Key Laboratory of Brain Stress and Behavior

Fengcheng, China

Key Laboratory of Brain Stress and Behavior

Fengcheng, China

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Yang F.,PLA Fourth Military Medical University | Fu H.,PLA Fourth Military Medical University | Fu H.,Key Laboratory of Brain Stress and Behavior | Lu Y.-F.,PLA Fourth Military Medical University | And 13 more authors.
Neuroscience Bulletin | Year: 2014

Intractable central post-stroke pain (CPSP) is one of the most common sequelae of stroke, but has been inadequately studied to date. In this study, we first determined the relationship between the lesion site and changes in mechanical or thermal pain sensitivity in a rat CPSP model with experimental thalamic hemorrhage produced by unilateral intra-thalamic collagenase IV (ITC) injection. Then, we evaluated the efficacy of gabapentin (GBP), an anticonvulsant that binds the voltage-gated Ca2+ channel α2δ and a commonly used anti-neuropathic pain medication. Histological case-by-case analysis showed that only lesions confined to the medial lemniscus and the ventroposterior lateral/medial nuclei of the thalamus and/or the posterior thalamic nucleus resulted in bilateral mechanical pain hypersensitivity. All of the animals displaying CPSP also had impaired motor coordination, while control rats with intra-thalamic saline developed no central pain or motor deficits. GBP had a dose-related anti-allodynic effect after a single administration (1, 10, or 100 mg/kg) on day 7 post-ITC, with significant effects lasting at least 5 h for the higher doses. However, repeated treatment, once a day for two weeks, resulted in complete loss of effectiveness (drug tolerance) at 10 mg/kg, while effectiveness remained at 100 mg/kg, although the time period of efficacious analgesia was reduced. In addition, GBP did not change the basal pain sensitivity and the motor impairment caused by the ITC lesion, suggesting selective action of GBP on the somatosensory system. © 2014, Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg.


Liu M.-G.,PLA Fourth Military Medical University | Liu M.-G.,Seoul National University | Chen X.-F.,PLA Fourth Military Medical University | Chen X.-F.,Key Laboratory of Brain Stress and Behavior | And 6 more authors.
Neuroscience Bulletin | Year: 2012

Simultaneous multisite recording using multi-electrode arrays (MEAs) in cultured and acutely-dissociated brain slices and other tissues is an emerging technique in the field of network electrophysiology. Over the past 40 years, great efforts have been made by both scientists and commercial concerns, to advance this technique. The MEA technique has been widely applied to many regions of the brain, retina, heart and smooth muscle in various studies at the network level. The present review starts from the development of MEA techniques and their uses in brain preparations, and then specifically concentrates on the use of MEA recordings in studies of synaptic plasticity at the network level in both the temporal and spatial domains. Because the MEA technique helps bridge the gap between single-cell recordings and behavioral assays, its wide application will undoubtedly shed light on the mechanisms underlying brain functions and dysfunctions at the network level that remained largely unknown due to the technical difficulties before it matured. © Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2012.


Liu M.-G.,PLA Fourth Military Medical University | Liu M.-G.,Seoul National University | Liu M.-G.,King's College | Chen J.,PLA Fourth Military Medical University | And 2 more authors.
Progress in Neurobiology | Year: 2014

Affective disorders and cognitive deficits are common comorbidities of chronic pain in the clinical setting, which severely affect the quality of life of pain patients and impose a great difficulty upon clinical pain therapy. Despite large numbers of human studies examining this issue, there are surprisingly few reports investigating the comorbidities of chronic pain in animal models. This review summarizes and integrates previous reports of animal studies on pain and comorbidity, covering pain-evoked anxiety, depression, attentional deficits, cognitive impairment and locomotor dysfunction in rodents. Moreover, pain-induced alterations in synaptic plasticity are also discussed in terms of long-term potentiation and long-term depression, synaptic transmission, neuronal excitability and structural correlates in 'pain matrix'. Finally, we conclude this review by pointing out some unresolved problems and future research directions. © 2014 Elsevier Ltd.


