threat manipulation. For Experiment 2, we found that accuracy was affected by threat, such that the distractor load negatively impacted accuracy only in the threat condition. We also found threat-related differences in parietal cortex activity. Overall, these findings suggest that threat affects distractor susceptibility, impairing filtering of distracting information. This effect is possibly mediated by hyperarousal of parietal cortex during threat.
Topics: Humans; Male; Female; Young Adult; Magnetic Resonance Imaging; Memory, Short-Term; Attention; Reflex, Startle; Adult; Visual Perception; Brain; Photic Stimulation; Fear; Adolescent; Brain Mapping; Oxygen; Anxiety; Reaction Time
PubMed: 38809714
DOI: 10.1093/scan/nsae036 -
Frontiers in Endocrinology 2024Polycystic ovary syndrome (PCOS) is a common multifactorial and polygenic disorder of the endocrine system, affecting up to 20% of women in reproductive age with a still...
INTRODUCTION
Polycystic ovary syndrome (PCOS) is a common multifactorial and polygenic disorder of the endocrine system, affecting up to 20% of women in reproductive age with a still unknown etiology. Follicular fluid (FF) represents an environment for the normal development of follicles rich in metabolites, hormones and neurotransmitters, but in some instances of PCOS the composition can be different. Vasoactive intestinal peptide (VIP) is an endogenous autonomic neuropeptide involved in follicular atresia, granulosa cell physiology and steroidogenesis.
METHODS
ELISA assays were performed to measure VIP and estradiol levels in human follicular fluids, while AMH, FSH, LH, estradiol and progesterone in the plasma were quantified by chemiluminescence. UHPLC/QTOF was used to perform the untargeted metabolomic analysis.
RESULTS
Our ELISA and metabolomic results show: i) an increased concentration of VIP in follicular fluid of PCOS patients (n=9) of about 30% with respect to control group (n=10) (132 ± 28 pg/ml versus 103 ± 26 pg/ml, p=0,03) in women undergoing fertilization (IVF), ii) a linear positive correlation (p=0.05, r=0.45) between VIP concentration and serum Anti-Müllerian Hormone (AMH) concentration and iii) a linear negative correlation between VIP and noradrenaline metabolism. No correlation between VIP and estradiol (E2) concentration in follicular fluid was found. A negative correlation was found between VIP and noradrenaline metabolite 3,4-dihydroxyphenylglycolaldehyde (DOPGAL) in follicular fluids.
CONCLUSION
VIP concentration in follicular fluids was increased in PCOS patients and a correlation was found with noradrenaline metabolism indicating a possible dysregulation of the sympathetic reflex in the ovarian follicles. The functional role of VIP as noradrenergic modulator in ovarian physiology and PCOS pathophysiology was discussed.
Topics: Humans; Female; Polycystic Ovary Syndrome; Vasoactive Intestinal Peptide; Fertilization in Vitro; Follicular Fluid; Adult; Estradiol; Anti-Mullerian Hormone; Case-Control Studies
PubMed: 38774232
DOI: 10.3389/fendo.2024.1331282 -
The Journal of the Acoustical Society... May 2024Medial olivocochlear (MOC) efferents modulate outer hair cell motility through specialized nicotinic acetylcholine receptors to support encoding of signals in noise....
Medial olivocochlear (MOC) efferents modulate outer hair cell motility through specialized nicotinic acetylcholine receptors to support encoding of signals in noise. Transgenic mice lacking the alpha9 subunits of these receptors (α9KOs) have normal hearing in quiet and noise, but lack classic cochlear suppression effects and show abnormal temporal, spectral, and spatial processing. Mice deficient for both the alpha9 and alpha10 receptor subunits (α9α10KOs) may exhibit more severe MOC-related phenotypes. Like α9KOs, α9α10KOs have normal auditory brainstem response (ABR) thresholds and weak MOC reflexes. Here, we further characterized auditory function in α9α10KO mice. Wild-type (WT) and α9α10KO mice had similar ABR thresholds and acoustic startle response amplitudes in quiet and noise, and similar frequency and intensity difference sensitivity. α9α10KO mice had larger ABR Wave I amplitudes than WTs in quiet and noise. Other ABR metrics of hearing-in-noise function yielded conflicting findings regarding α9α10KO susceptibility to masking effects. α9α10KO mice also had larger startle amplitudes in tone backgrounds than WTs. Overall, α9α10KO mice had grossly normal auditory function in quiet and noise, although their larger ABR amplitudes and hyperreactive startles suggest some auditory processing abnormalities. These findings contribute to the growing literature showing mixed effects of MOC dysfunction on hearing.
