Jian-Yi Zhang

Endogenous BDNF is required for myelination and regeneration of injured sciatic nerve in rodents

Following a peripheral nerve injury, brain‐derived neurotrophic factor (BDNF) and the p75 neurotrophin receptor are upregulated in Schwann cells of the Wallerian degenerating nerves. However, it is not known whether the endogenous BDNF is critical for the functions of Schwann cells and regeneration of injured nerve. Treatment with BDNF antibody was shown to retard the length of the regenerated nerve from injury site by 24%. Histological and ultrastructural examination showed that the number and density of myelinated axons in the distal side of the lesion in the antibody‐treated mice was reduced by 83%. In the BDNF antibody‐treated animals, there were only distorted and disorganized myelinated fibres in the injured nerve where abnormal Schwann cells and phagocytes were present. As a result of nerve degeneration in BDNF antibody‐treated animals, subcellular organelles, such as mitochondria, disappeared or were disorganized and the laminal layers of the myelin sheath were loosened, separated or collapsed. Our in situ hybridization revealed that BDNF mRNA was expressed in Schwann cells in the distal segment of lesioned nerve and in the denervated muscle fibres. These results indicate that Schwann cells and muscle fibres may contribute to the sources of BDNF during regeneration and that the deprivation of endogenous BDNF results in an impairment in regeneration and myelination of regenerating axons. It is concluded that endogenous BDNF is required for peripheral nerve regeneration and remyelination after injury.

Brain derived neurotrophic factor (BDNF) contributes to the pain hypersensitivity following surgical incision in the rats.

BackgroundThe pathogenic role of brain derived neurotrophic factor (BDNF) in the incisional pain is poorly understood. The present study explores the role of the BDNF in the incision-induced pain hypersensitivity.MethodsA longitudinal incision was made in one plantar hind paw of isoflurane-anesthetized rats. Dorsal root ganglias (DRG) and spinal cords were removed at various postoperative times (1–72 h). Expression pattern of BDNF was determined by immunohistochemistry and double-labeling immunofluorescence. Lidocaine-induced blockade of sciatic nerve function was used to determine the importance of afferent nerve activity on BDNF expression in the DRG and spinal cord after incision. BDNF antibody was administered intrathecally (IT) or intraperitoneal (IP) to modulate the spinal BDNF or peripheral BDNF after incision.ResultsAfter hind-paw incision, the BDNF was upregulated in the ipsilateral lumbar DRG and spinal cord whereas thoracic BDNF remained unchanged in response to incision. The upregulated BDNF was mainly expressed in the large-sized neurons in DRG and the neurons and the primary nerve terminals in the spinal cord. Sciatic nerve blockade prevented the increase of BDNF in the DRG and spinal cord. IT injection of BDNF antibody greatly inhibited the mechanical allodynia induced by incision whereas IP administration had only marginal effect.ConclusionThe present study showed that incision induced the segmental upregulation of BDNF in the DRG and spinal cord through somatic afferent nerve transmission, and the upregulated BDNF contributed to the pain hypersensitivity induced by surgical incision.

Cytosine arabinoside treatment impairs the remote spatial memory function and induces dendritic retraction in the anterior cingulate cortex of rats

Clinical studies on cancer patients have revealed that chemotherapy is associated with long-term cognitive impairment. In the present study, we used a rat model to evaluate the effects of the anticancer drug cytosine arabinoside (Ara-C) on spatial learning, memory, and the dendritic morphology of neurons in the anterior cingulate cortex (ACC) and hippocampus. The drug was observed to induce deficits in the long-term spatial memory function but not in the spatial learning and recent memory, as was assessed by performing the Morris water maze test. In the Ara-C treated rats, retraction of the apical dendrites was noted in the neurons in the ACC but not in the pyramidal neurons in the hippocampal region CA1. Our in vivo adult rat model of neurotoxicity provides data on the long-term cognitive and cellular morphometric alterations in the frontal lobes induced by Ara-C treatment. Retraction of the apical dendrites of the pyramidal neurons in the ACC may contribute to the remote spatial memory impairment induced by Ara-C treatment.

