Fei Luo

Evidence from brain imaging with fMRI supporting functional specificity of acupoints in humans

We tested whether the stimulation of acupoints in the same spinal segments could induce different central responses with functional magnetic resonance imaging (fMRI) study. Stimulation of acupoints ST36/SP6 (Zusanli/Sanyinjiao) or GB34/BL57 (Yanglingquan/Chengshan) both activated primary and secondary somatosensory area, insula, ventral thalamus, parietal Brodmann Area 40, temporal lobe, putamen, and cerebellum, while de-activated amygdala. Nevertheless, ST36/SP6 stimulation specifically activated orbital frontal cortex and de-activated hippocampus. Alternatively, stimulation of GB34/BL57 activated dorsal thalamus and inhibited those of primary motor area and premotor cortex. Thus, stimulation of acupoints in the same spinal segments induced distinct though overlapped cerebral response patterns, which indicated the existence of acupoint specificity.

Stress or drug priming induces reinstatement of extinguished conditioned place preference.

To construct a model for the relapse of drug use, we investigated the reinstatement of morphine-induced conditioned place preference (CPP) in rats. After the morphine CPP paradigm was established, rats were left extinguishing for 9 days, then exposed to 15 min of random foot shock or s.c. drug priming with different doses of morphine or amphetamine, respectively. Foot shock or a higher dose (0.25 mg/kg) of both drugs could reinstate the CPP induced by 4 mg/kg of morphine after a 9-day extinction, while a lower dose (0.125 mg/kg) of both drugs had no effect. It is concluded that the CPP extinction-reinstatement paradigm might be used as a model to investigate the mechanism of relapse in addicts.

Neuronal responses in the frontal cortico-basal ganglia system during delayed matching-to-sample task: ensemble recording in freely moving rats

Abstract. Electrophysiological recording of single neuron activity has been conducted in rats to investigate the patterns of distributed neuronal responses in the frontal cortico-basal ganglia system that code information during a spatial-delayed matching-to-sample task (DMTSt). Rats were trained to press one of the two retractable levers presented randomly as a sample response. The first valid nose-poke after a delay resulted in the presentation of both levers. Pressing the same lever as the sample lever led to a water reward (match to sample), whereas pressing the lever opposite the sample lever resulted in a time-out (house light turned off). One hundred seventy-one neurons in the medial prefrontal cortex (mPFC), 51 in the dorsal striatum (STR), and 93 in the nucleus accumbens (NAc) were recorded during DMTSt. Different patterns of neuronal responses were observed during different behavioral episodes (sample, delay, and match phases) in all three recording areas. Space-related neuronal responses specific to the side of the lever pressed were more often found in the sample phase than in the match phase in all three areas studied. Neuronal responses specific to either correct or error trials were observed with similar percentages in the mPFC and the NAc, while the incidence of correct/error-coded activity in the STR was lower. Ensemble neuronal activity that coded sample versus match lever presses was observed in three out of five rats in sets of trials with similar speed and trajectory of lever press. The results reveal specific patterns of neural responses in the frontal cortico-basal ganglia system in rats during the DMTSt and suggest the existence of specific neuronal coding for different behavioral events associated with a learned short-term memory process.

High frequency stimulation of the subthalamic nucleus improves treadmill locomotion in unilateral 6-hydroxydopamine lesioned rats.

This study investigated the influence of electrical stimulation of the subthalamic nucleus (STN) on motor impairment induced by unilateral 6-hydroxydopamine (6-OHDA) lesions in the medial forebrain bundle. Rats were trained to walk on a treadmill and then implanted with microelectrode arrays in and near the STN. The neurotoxin 6-OHDA was injected into the medial forebrain bundle (MFB) unilaterally to produce a targeted lesion of the dopaminergic system. Successful lesions produced impaired treadmill walking behavior. High frequency stimulation (HFS) of the STN improved treadmill walking immediately and restored normal walking patterns. The same HFS failed to evoke visible side effects such as stepping, turning, raising of the head or facial muscle contraction in the absence of treadmill movement, or to change rotational behaviors elicited by the dopamine (DA) agonist apomorphine in unilateral lesioned rats. This suggests that the stimulation did not cause movement by an activation of brainstem locomotor regions or an increase attention leading to movement. Apomorphine-induced rotation may represent an imbalance of dopaminergic activation which remains during HFS. This work may provide a rodent model for deep brain stimulation (DBS) in patients with Parkinsons disease, and be suitable for further investigation of the neural mechanisms underlying the therapeutic effects of DBS.

High-frequency stimulation of the subthalamic nucleus reverses limb-use asymmetry in rats with unilateral 6-hydroxydopamine lesions

Deep brain stimulation (DBS) is a widely used clinical treatment for Parkinsons disease (PD). A rodent model of DBS is a necessary tool for understanding the neural mechanisms of this method. Our previous study showed that high-frequency stimulation (HFS) of the subthalamic nucleus (STN) improved treadmill locomotion in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of nigrostriatal dopamine (DA) neurons. The present study tested DBS effects on limb-use asymmetry (LUA) during vertical/lateral exploration in a cylindrical chamber in rats with similar unilateral nigrostriatal DA lesions. Limb-use asymmetry assessment has been used to detect functional capacity over a wide range of dopamine depletion. Before lesioning, rats exhibited regular rearing activity and used both forelimbs equally often to support weight during exploration of the walls of the cylinder. After unilateral nigrostriatal DA lesioning, rats displayed reduced rearing activity and predominant use of the ipsilateral (good) forelimb to touch the wall. HFS of the STN, but not of other nearby regions surrounding the STN, in the lesioned rats restored normal rearing activity and reversed the limb-use asymmetry caused by the unilateral DA depletion. This study is consistent with the possibility that there can be beneficial effects of STN-DBS on behavioral impairments in unilateral DA-depleted rats and may suggest an appropriate rodent model for DBS study.

