Inhibition Of Propofol On LFPs Network And Neural Population Activity During Working Memory Task

ObjectivePropofol (2,6-diisopropylphenol) is widely used for surgical anesthesia and sedation in postoperative care. In recent years, there are some research reports about human memory dysfunction caused by propofol anesthesia. Working memory refers to a cognitive function that provides concurrent temporary storage and manipulation of the information necessary to perform complex cognitive tasks, and prefrontal cortex (PFC) plays an essential role in working memory. This study based on the use of extracellular multi-electrode array in PFC of vivo rats which can record two different kinds of electrical signals during working memory task:local field potentials (LFPs) and action potentials (APs), analyze the LFPs functional connectivity and neural population activity. To investigate the mechanism of propofol anesthesia cause working memory dysfunction.Methods1. Male SD rats (n=14, weighing between300and350g). The rats’ care and surgical procedures were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the Tianjin medical University guidelines for the use and care of laboratory animals in research;2. Rats were habituated to a Y type maze until they were readily eating peanut tablets placed at the end of each arm and acclimated to handling. After habituation, rats were trained on the delayed alternation task until the correct rat was up to85%in3continue days;3. After the training sessions, rats were randomly allocated to either sham or anesthesia exposure groups. Rats in the anesthesia group were injected propofol at a rate of0.9mg·kg-1·min-1via a tail vein catheter for2h.4. The rats were implanted with16-channel tungsten micro wire electrode array (impedance with600-800kΩ) targeting the PFC (2.5-4.5mm anterior to bregma and0.2-1.0mm lateral to midline). The use of extracellular multielectrode array in PFC of vivo rats which can record two different kinds of electrical signals during working memory task:local field potentials (LFPs) and action potentials (APs)5. We investigated the time evolution of frequency power spectrum of the WM task by applying the short-time Fourier transform with a500ms wide Hamming window to the LFPs data, and found that0-band and γ-band of LFPs were essential to the coding of working memory.6. We applied the multi-variables Granger causality which is directed transform function to θ-band and y-band of LFPs to investigate the functional connectivity.7. We computed the average firing rate of each neuron which in the neural population during rat working memory task, and raised the one into neural ensemble when the average firing rate was more2times higher than the average firing rate of neural population. We investigate the neural population activity and the single neuron activity during rat work memory task.Results1. Compared with control group, the Y-maze behavioral results after propofol anesthesia (iv.0.9mg·kg-1min-1,2h):24h,57%±5%vs.90%±3%(p<0.01);48h,75%±4%vs.91%±2%(p<0.05);72h,88%±3%vs.90%±3%(p>0.05).2. The LFPs frequency power spectrum showed that θ-band and y-band of LFPs were essential to the coding of working memory. Compared the frequency power spectrum with control group after propofol anesthesia (iv.0.9mg·kg-1min-1,2h):the power of0-band (p<0.05) and y-band (p<0.01) of LFPs were significant decrease in24h; the power of θ-band(p<0.05) and y-band (p<0.05) of LFPs were significant decrease in48h; no different was found in72h (p>0.05).3. Effect of propofol on LFPs functional connectivity during rat working memory task, Compared with the control group, after propofol anesthesia (iv.0.9mg·kg-1min-1,2h):24h,0-band LFPs0.0082±0.0021vs.0.0162±0.0012(p<0.01), y-band LFPs0.0032±0.0011vs.0.0122±0.0013(p<0.01);48h,θ-band LFPs0.0140±0.0023vs.0.0165±0.0019(p>0.05), y-band LFPs0.0065±0.0013vs.0.0119±0.0028(p<0.01);72h,0-band LFPs0.0157±0.0029vs.0.0165±0.0014(p>0.05), y-band LFPs0.0117±0.0024vs.0.0121±0.0015(p>0.05).4. Effect of propofol on working memory LFPs network characteristic (1) Effect of propofol on working memory LFPs connection densityCompared with the control group, after propofol anesthesia (iv.0.9mg·kg-1min-1,2h):24h,θ-band LFPs0.22±0.03vs.0.42±0.07(p<0.01), y-band LFPs0.12±0.03vs.0.63±0.05(p<0.01);48h,θ-band LFPs0.30±0.04vs.0.48±0.06(p<0.05), y-band LFPs0.48±0.04vs.0.62±0.03(p<0.05);72h,0-band LFPs0.41±0.02vs.0.47±0.05(p>0.05), y-band LFPs0.61±0.05vs.0.63±0.04(p>0.05).(2) Effect of propofol on working memory LFPs global efficiencyCompared with the control group, after propofol anesthesia (iv.0.9mg·kg-1min-1,2h):24h,0-band LFPs0.57±0.02vs.0.62±0.04(p>0.05), y-band LFPs0.24±0.02vs.0.72±0.06(p<0.01);48h,θ-band LFPs0.58±0.04vs.0.67±0.02(p>0.05), y-band LFPs0.49±0.07vs.0.73±0.02(p<0.05);72h,0-band LFPs0.62±0.02vs.0.66±0.02(p>0.05), y-band LFPs0.69±0.04vs.0.73±0.04(p>0.05).5. Effect of propofol on working memory neural population activity(1) Effect of propofol on neural ensemble frequency coding during rat working memory task, compared with the control group, after propofol anesthesia (iv.0.9mg·kg-1min-1,2h):the number of neurons in neural ensemble was significant decrease in24h (p<0.01) and48h (p<0.05), no different in72h (p>0.05).(2) Effect of propofol on single neuron activity, we investigate the ratio between the number of neurons in neural ensemble and the number of neurons in neural population during rat work memory task, compared with the control group, after propofol anesthesia (iv.0.9mg·kg-1min-1,2h):24h,24.3%±4.7%vs.80.6%±13.5%(p<0.01);48h,48.6%±11.2%vs.81.2%±11.4%(p<0.05);72h,78.3%±10.2%vs.82.6%±15.1%(p>0.05).Conclusions(1) A prominent inhibition on rats WM function is induced by propofol anesthesia with0.9mg·kg-1min-1,2h, but the inhibition dose lasts less than72hours;(2) Propofol anesthesia may mainly inhibit the functional connectivity of gamma-band LFPs which play a key role and eventually lead to memory dysfunction;(3) The functional connectivity among γ-band of LFPs during rats working memory task could be inhibited in48h after propofol anesthesia with0.9mg·kg-1min-1,2h, no different was found after72h; The functional connectivity among θ-band of LFPs could be inhibited in24h, no different was found after48h.(4) The connection density among θ-band and γ-band of LFPs during rats working memory task could be inhibited in48h after propofol anesthesia with0.9mg·kg-1min-1,2h, no different was found after72h;(5) The global efficiency among y-band of LFPs during rats working memory task could be inhibited in48h after propofol anesthesia with0.9mg·kg-1min-1,2h, no different was found after72h; no different was found in θ-band of LFPs;(6) Propofol inhibited neural ensemble frequency coding and single neuron activity of adult rats and in48hours after anesthesia, but the inhibition lasted less than72hours after anesthesia.