Biphasic Activation of Extracellular Signal-regulated Kinase in Anterior Cingulate Cortex Distinctly Regulates the Development of Pain-related Anxiety and Mechanical Hypersensitivity in Rats after Incision

Background: A recent study has demonstrated that surgical incision induces an anxiety-like behavior but its relationship with incision-evoked mechanical hypersensitivity remains elusive. Extracellular signal-regulated kinase (ERK) activity in the anterior cingulate cortex (ACC) is important for the affective pain. The current study aims to explore ERK1/2 activity in the ACC and its role in the development of anxiety and mechanical hypersensitivity after incision. Methods: Anxiety-like behavior was measured by elevated plus maze experiment and open field test after hind paw incision. ERK1/2 phosphorylation was determined by immunohistochemistry and Western blot. Cannulae were implanted into the bilateral ACC for the intra-ACC injection of ERK inhibitors PD98059 and U0126. Brushing (innocuous stimulus) was used to investigate its effect on ERK activation under the incision-evoked painful condition. Results: The anxiety-like behavior induced by the hind paw incision persisted longer than mechanical hypersensitivity. One hind paw incision resulted in a biphasic ERK activation in bilateral ACC. Inhibiting ERK activation in the early phase attenuated pain-related anxiety and mechanical hypersensitivity whereas inhibiting ERK activation in the late phase only reduced the anxiety-like behavior. During the time interval between two phases of ERK activation, brushing the incised skin dramatically increased ERK phosphorylation in the ACC. Conclusions: These data suggest that in the early phase of postoperative pain, pain-related anxiety and mechanical hypersensitivity are tightly linked and regulated by the ERK activation in the ACC. However, in the late phase of postoperative pain, ERK activation in the ACC is only required for the expression of pain-related anxiety but not mechanical hypersensitivity.

Insulin-like growth factor 2 mitigates depressive behavior in a rat model of chronic stress.

Depression is a common psychiatric disorder associated with chronic stress. Insulin-like growth factor 2 (IGF2) is a growth factor that serves important roles in the brain during development and at adulthood. Here, the role of IGF2 expression in the hippocampus was investigated in a rat model of depression. A chronic restraint stress (CRS) model of depression was established in rats, exhibiting depression-like behavior as assessed with the sucrose preference test (SPT) and forced swimming test (FST), and with evaluation of the corticosterone levels. Hippocampal IGF2 levels were significantly lower in rats suffering CRS than in controls, as were levels of pERK1/2 and GluR1. Lentivirus-mediated hippocampal IGF2 overexpression alleviated depressive behavior in restrained rats, elevated the levels of pERK1/2 and GluR1 proteins, but it did not affect the expression of pGSK3β, GluR2, NMDAR1, and NMDAR2A. These results suggest the chronic restraint stress induces depressive behavior, which may be mediated by ERK-dependent IGF2 signaling, pointing to an antidepressant role for this molecular pathway.

Anterior cingulate cortical lesion attenuates food foraging in rats

We have developed a novel laboratory rodent model to detect competitive, non-competitive and no-hurdle foraging behaviors as seen in natural environment. However, it is not clear which brain region is important for the food foraging activity. In the present study, we evaluated the effect of lesions in the bilateral anterior cingulate cortex (ACC) on the rat food foraging behavior with the established model. In contrast to the sham lesion group (saline microinjection into the ACC), bilateral complete ACC chemical lesions (kainic acid microinjection into the ACC) significantly decreased the amount of foraged food in the competitive food foraging tests, non-competitive or no-hurdle foraging test. Moreover, the deficit of the food foraging activity was more prominent in the competitive food foraging test than in the non-competitive food and no-hurdle foraging test after ACC lesions. No alterations after ACC lesions were found in other behaviors including elevated plus-maze test (EPM), forced swimming test (FST), open field test (OFT), sucrose preference test and exploratory behavior. These findings suggest that the ACC mediate the food foraging-related behaviors.

Development of Anxiety-Like Behavior via Hippocampal IGF-2 Signaling in the Offspring of Parental Morphine Exposure: Effect of Enriched Environment

Opioid addiction is a major social, economic, and medical problem worldwide. Long-term adverse consequences of chronic opiate exposure not only involve the individuals themselves but also their offspring. Adolescent maternal morphine exposure results in behavior and morphologic changes in the brain of their adult offspring. However, few studies investigate the effect of adult opiate exposure on their offspring. Furthermore, the underlying molecular signals regulating the intergenerational effects of morphine exposure are still elusive. We report here that morphine exposure of adult male and female rats resulted in anxiety-like behavior and dendritic retraction in the dentate gyrus (DG) region of the hippocampus in their adult offspring. The behavior and morphologic changes were concomitant with the downregulation of insulin-like growth factor (IGF)-2 signaling in the granular zone of DG. Overexpression of hippocampal IGF-2 by bilateral intra-DG injection of lentivirus encoding the IGF-2 gene prevented anxiety-like behaviors in the offspring. Furthermore, exposure to an enriched environment during adolescence corrected the reduction of hippocampal IGF-2 expression, normalized anxiety-like behavior and reversed dendritic retraction in the adult offspring. Thus, parental morphine exposure can lead to the downregulation of hippocampal IGF-2, which contributed to the anxiety and hippocampal dendritic retraction in their offspring. An adolescent-enriched environment experience prevented the behavior and morphologic changes in their offspring through hippocampal IGF-2 signaling. IGF-2 and an enriched environment may be a potential intervention to prevention of anxiety and brain atrophy in the offspring of parental opioid exposure.