Yu Y.-Q.,PLA Fourth Military Medical University | Yu Y.-Q.,Key Laboratory of Brain Stress and Behavior | Zhao Z.-Y.,PLA Fourth Military Medical University | Zhao Z.-Y.,Key Laboratory of Brain Stress and Behavior | And 9 more authors.
NeuroMolecular Medicine | Year: 2013

Tetrodotoxin-resistant (TTX-R) sodium channels NaV1.8 and NaV1.9 in dorsal root ganglion (DRG) neurons play important roles in pathological pain. We recently reported that melittin, the major toxin of whole bee venom, induced action potential firings in DRG neurons even in the presence of a high concentration (500 nM) of TTX, indicating the contribution of TTX-R sodium channels. This hypothesis is fully investigated in the present study. After subcutaneous injection of melittin, NaV1.8 and Na V1.9 significantly upregulate mRNA and protein expressions, and related sodium currents also increase. Double immunohistochemical results show that NaV1.8-positive neurons are mainly medium- and small-sized, whereas NaV1.9-positive ones are only small-sized. Antisense oligodeoxynucleotides (AS ODNs) targeting NaV1.8 and Na V1.9 are used to evaluate functional significance of the increased expressions of TTX-R sodium channels. Behavioral tests demonstrate that AS ODN targeting NaV1.9, but not NaV1.8, reverses melittin-induced heat hypersensitivity. Neither NaV1.8 AS ODN nor NaV1.9 AS ODN affects melittin-induced mechanical hypersensitivity. These results provide previously unknown evidence that upregulation of Na V1.9, but not NaV1.8, in small-sized DRG neurons contributes to melittin-induced heat hypersensitivity. Furthermore, melittin-induced biological effect indicates a potential strategy to study properties of TTX-R sodium channels. © 2012 Springer Science+Business Media New York.


Li Z.,PLA Fourth Military Medical University | Li Z.,Key Laboratory of Brain Stress and Behavior | Lu Y.-F.,PLA Fourth Military Medical University | Lu Y.-F.,Key Laboratory of Brain Stress and Behavior | And 15 more authors.
Pain | Year: 2014

Empathy for the pain experience of others can lead to the activation of pain-related brain areas and can even induce aberrant responses to pain in human observers. Recent evidence shows this high-level emotional and cognitive process also exists in lower animals; however, the mechanisms underlying this phenomenon remain unknown. In the present study we found that, after social interaction with a rat that had received subcutaneous injection of bee venom (BV), only the cagemate observer (CO) but not the noncagemate observer (NCO) showed bilateral mechanical hypersensitivity and an enhanced paw flinch reflex following BV injection. Moreover, neuronal activities labeled by c-Fos immunoreactivity in the spinal dorsal horn of CO rats were also significantly increased relative to the control 1 hour after BV injection. A stress-related response can be excluded because serum corticosterone concentration following social interaction with demonstrator rats in pain was not changed in CO rats relative to NCO and isolated control rats. Anxiety can also be excluded because anxiety-like behaviors could be seen in both the CO and NCO rats tested in the open-field test. Finally, bilateral lesions of the medial prefrontal cortex eliminated the enhancement of the BV-induced paw flinch reflex in CO rats, but bilateral lesions of either the amygdala or the entorhinal cortex failed. Together, we have provided another line of evidence for the existence of familiarity-dependent empathy for pain in rats and have demonstrated that the medial prefrontal cortex plays a critical role in processing the empathy-related enhancement of spinal nociception. ©2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.


Chen J.,PLA Fourth Military Medical University | Chen J.,Key Laboratory of Brain Stress and Behavior | Chen J.,Beijing Institute for Brain Disorders | Guan S.-M.,PLA Fourth Military Medical University | And 4 more authors.
Neuroscience Bulletin | Year: 2016