Topics: Animals; Mice, Knockout; Evoked Potentials, Auditory, Brain Stem; Noise; Auditory Threshold; Receptors, Nicotinic; Acoustic Stimulation; Reflex, Startle; Perceptual Masking; Behavior, Animal; Mice; Mice, Inbred C57BL; Cochlea; Male; Phenotype; Olivary Nucleus; Auditory Pathways; Female; Auditory Perception; Hearing
PubMed: 38738939
DOI: 10.1121/10.0025985 -
Behaviour Research and Therapy Jul 2024Previous studies showed that glucose has beneficial effects on memory function and can enhance contextual fear learning. To derive potential therapeutic interventions,... (Randomized Controlled Trial)
Randomized Controlled Trial
Previous studies showed that glucose has beneficial effects on memory function and can enhance contextual fear learning. To derive potential therapeutic interventions, further research is needed regarding the effects of glucose on fear extinction. In two experimental studies with healthy participants (Study 1: N = 68, 39 females; Study 2: N = 89, 67 females), we investigated the effects of glucose on fear extinction learning and its consolidation. Participants completed a differential fear conditioning paradigm consisting of acquisition, extinction, and return of fear tests: reinstatement, and extinction recall. US-expectancy ratings, skin conductance response (SCR), and fear potentiated startle (FPS) were collected. Participants were pseudorandomized and double-blinded to one of two groups: They received either a drink containing glucose or saccharine 20 min before (Study 1) or immediately after extinction (Study 2). The glucose group showed a significantly stronger decrease in differential FPS during extinction (Study 1) and extinction recall (Study 2). Additionally, the glucose group showed a significantly lower contextual anxiety at test of reinstatement (Study 2). Our findings provide first evidence that glucose supports the process of fear extinction, and in particular the consolidation of fear extinction memory, and thus has potential as a beneficial adjuvant to extinction-based treatments. Registered through the German Clinical Trials Registry (https://www.bfarm.de/EN/BfArM/Tasks/German-Clinical-Trials-Register/_node.html; Study 1: DRKS00010550; Study 2: DRKS00018933).
Topics: Humans; Extinction, Psychological; Fear; Female; Male; Glucose; Adult; Young Adult; Double-Blind Method; Conditioning, Classical; Galvanic Skin Response; Reflex, Startle; Adolescent; Mental Recall
PubMed: 38728832
DOI: 10.1016/j.brat.2024.104553 -
Behaviour Research and Therapy Jul 2024Although observational fear learning has been implicated in the development of phobic-related fears, studies investigating observational learning of fear of bodily...
Although observational fear learning has been implicated in the development of phobic-related fears, studies investigating observational learning of fear of bodily symptoms remain scarce. Therefore, the aim of the present study was to investigate whether fear in response to bodily symptoms can be acquired simply by observing a fearful reaction to provocation of aversive bodily symptoms in others. Forty healthy participants underwent an observational fear conditioning paradigm consisting of two phases. In the first phase, participants observed a demonstrator reacting to an aversive bodily symptom provocation (unconditioned stimulus or US, i.e., labored breathing) paired with one conditioned stimulus (CS+) but not with the other one (CS-, both CSs were geometric symbols presented on a screen the demonstrator was watching). In the second phase, participants were directly presented with the same conditioned stimuli, but in the absence of the US. Our results revealed enhanced conditioned fear responses in the beginning of the second phase to the CS + as compared to CS-, as indexed by greater skin conductance and subjective fear responses, as well as greater potentiation of startle eyeblink responses to the CS + as compared to the ITI. Taken together, these findings implicate that fear of bodily symptoms can be learned through observation of others, that is, without first-hand experience of bodily threat.
Topics: Humans; Fear; Female; Male; Conditioning, Classical; Reflex, Startle; Young Adult; Galvanic Skin Response; Adult; Adolescent; Blinking
PubMed: 38718630
DOI: 10.1016/j.brat.2024.104555 -
Brain and Behavior May 2024Chronic adolescent stress profoundly affects prefrontal cortical networks regulating top-down behavior control. However, the neurobiological pathways contributing to...
INTRODUCTION
Chronic adolescent stress profoundly affects prefrontal cortical networks regulating top-down behavior control. However, the neurobiological pathways contributing to stress-induced alterations in the brain and behavior remain largely unknown. Chronic stress influences brain growth factors and immune responses, which may, in turn, disrupt the maturation and function of prefrontal cortical networks. The tumor necrosis factor alpha-converting enzyme/a disintegrin and metalloproteinase 17 (TACE/ADAM17) is a sheddase with essential functions in brain maturation, behavior, and inflammatory responses. This study aimed to determine the impact of stress on the prefrontal cortex and whether TACE/ADAM17 plays a role in these responses.
METHODS
We used a Lewis rat model that incorporates critical elements of chronic psychosocial stress, such as uncontrollability, unpredictability, lack of social support, and re-experiencing of trauma.
RESULTS
Chronic stress during adolescence reduced the acoustic startle reflex and social interactions while increasing extracellular free water content and TACE/ADAM17 mRNA levels in the medial prefrontal cortex. Chronic stress altered various ethological behavioral domains in the observation home cages (decreased ingestive behaviors and increased walking, grooming, and rearing behaviors). A group of rats was injected intracerebrally either with a novel Accell™ SMARTpool TACE/ADAM17 siRNA or a corresponding siRNA vehicle (control). The RNAscope Multiplex Fluorescent v2 Assay was used to visualize mRNA expression. Automated puncta quantification and analyses demonstrated that TACE/ADAM17 siRNA administration reduced TACE/ADAM17 mRNA levels in the medial prefrontal cortex (59% reduction relative to control). We found that the rats that received prefrontal cortical TACE/ADAM17 siRNA administration exhibited altered eating patterns (e.g., increased food intake and time in the feeding zone during the light cycle).
CONCLUSION
This study supports that the prefrontal cortex is sensitive to adolescent chronic stress and suggests that TACE/ADAM17 may be involved in the brain responses to stress.
Topics: Animals; Male; Rats; ADAM17 Protein; Behavior, Animal; Prefrontal Cortex; Rats, Inbred Lew; Reflex, Startle; Stress, Psychological; Female
PubMed: 38715397
DOI: 10.1002/brb3.3482 -
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