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1、精品论文Effects of chronic morphine exposure on visual response variability and latency in cats1Long Zaiyang *, Liang Zhen, He LihuaSchool of Life Science, University of Science and Technology of China, Hefei, Anhui, P. R.China (230027)E-mail: AbstractChronic morphine exposure results in a degradation o
2、f the functional properties of corticalneurons. However, little evidence has been shown about morphines effects on the variability of visual response. To investigate whether chronic morphine exposure influences variability, we compared neurons of lateral geniculate nucleus (LGN) in morphine- and sal
3、ine-treated cats. We found LGN neurons exhibited significantly increased variability after morphine administration. It is known that variability might act as one of the factors affecting response latency. Therefore, we correlated increased variability and prolonged latency, and this study showed the
4、 change of variability might contribute to delayed response accompanied by morphine. Increased variability together with prolonged latency should play important role in functional degradation in cortical areas after chronic morphine exposure.Keywords: lateral geniculate nucleus; morphine; trial-to-t
5、rial variability; response latency1. IntroductionChronic morphine exposure results in maladaptive changes in visual structure and function. It has been demonstrated that drug abuse changes both the inhibitory and excitatory neurotransmission in many brain areas1-4. Previous studies showed that chron
6、ic morphine exposure leads to functional decline of receptive field properties of V1 and LGN neurons5, 6. It is also reported in another our manuscript that LGN neurons have significantly prolonged response latency in morphine-treated cats. However, the causation of these functional and temporal pro
7、perties decline is not very clear after chronic morphine exposure.It is well accepted that visual response variability plays an important role in signaling and coding in visual pathway7-11. The performance of the neural system is restricted by the variability with which information transfer from one
8、 cell to another12. For example, the response latency is influenced by response variability, because the less variable the spike train stimulated by external, the shorter time would be needed to reach the peak in the post-stimulus time histogram.Besides response variability, neural response time is
9、co-affected by axonal conduct rate, actionpotential initiation, signal synchronization and other factors13. All these factors might contribute to delayed visual response of animals after morphine administration. So in present study, we examined the effects of chronic morphine exposure on response va
10、riability and its relationship with prolonged response latency, aiming to explore the potential neural mechanisms underlying the morphine-related changes of response latency.2. Materials and methods2.1 Subjects and drug exposureThe experiments were performed on 8 healthy adult male cats (2-3 kg), 4
11、of which were allotted to morphine treatment group and the other 4 to saline group as control. All cats were examined ophthalmoscopically to avoid obvious optical or retinal problems which could impair the visual function, and treated strictly in accordance with the National Institute of Healths Gui
12、de for the Care1Supported by the Specialized Research Fund for the Doctoral Program of Higher Education (20040358046).-6-and Use of Laboratory Animals. We used the similar way of morphine administration as other researchers14. Morphine cats were given morphine sulfate (10mg/kg) by cervical subcutane
13、ous injection twice per day at 9:00 and 21:00 for 10 days before the electrophysiological experiments. Control cats were treated similarly with saline instead of morphine.2.2 Preparation for extracellular recordingOn the 11th day of administration, animals were prepared for extracellular single-unit
14、 recording as described previously15, 16. Typical recording section lasted for 3 days. During this period, morphine or saline was injected in the same way as described above.2.3 Visual stimulationComputer-controlled visual stimuli consisting of flicker were presented on a CRT (Cathode-Ray Tube) moni
15、tor (1024768, 85 Hz, SONY, Tokyo, Japan), placed 57cm away from animals eyes. The program to generate stimulus was written in MATLAB (MathWorks, Natick, USA), using the extensions provided by the high-level Psychophysics Toolbox17 and the low-level Video Toolbox18. The visual stimulus was a flashing
16、 spot within receptive field with optimal size for each cell, which iscommonly used in related studies. The mean luminance of the display was 19 cd/ and theenvironment luminance on the cornea was 0.1 lux. For each cell, we presented the identical visual stimulus for 50 times, with an ON period of 0.