Melittin is a basic 26-amino-acid polypeptide that constitutes 40–60% of dry honeybee (Apis mellifera) venom. Although much is known about its strong surface activity on lipid membranes, less is known about its pain-producing effects in the nervous system. In this review, we provide lines of accumulating evidence to support the hypothesis that melittin is the major pain-producing substance of bee venom. At the psychophysical and behavioral levels, subcutaneous injection of melittin causes tonic pain sensation and pain-related behaviors in both humans and animals. At the cellular level, melittin activates primary nociceptor cells through direct and indirect effects. On one hand, melittin can selectively open thermal nociceptor transient receptor potential vanilloid receptor channels via phospholipase A2-lipoxygenase/cyclooxygenase metabolites, leading to depolarization of primary nociceptor cells. On the other hand, algogens and inflammatory/pro-inflammatory mediators released from the tissue matrix by melittin’s pore-forming effects can activate primary nociceptor cells through both ligand-gated receptor channels and the G-protein-coupled receptor-mediated opening of transient receptor potential canonical channels. Moreover, subcutaneous melittin up-regulates Nav1.8 and Nav1.9 subunits, resulting in the enhancement of tetrodotoxin-resistant Na+ currents and the generation of long-term action potential firing. These nociceptive responses in the periphery finally activate and sensitize the spinal dorsal horn pain-signaling neurons, resulting in spontaneous nociceptive paw flinches and pain hypersensitivity to thermal and mechanical stimuli. Taken together, it is concluded that melittin is the major pain-producing substance of bee venom, by which peripheral persistent pain and hyperalgesia (or allodynia), primary nociceptive neuronal sensitization, and CNS synaptic plasticity (or metaplasticity) can be readily induced and the molecular and cellular mechanisms underlying naturally-occurring venomous biotoxins can be experimentally unraveled. © 2016 Shanghai Institutes for Biological Sciences, CAS and Springer Science+Business Media Singapore


Yu Y.-Q.,PLA Fourth Military Medical University | Yu Y.-Q.,Beijing Institute for Brain Disorders | Chen X.-F.,PLA Fourth Military Medical University | Chen X.-F.,Beijing Institute for Brain Disorders | And 7 more authors.
Physiological Research | Year: 2014

In the mammalian autonomic nervous system, tonic and phasic neurons can be differentiated on firing patterns in response to long depolarizing current pulse. However, the similar firing patterns in the somatic primary sensory neurons and their functional significance are not well investigated. Here, we identified two types of neurons innervating somatic sensory in rat dorsal root ganglia (DRG). Tonic neurons fire action potentials (APs) in an intensity-dependent manner, whereas phasic neurons typically generate only one AP firing at the onset of stimulation regardless of intensity. Combining retrograde labeling of somatic DRG neurons with fluorescent tracer DiI, we further find that these neurons demonstrate distinct changes under inflammatory pain states induced by complete Freund's adjuvant (CFA) or bee venom toxin melittin. In tonic neurons, CFA and melittin treatments significantly decrease rheobase and AP durations (depolarization and repolarization), enhance amplitudes of overshoot and afterhyperpolarization (AHP), and increase the number of evoked action potentials. In phasic neurons, however, the same inflammation treatments cause fewer changes in these electrophysiological parameters except for the increased overshoot and decreased AP durations. In the present study, we find that tonic neurons are more hyperexcitable than phasic neurons after peripheral noxious inflammatory stimulation. The results indicate the distinct contributions of two types of DRG neurons in inflammatory pain. © 2014 Institute of Physiology v.v.i.


Lu Y.-F.,PLA Fourth Military Medical University | Lu Y.-F.,Key Laboratory of Brain Stress and Behavior | Wang Y.,PLA Fourth Military Medical University | Wang Y.,Key Laboratory of Brain Stress and Behavior | And 15 more authors.
Neuroscience Bulletin | Year: 2014

To explore whether experiencing inflammatory pain has an impact upon intracortical synaptic organization, the planar multi-electrode array (MEA) technique and 2-dimensional current source density (2D-CSD) imaging were used in slice preparations of the anterior cingulate cortex (ACC) from rats. Synaptic activity across different layers of the ACC was evoked by deep layer stimulation through one electrode. The layer-localization of both local field potentials (LFPs) and the spread of current sink calculated by 2D-CSD analysis was characterized pharmacologically. Moreover, the induction of long-term potentiation (LTP) and changes in LTP magnitude were also evaluated. We found that under naïve conditions, the current sink was initially generated in layer VI, then spread to layer V and finally confined to layers II-III. This spatial pattern of current sink movement typically reflected changes in depolarized sites from deep layers (V-VI) to superficial layers (II-III) where intra- and extracortical inputs terminate. In the ACC slices from rats in an inflamed state (for 2 h) caused by intraplantar bee-venom injection, the spatial profile of intra-ACC synaptic organization was significantly changed, showing an enlarged current sink distribution and a leftward shift of the stimulus-response curves relative to the naïve and saline controls. The change was more distinct in the superficial layers (II-III) than in the deep site. In terms of temporal properties, the rate of LTP induction was significantly increased in layers II-III by inflammatory pain. However, the magnitude of LTP was not significantly enhanced by this treatment. Taken together, these results show that inflammatory pain results in distinct spatial and temporal plasticity of synaptic organization in the ACC, which may lead to altered synaptic transmission and modulation. © 2014 Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg.


