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Many people affected by fragile X syndrome (FXS) and autism spectrum disorders have sensory processing deficits, such as hypersensitivity to auditory, tactile, and visual stimuli. Like FXS in humans, loss of Fmr1 in rodents also cause sensory, behavioral, and cognitive deficits. However, the neural mechanisms underlying sensory impairment, especially vision impairment, remain unclear. It remains elusive whether the visual processing deficits originate from corrupted inputs, impaired perception in the primary sensory cortex, or altered integration in the higher cortex, and there is no effective treatment. In this study, we used a genetic knockout mouse model (Fmr1KO), in vivo imaging, and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex (V1). Specifically, Fmr1KO mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli. This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons. These effects were ameliorated by the acute application of GABAA receptor activators, which enhanced the activity of inhibitory neurons, or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice. Overall, V1 plays an important role in the visual abnormalities of Fmr1KO mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.
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Animals , Humans , Mice , Disease Models, Animal , Fragile X Mental Retardation Protein/metabolism , Fragile X Syndrome/metabolism , Mice, Knockout , Neurons/metabolismABSTRACT
Background:Visceral hypersensitivity is considered to be one of the major pathophysiological mechanisms of irritable bowel syndrome. Aims:To investigate the expression of TRPV1 and electrophysiological characteristics of colon-specific dorsal root ganglion( DRG)neurons in rat model of visceral hypersensitivity. Methods:Twenty 10-day-old rats were randomly divided into two groups. In model group,visceral hypersensitivity was induced by colorectal administration of acetic acid;while in control group the same amount of saline was administered. Colon-specific DRG neurons were labeled retrogradely by injection of DiI,a fluorochrome,into the colon wall. Expression of TRPV1 in DRG neurons was detected by immunofluorescence and the electrophysiological characteristics of DRG neurons was detected by using patch-clamp technique. Results:In model group,the expression rate of TRPV1 in colon-specific DRG neurons was significantly higher than that in controls(46. 1% vs. 36. 6% ,P <0. 01),the average rheobase was significantly decreased[(57. 80 ±1. 32)pA vs.(73. 45 ± 4. 51)pA,P < 0. 05],while the frequency of action potentials(APs)in response to doubling rheobase stimulation was significantly increased[(8. 20 ± 1. 10)Hz vs. (4. 54 ± 0. 66)Hz,P < 0. 05]. Score of abdominal withdrawal reflex(AWR)under a 60 mm Hg colorectal distention was positively correlated with the expression rate of TRPV1 and the frequency of APs in response to doubling rheobase stimulation(r = 0. 87 and r = 0. 73,P < 0. 01),but was negatively correlated with the rheobase(r = - 0. 81,P < 0. 01)in model group. Conclusions:Increased expression of TRPV1 and excitability in colon-specific DRG neurons might be a crucial step in formation of visceral hypersensitivity.
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Objective To investigate the way of fear conditioning memory model evoked and erased by foot-shock in tree shrew. Methods First, detect the tree shrew activities regularly in light/dark box. Second, test a suitable voltage degree of foot shock on tree shrew. Third, investigate the memory formation and erasing of fear conditioning on tree shrew of trial group. Results The duration of tree shrew (n=4) stay in the dark-box was significantly lon-ger than that of in the light box (P<0. 01) in normal condition. In the same environment of two light boxes, given different voltage degrees, the durations of tree shrew (n=6) stay in the stimulating chamber gradually reduced and the durations of tree shrew stay had significant difference between stimulatus chamber and no stimulatus chamber when the stimulus voltage up to 12 V ( P<0. 05 ) , 16 V ( P<0. 01 ) and 20 V ( P<0. 01 ) . The animal of trial group ( n=4 ) could build up the fear conditioning memory of the dark box with the stimulus of 16 V foot-shock in the dark box ( P<0. 001 ) . After formation of the fear conditioning memory, the same stimulus in light box ap-peared for 4 days. The durations of tree shrew stay in trial group (n=4) decreased in light box, and there was no significant difference between the trial group and the control group. Conclusion Tree shrew prefers to stay in the dark box. The suitable voltage for foot-shock on tree shrew is 16 V. The fear conditioning memory can be evoked and erased by foot-shock.
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Objective To explore whether gap junction disturbances are involved in the pathogenesis of levodopa-induced dyskinesia ( LID ). Methods The hemi-parkinsonian ( PD ) rat was treated intraperitoneally with L-dopa methylester (20 mg/kg) and benserazid (10 mg/kg) for 21 days and abnormal involuntary movement was evaluated to establish LID rat model. The experimental animals were divided into three groups: LID group, PD group and normal control group, respectively. The behavior responses of intraperitoneal injection of different doses of carbenoxolon and intracerebroventricular injection of quinine were observed to estimate the effects of gap junctional blockade on the abnormal involuntary movement ( AIM ) in the rat model of LID. Double immunofluorescence labeling was used to analyze the expression of connexin 36 ( Cx36 ) in enkephalin positive medium spiny neurons and parvalbumin ( PV ) positive interneurons in the striatum. Western blottings was used to observe the expression of Cx36 in the striatum and moter cortex. Results Behavioral characteristics indicated that high dose of carbenoxolone ( >60 mg/kg) intraperitoneal injection and intracerebroventricular injection of quinine ( 0.5, 1.0, 2.0 μmol/L, > 2.5 μmol/L ) could decrease the AIM score of LID rats. Western blotting indicated that expression of Cx36 in lesioned striatum and motor cortex of LID rat model was 219.56% ±18.12% and 226.03% ±16.33%, respectively, which induced a significant upregulation in comparison with the normal control group (104.05% ±3.82%, t=15.389, P<0.01;105.27% ±2.82%,t=8.074, P<0.01) and untreated PD group (119.31% ±8.92%, t=13.356, P<0.01; 138.20% ±17.88%, t=5.872, P<0.01). Double immunofluorescence labeling staining revealed that Cx36 expression was increased in Enk-positive striatum neurons in LID model ( 57.59% ±5.36%) compared with that in normal control group (32.67% ±4.22%) and PD group (37.24% ±0.86%, F=78.060, P<0.01). The expression of Cx36 in PV-positive interneurons was also elevated in LID group (68.49% ±11.60%) in comparison with normal control group ( 40.43% ± 2.30%) and PD group ( 31.92% ± 5.68%, F = 39.567, P < 0.01 ).Conclusions The Cx36 expression is generally increased in lesioned striatum and motor cortex of LID rat model. In the striatum, the up-regulation of Cx36 is specifically observed in Enk-positive striatum neurons and in PV-positive interneurons. The dyskinesia behavior of LID rats can be significantly reduced by treatment with gap junction blockade. All these results suggest that gap junction dysfunction may play an important role in the pathogenesis of LID.