Activation of Anterior Cingulate Cortex Extracellular Signal-Regulated Kinase-1 and -2 (ERK1/2) Regulates Acetic Acid-Induced, Pain-Related Anxiety in Adult Female Mice

In visceral pain, anxiety and pain occur simultaneously, but the etiogenesis of this effect is not yet well-described. The anterior cingulate cortex (ACC) is known to be associated with the affective response to noxious stimuli. The aim of the current study is to define the role of ACC extracellular signal-regulated (ERK)-1 and-2 (ERK1/2) activity in the development of pain-related anxiety/depression and the nocifensive response in acetic acid (AA)-elicited visceral pain. The model of visceral pain was created by intraperitoneal (ip) injection of AA to female Kunming mice. We found that AA injection resulted in a dynamic, bilateral ERK1/2 activation pattern in the ACC. Inhibition of ERK1/2 activation 2 hr after AA injection by subcutaneous (sc) injection of the mitogen-activating extracellular kinase (MEK) inhibitor, SL327, had no effect on the nocifensive responses, but did attenuate anxiety-like behavior, as determined by elevated plus-maze and open-field testing results. These data suggest that AA-induced visceral pain activates expression of ACC ERK1/2, which regulates visceral pain-related anxiety, but not the nocifensive response.

A simple method for detection of food foraging behavior in the rat: involvement of NMDA and dopamine receptors in the behavior

Food foraging behavior involves food removing, hoarding, and competitive preying upon other animals. It is also associated with high cognitive functions such as investing effort into decision making, but no established laboratory model is available to detect the behaviors. In the present study, we have developed a novel laboratory rodent model to detect competitive, non-competitive, and no-hurdle foraging conditions that can mimic the corresponding environment in nature. We found that normal rats consistently foraged the food from a food container to the field and spread food into piles in the open field. There was no difference between male and female rats in the amount of foraged food in the competitive, non-competitive, and no-hurdle food foraging tests. The amount of foraged food was consistent each day for five consecutive days with a slight increase in following days. There was no significant difference in the amount of food foraged in the presence or absence of bedding materials. A dramatic decrease of foraged food was found in the rats after administration of haloperidol (dopamine D2 receptor antagonist) in the competitive, non-competitive, and no-hurdle food foraging tests. Treatment with MK-801 (non-competitive N-methy-D-aspartate receptor antagonist) reduced the foraged food in the competitive food foraging test, but did not affect the foraged food in the non-competitive and no-hurdle food foraging tests. Our study provides a simple but consistent analogue of natural food foraging behavior. Our study also suggests that dopaminergic and glutaminergic systems are differentially involved in the food foraging behaviors.

Sex-differential modulation of visceral pain by brain derived neurotrophic factor (BDNF) in rats.

In spite of the fact that brain derived neurotrophic factor (BDNF) has been reported to be implicated in the development of visceral pain, it remains to be determined whether the role of BDNF in pain is gender dependent. The present study investigated the effect of BDNF on visceral pain in different gender rats. A model for visceral pain was established by intraperitoneal (i.p.) injection of acetic acid (AA) into Sprague-Dawley rats: males, females and females with an ovariectomy (OVX). The pain behavior index was assessed by counting the number of abdominal contractions for 60min after i.p. injection of AA. Anti-BDNF antibody, or BDNF, was administered 1h before the AA injection to examine the role of BDNF in visceral pain. After the AA injection, the number of abdominal contraction was dramatically increased in all rats but females showed more severe pain behavior than males. The higher sensitivity to AA-induced nocifensive response was attenuated by OVX. Pretreatment with anti-BDNF antibody significantly exacerbated the nocifensive response in males but attenuated it in females. While exogenous BDNF administration did not alter AA injection-induced nocifensive response in females, BDNF pretreatment attenuated the nocifensive response in males but exacerbated it in females with OVX. The present study suggests there is a gender dichotomy in visceral pain induced by AA injection. In addition, the modulation of visceral pain by BDNF is also sex dependent, i.e., BDNF facilitates the visceral pain in female rats but displays an opposite effect in male rats. Our results may have important implications in the management of clinical pain.