Xie F.,PLA Fourth Military Medical University | Xie F.,Key Laboratory of Brain Stress and Behavior | Fu H.,PLA Fourth Military Medical University | Fu H.,Key Laboratory of Brain Stress and Behavior | And 5 more authors.
PLoS ONE | Year: 2013

To establish the role of the metabolic state in the pathogenesis of polyneuropathy, an age- and sex-matched, longitudinal study in rats fed high-fat and high-sucrose diets (HFSD) or high-fat, high-sucrose and high-salt diets (HFSSD) relative to controls was performed. Time courses of body weight, systolic blood pressure, fasting plasma glucose (FPG), insulin, free fatty acids (FFA), homeostasis model assessment-insulin resistance index (HOMA-IR), thermal and mechanical sensitivity and motor coordination were measured in parallel. Finally, large and small myelinated fibers (LMF, SMF) as well as unmyelinated fibers (UMF) in the sciatic nerves and ascending fibers in the spinal dorsal column were quantitatively assessed under electron microscopy. The results showed that early metabolic syndrome (hyperinsulinemia, dyslipidemia, and hypertension) and prediabetic conditions (impaired fasting glucose) could be induced by high energy diet, and these animals later developed painful polyneuropathy characterized by myelin breakdown and LMF loss in both peripheral and central nervous system. In contrast SMF and UMF in the sciatic nerves were changed little, in the same animals. Therefore the phenomenon that high energy diets induce bilateral mechanical, but not thermal, pain hypersensitivity is reflected by severe damage to LMF, but mild damage to SMF and UMF. Moreover, dietary sodium (high-salt) deteriorates the neuropathic pathological process induced by high energy diets, but paradoxically high salt consumption, may reduce, at least temporarily, chronic pain perception in these animals. © 2013 Xie et al.


Yang Y.,Capital Medical University | Yang F.,PLA Fourth Military Medical University | Yang F.,Capital Medical University | Li C.-L.,PLA Fourth Military Medical University | And 12 more authors.
Neuroscience Bulletin | Year: 2016

The α2δ-1 subunit of the voltage-gated Ca2+ channel (VGCC) is a molecular target of gabapentin (GBP), which has been used as a first-line drug for the relief of neuropathic pain. GBP exerts its anti-nociceptive effects by disrupting trafficking of the α2δ-1 subunit to the presynaptic membrane, resulting in decreased neurotransmitter release. We previously showed that GBP has an anti-allodynic effect in the first two weeks; but this is followed by insensitivity in the later stage after repeated administration in a rat model of central post-stroke pain (CPSP) hypersensitivity induced by intra-thalamic hemorrhage. To explore the mechanisms underlying GBP insensitivity, the cellular localization and time-course of expression of the α2δ-1 subunit in both the thalamus and spinal dorsal horn were studied in the same model. We found that the α2δ-1 subunit was mostly localized in neurons, but not astrocytes and microglia. The level of α2δ-1 protein increased in the first two weeks after injury but then decreased in the third week, when GBP insensitivity occurred. Furthermore, the α2δ-1 down-regulation was likely caused by later neuronal loss in the injured thalamus through a mechanism other than apoptosis. In summary, the present results suggest that the GBP receptor α2δ-1 is mainly expressed in thalamic neurons in which it is up-regulated in the early stage of CPSP but this is followed by dramatic down-regulation, which is likely associated with GBP insensitivity after long-term use. © 2016, Shanghai Institutes for Biological Sciences, CAS and Springer Science+Business Media Singapore Pte Ltd.

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