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Objective To investigate the effects of bisphenol A(BPA)exposure to perinatal on learning and memory behaviour in F1 generation male rats.Methods From the 11th day of gestation to the 7th day of field test was used to detect the locomotion activity,the Morris water maze was employed to measure learning and memory ability and long-term potentiation(LTP)were recorded to detect the synaptic plasticity in hippocampus CA1 with extracellular recording.Results The crossing number of BPA group(70.35±13.56)was much more than control group((29.32±14.12),P＜0.05).The number of standing up and ornament of BPA group((38.52±6.52),(6.26±2.78))were both higher than control group((10.35±8.38),(2.67±1.46),P＜0.05).BPA rats had longer escape latencies to find platform((55.22±5.78)s)than control rats((21.22±2.65)s,P＜0.05).Conditional protocol with high-frequency stimulation evoked a stable LTP in hippocampus CA1 region in control rats((162.13±10.12)%),however the LTP could not be induced with the same conditional protocol in BPA-exposed rats((101.05±7.58)%,P＜0.05).Conclusion Perinatal BPA exposure impaires learning and memory ability in F1 generation male rats related to presynaptic dysfunction.
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AIM To study the role of serot on in (5-HT) in ventrolateral preoptic nucleus(VLPO) on sleep and wakefulness cycl e of rat by microinjection of 5-hydroxytryptaphan (5-HTP , precursor of 5-HT ) , non-special 5-HT receptor antagonist methysergide (MS) and 5-HT retake i nhibitor fluoxetine. METHODS Stereotaxic, microinjection and po lysomnography (PSG) were used in the experiment. RESULTS There was no significant effect by microinjection of 5-HTP(0 5 ?g,0 1 ?l) into VLPO,but microinjection of 5-HTP(1 ?g,0 1 ?l)and fluoxetine lead wake i ncreased and sleep decreased; while microinjection of non-selective serotonin receptor antagonist MS lead to the opposited effect. The chang of sleep-wakefu lness cycle caused by 5-HTP or MS were significantly assiociated with time. CONCLUSION 5-HT involved in the regulation of sleep-wake cycle a nd promoted wake in the VLPO and its role of promotion may involve the gene exp ression of post-synaptic neurons.
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AIM To investigate the effects of several 5-hydroxytryptamine(5-HT) subtype receptor antagonists on late slow excitatory postsynaptic potential(LS-EPSP) of the neurons of guinea pig inferior mesenteric ganglion(IMG). METHODS Intracellular recordings were made from neurons of the isolated guinea pig IMG. RESULTS Cyproheptadine and BRL 24924 suppressed LS-EPSP of 5-HT sensitive neurons reversibly, while mianserin, MDL 72222 and spiperone showed no significant effect. Continuous superfusion of IMG with MCPP suppressed LS-EPSP of 5-HT sensitive neurons by 5-HT 1P receptor desensitizated. CONCLUSION LS-EPSP of 5-HT sensitive neuron is mediated by 5-HT 1P subtype receptor.
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Aim To explore the neuroprotective effects of preconditioning with resveratrol on focal cerebral ischemia-reperfusion injury in rats.Methods Forty-five Sprague-Dawley rats were randomly divided into sham group,ischemic-reperfusion group(I/R)and resveratrol preconditioning ischemic-reperfusion group(Res+I/R).Each group had 15 animals.The middle cerebral artery in rats was occluded for 90 min by an intraluminal filament and then reperfused to cause transient focal cerebral ischemia.In the resveratrol preconditioning group,the resveratrol(30 mg?kg-1)was injected intraperitoneally 30 min before ischemia.Twenty-four hours after reperfusion,the infarct volume was shown with 2,3,5-triphenyl tetrazolium chloride(TTC)staining.The spatial learning and memory ability of rats was measured by Morris water maze 72 h after reperfusion.Electrophysiological recordings were conducted to detect the effects of resveratrol on Schaffer collateral-CA1 synaptic transmission in ischemic rats.Results The infarct volume and neurological score in Res+I/R group were lower than I/R group(P
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Aim To study the effects of a novel psychoactive drug,modafinil,on the GABAA receptor-induced current in rat hippocampus pyramidal neurons.Methods Whole-cell patch-clamp recordings were applied in cultured hippocampus pyramidal neurons.Results The GABA-activated currents were blocked by bicuculline,a competitive antagonist of GABAA receptor.Modafinil could partly inhibit IGABA.Pre-treating hippocampus neurons with glibenclamide for 30 min,modafinil-induced inhibition on IGABA was removed.Conclusion Modafinil is different from other psychostimulants.The protection of modafinil may be via modulating ATP sensitive potassium channel activation.