Effects of lesions of various brain areas on drug priming or footshock-induced reactivation of extinguished conditioned place preference

We have previously shown with a model of morphine-induced conditioned place preference (CPP) that a brief exposure to footshock stress or a priming dose of morphine could reactivate drug-seeking behavior after a long drug-free period. The present study was designed to examine the possible role of certain brain areas in such a reactivation. After the rats were successfully trained with morphine (4 mg/kg, i.p.) through a CPP paradigm (10 sessions of daily pairing of morphine with one of the two compartments), different parts of nucleus accumbens (NAc), ventral tegmental area (VTA), and central (Ce) or lateral (La) nucleus of amygdala were lesioned with a DC current passing through the respective location. After a 9-day abstinence period, random intermittent footshock (DC square wave, 0.5 mA, 0.5 s width, off time 10-70 s) or drug priming (morphine 0.25 mg/kg, s.c.) reactivated the place preference in sham lesion rats. However, the effect of drug priming could be completely abolished by lesions placed either at VTA, or the majority or shell part, but not the core of NAc. On the other hand, the effect of footshock stressor could be eliminated by a lesion placed at Ce but not La. These results suggest that, while both drug priming and footshock stress are effective in reactivating drug-seeking behavior, they might work through different neurochemical mechanisms and anatomical pathways.

Peripheral electric stimulation inhibits morphine-induced place preference in rats

Conditioned place preference (CPP) is a commonly used model to detect rewarding effect of drugs. To observe the effect of peripheral electric stimulation (PES) on morphine-induced CPP, we trained the rats with morphine in a CPP paradigm. Twelve hours before the testing phase, rats were given PES via stainless-steel needles with frequencies of 2, 100, or 2/100 Hz, respectively. PES of 2 and 2/100 Hz significantly decreased CPP in morphine-trained animals in a naloxone reversible manner, while PES of 100 Hz, foot shock, needle insertion, or plain restraining, showed no effect. Thus, PES with a low-frequency component (2 Hz) could specifically inhibit the expression of morphine-induced CPP, presumably via activation of opioid receptors.

Parallel pain processing in freely moving rats revealed by distributed neuron recording.

The present study was designed to examine the possible differential roles of the medial and lateral pain systems in pain perception. We used a microwire array recording technique to record the pain-evoked neural activity of multiple neurons in freely moving rats. Noxious radiant heat was delivered to either hind-paw in a randomized order. A total of 256 single units were recorded in primary somatosensory cortex (SI), anterior cingulate cortex (ACC), and medial dorsal (MD) and ventral posterior (VP) thalamus during the painful stimulation. The results showed that SI neurons displayed a strong pain-related excitatory response with short duration and significant contralateral bias; VP had very similar functional patterns to that of SI. This suggested that SI, together with VP, participate in the processing of the sensory-discriminative aspect of pain. In contrast, ACC and MD shared common characteristics of moderate and longer-lasting increase of neural activity, bilateral receptive fields without contralateral preference, as well as the anticipatory response at the start of a painful stimulus, corresponding to the specific role of ACC and MD in the affective-motivational aspects of pain. The results provide an initial demonstration of distributed activity patterns within different pain systems in awake and freely moving rats, hence, providing confirmation of the existence of the dual pain pathways.

Nocistatin reverses the effect of orphanin Fq/nociceptin in antagonizing morphine analgesia

Nocistatin is a recently characterized neuropeptide derived from the preprohormone containing nociceptin (Orphanin FQ, OFQ). Nocistatin was reported to antagonize OFQ induced allodynia, hyperalgesia and prostaglandin E2-elicited pain responses. The aim of the present study was to determine whether nocistatin, injected intracerebroventricularly (i.c.v.), would reverse the anti-morphine effect of OFQ in rats using the tail-flick latency (TFL) as the nociceptive index. I.c.v. injection of nocistatin at doses of 0.005, 0.05, 0.5, 5, 50, and 500 ng produced no significant changes in the basal TFL, nor did it affect morphine analgesia. However, it significantly reversed the antagonistic effect of OFQ on morphine analgesia when co-injected i.c.v. at doses of 0.05, 0.5, 5, 50 and 500 ng per rat with OFQ. The dose-response curve was bell-shaped and the most effective dose was 0.5 ng. The results suggest that nocistatin can reverse the anti-morphine effect of OFQ in rat brain.

Brain opioid-receptors are involved in mediating peripheral electric stimulation-induced inhibition of morphine conditioned place preference in rats

Conditioned place preference (CPP) paradigm has been suggested as one of the animal models for drug craving. The present study was performed to examine the effect of 100 Hz peripheral electric stimulation (PES) on the expression of morphine-induced CPP. Rats were trained with morphine for 4 days to establish the CPP paradigm in a three-chamber unbiased apparatus. Morphine-induced CPP was maintained up to 4 weeks when tests were given once a week. PES of 100 Hz administered 30 min a day for 3 days significantly attenuated morphine-induced CPP (P<0.01). I.c.v. injection of the delta-opioid receptor antagonist naltrindole (NTI) or the kappa-antagonist norbinaltorphimine (nor-BNI) but not the mu-antagonist cyclic D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP), completely blocked the inhibitory effect of 100 Hz PES on the expression of morphine-induced CPP (P<0.05-0.01). These results indicate that the anti-craving effects induced by repeated PES of 100 Hz is mediated by the activation of supra-segmental delta- and kappa-opioid receptors in the central nervous system.