17、5s and an OFF period of 3s.2.4 Data collection and analysisAfter the neuronal signals were amplified with a microelectrode amplifier (Nihon Kohden, Tokyo, Japan) and a differential amplifier (FHC, Bowdoinham, USA), action potentials were fed into a window discriminator with an audio monitor. The ori
18、ginal voltage traces were digitized using an acquisition board (National Instruments, Austin, USA) controlled by IGOR software (WaveMetrics, Portland, USA). The original data were saved for online and offline analysis. The post-stimulus time histograms (PSTH) of neuronal responses with a bin width o
19、f 1 ms were obtained. Then the risingbranch of the first peak in PSTH with an amplitude equal or larger than three times of spontaneousactivity was fitted by a Gaussian curve ( y = y00+ A exp( x x0) / ) 2 ) ) whose time offset (x )was taken as the response latency (Peak latency) and half-width () as
20、 a measure of the trial-to-trial variability19.3. ResultsThe data included 143 cells of LGN from morphine-treated cats (abbreviated to MCs) and 131 cells from saline-treated cats (abbreviated to control). Other 4 cells from MCs and 5 cells from control were excluded because they had abnormally low r
21、esponses. Two typical PSTHs are represented in Figure 1. Compared with those in control group, the cells recorded in morphine-treated cats showed significant prolonged response latency and increased response variability (Table 1). The average for morphine-treated cells is significantly larger than t
22、hat for control cells (13.74ms, 5.94ms; Mann-Whitney test, p0.001). This indicates that morphine-treated neurons have higher trial-to-trial variability.Table1: Latency and for cells in morphine and saline treated cats ( Data are presented as meanSE)VariabilityMCsControlMann-Whitney testPeak latency/
23、ms27.581.3120.890.86p0.001/ms13.741.045.940.46p0.001We analyzed 93 on- and 50 off-center cells, 92 X and 51 Y cells, 80 layer A, 41 layer A1 and 22 layer C neurons in MCs, 94 on- and 37 off-center cells, 89 X and 39 Y cells, 72 layer A, 33 layer A1 and 26 layer C neurons in control respectively. Thr
24、ee saline-treated cells are excluded since their responses to flicker phase were not measured so that X or Y types could not be identified accurately. Different layer neurons and on/off-center neurons all exhibit significantly elevated variability. Though X cells had significantly increased variabil
25、ity, while Y cells had a tendency to variability increase in MCs, we believe there is a consistent effect of chronic morphine exposure on different LGN neurons. So comparisons of data between the two groups ignore the different types.(A)(B)Figure1: The post-stimulus time histograms (PSTH) of neurona
26、l responses obtained from one example saline-treated cell (A) and one morphine-treated cell (B) with a bin width of 1 ms. The responses are driven by aflashing spot within receptive field with optimal size for each cell. The luminance of the stimulus was 38 cd/ forwhite and 0.1 lux for black. Black
27、lines represent the raising branch of the Gaussian curve used to fit the peak inPSTH. We can get time offset (x0) presenting peak latency and half-width () presenting trial-to-trial variability.Furthermore, since response latency could be affected by variability, we studied the relationship between
28、changed response variability and latency after chronic morphine exposure. Response latency is considerably longer in MCs than in control (27.3ms, 20.7ms; Mann-Whitney test, p0.001), which hasbeen showed in our other manuscript recently (Figure 2A). Figure 2B represents the percentage of saline- and
29、morphine-treated cells with any given half-width () are shown in cumulative distribution plots. We used two-tailed Bivariate Correlation (Spearmans Rho) to check the connection of increased response variability and prolonged latency as following. Response variability was correlated with response lat
30、ency (Correlation coefficient r=0.51, p0.001 for morphine-treated cats; r=0.49, p0.001 for control cats). Figure 3 shows that morphine-treated cells exhibited longer latency as well as higher variability than saline-treated cells did.(A)(B)Figure2: The percentages of saline- and morphine-treated cel
31、ls with any given peak latency are shown in cumulative distribution plots in A. MCs had longer latencies than control. The percentages of saline- and morphine-treated cells with any given half-width () are shown in cumulative distribution plots in B. It indicates that trial-to-trial variability is i
32、ncreased after chronic morphine exposure.Figure3: Scatter plot showing the half-width () and peak latency of cells in saline and morphine- treated cats.MCs exhibit significantly prolonged peak latency as well as increased trial-to-trial variability.4. DiscussionVariability is an important issue beca
33、use it limits the signal transferring and the reliability, shapes our modeling of information processing, and affects the neuronal pools underlying psychophysical performance8, 11, 20, 21. Here we found that chronic morphine exposure increase trial-to-trial response variability probably. Higher tria
34、l-to-trial variability might represent imprecise and uncorrelated firings between different trials during the same stimulus. It also makes more different to extract useful signals from unrelated noises.It has been shown that morphine abuse could affect opioid and dopamine receptors22, influence neur
35、otransmitter release such as dopamine and GABA 1, 23, alter the morphology of visual cortical neurons24.All these effects might further change response variability. For example, the decrease of the inhibition of GABA may depress the precision of neuron firings. However, further investigations must b
36、e done to reveal the detailed mechanisms.In addition, our results provide the evidence that both prolonged latency and increased variability occur in cat LGN after chronic morphine exposure. The prolonged latency is correlated with increased variability. This finding suggests variability increase mi
37、ght act as one of the factors which cause latency changes in morphine-treated cats. Certainly, other factors may affect response latency such as the speed of axon delivery and spike synchronization. The degradation of these two response properties may play an important role in functional degeneratio
38、n of LGN neurons, progressively, influence response properties and function of visual system in morphine administrated animals. However, much remains to be learned about the detailed mechanisms of variability increase and other contributions to latency prolongation after chronic morphine exposure.AC
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