Chang-Qi Li

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.

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.

Environmental Enrichment during Gestation Improves Behavior Consequences and Synaptic Plasticity in Hippocampus of Prenatal-Stressed Offspring Rats

Prenatal stress can result in various behavior deficits in offspring. Here we tested the effects of environmental enrichment during gestation used as a preventive strategy on the behavior deficits of prenatal-stressed offspring rats as well as the underlying structure basis. We compared the effect size of environmental enrichment during gestation on prenatal-stressed offspring to that of environmental enrichment after weaning. Our results showed that environmental enrichment during gestation partially prevented anxiety and the damage in learning and memory in prenatal-stressed offspring as evaluated by elevated plus-maze test and Morris water maze test. At the same time, environmental enrichment during gestation inhibited the decrease in spine density of CA1 and dentate gyrus neurons and preserved the expression of synaptophysin and glucocorticoid receptors (GRs) in the hippocampus of prenatal-stressed offspring. There was no significant difference in offspring behavior between 7-day environmental enrichment during gestation and 14-day offspring environmental enrichment after weaning. These data suggest that environmental enrichment during gestation effectively prevented the behavior deficits and the abnormal synapse structures in prenatal-stressed offspring, and that it can be used as an efficient preventive strategy against prenatal stresses.

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.

Surgical incision induces anxiety-like behavior and amygdala sensitization: effects of morphine and gabapentin.

The role of affective dimension in the postoperative pain is still poorly understood. The present study investigated the development of anxiety-like behavior and amygdala sensitization in incisional pain. Using hind-paw incision model in rats, we showed that surgical incision induced the anxiety-like behavior as determined by elevated plus-maze and open-field tests. Intraperitoneal (IP) morphine administration reversed mechanical allodynia and anxiety-like behavior in a dose-dependent manner. Gabapentin also partially reduced incision-evoked mechanical allodynia and anxiety-like behavior in a dose-dependent manner. After incision, the expression of phosphorylated cAMP response elements (CRE-) binding protein (p-CREB) was transiently upregulated in the central and basolateral nuclei in the bilateral amygdala. The upregulation of p-CREB was inhibited by morphine and gabapentin. The present study suggested that surgical incision could induce anxiety and amygdala sensitization that can be inhibited by morphine and gabapentin. Thus treatment of surgery-induced affective disturbances by morphine and gabapentin may be a potential important adjunct therapy in the postoperative pain management.

Foraging activity is reduced in a mouse model of depression.

Depression interferes with the human ability to make decisions. Multiple criteria have been adopted for the diagnosis of depression in humans, but no clear indicators are available in animal models to reflect the depressive mood, involving higher cognitive functions. The act of foraging is a species-specific behaviour which is believed to involve the decision-making and higher cognitive functions. We previously established a method to detect the foraging behaviour of rodents, in which our results demonstrated that NMDA and dopamine receptors were involved. Conversely, increased NMDA receptors and reduced dopamine have been reported in depression model rodents. However, we hypothesise that foraging activities may also be impaired in depression. To test the theory, we successfully established a mouse model of depression using the chronic unpredictable mild stress (CUMS) paradigm. Most interestingly, the food foraging activity of mice after CUMS was significantly reduced. In addition, the treatment of anti-depressant fluoxetine reversed most depressive symptoms and reduced glial fibrillary associated protein (GFAP) expression in the hippocampus, but was less effective in the reduction of foraging activities. However, clozapine reversed all symptoms of CUMS-exposed mice including reduction of GFAP expression in the hippocampus and impaired foraging activity. Our findings of GFAP expression as a marker to validate the CUMS protocol provide further validation of our hypothesis, that the reduced food foraging is probably a new behavioural finding of depression in which the serotoninergic system could not be singly involved. Our study suggests that NMDA receptors, serotoninergic and dopaminergic systems are differentially involved in these food foraging behaviours. Our data suggest that the foraging test in rodents can be a useful tool to assess the ability of decision-making in depression.

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.