Effect of crocin carotenoid on BDNF and CREB gene expression in brain ventral tegmental area of morphine treated rats

Objective: To investigate the effect of crocin carotenoid on BNDF and CREB gene expression in the brain ventral tegmental area(VTA) and the serum level of BDNF in morphine-treated rats compared to control. Methods: In this study, 40 male Wistar rats(200-250 g) were used in 5 experimental groups: 1) non morphine treat rats(control); 2) non morphine-treated rats with 25 mg/kg crocin carotenoid(i.p., for 21 d); 3) morphine treated rats(10 mg/kg twice a day, s.c., 21 d); 4 and 5) morphine-treated rats with 12.5 and 25 mg/kg crocin carotenoid, respectively. By the end of research, BDNF and CREB expression was determined by real-time-PCR method. ELISA analysis was also applied for assessing the serum BDNF level. Results: The data indicated that morphine treatment could cause a significant decrease in BDNF and CREB gene expression(P<0.01 and P<0.001, respectively) in brain VTA as well as serum level of BDNF(P<0.01) in comparison to control group. Treatment with 25 mg/kg crocin carotenoid caused a significant enhancement in BDNF and CREF gene expression(P<0.01 and P<0.05, respectively) and serum level of BDNF(P<0.01) in morphine-treated rats in comparison to morphine-treated group. Conclusions: Regarding to obtained results, crocin carotenoid can inhibit unfavorable effects of morphine on the neural system to some extent through enhancing BDNF and CREB gene expression in brain VTA and serum level of BDNF.

Local infusion of low, but not high, doses of alcohol into the anterior ventral tegmental area causes release of accumbal dopamine

The mesolimbic dopamine system consisting of dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (N.Acc.) mediates the reinforcing effects of addictive drugs including alcohol. Given that VTA is a heterogeneous area and that alcohol, in rather low doses, interacts directly with ligand-gated ion channels, we hypothesised that low, rather than high, doses of alcohol into the VTA activate the mesolimbic dopamine system and that alcohol may have different effects in the anterior and posterior parts of the VTA. The present study was undertaken to investigate this hypothesis. The present series of experiment show that infusion of a low dose of alcohol (20 mM) into the anterior, but not posterior, part of the VTA increases accumbal dopamine release in rats. In addition, higher doses of alcohol (100 or 300 mM) into the anterior or posterior part of the VTA do not affect the release of dopamine in the N.Acc., suggesting that low doses of alcohol can activate the mesolimbic dopamine system via mechanisms in the VTA. These data contribute to understanding the neuronal mechanisms underlying the dependence-producing properties of alcohol and could tentatively contribute to that new treatment strategies for alcohol use disorder can be developed.

Potentiation of the lateral habenula-ventral tegmental area pathway underlines the susceptibility to depression in mice with chronic pain

Chronic pain often develops severe mood changes such as depression.However,how chronic pain leads to depression remains elusive and the mechanisms determining individuals’responses to depression are largely unexplored.Here we found that depression-like behaviors could only be observed in 67.9%of mice with chronic neuropathic pain,leaving 32.1%of mice with depression resilience.We determined that the spike discharges of the ventral tegmental area(VTA)-projecting lateral habenula(LHb)glutamatergic(Glu)neurons were sequentially increased in sham,resilient and susceptible mice,which consequently inhibited VTA dopaminergic(DA)neurons through a LHbGlu-VTAGABA-VTADA circuit.Furthermore,the LHbGlu-VTADA excitatory inputs were dampened via GABAB receptors in a pre-synaptic manner.Regulation of LHb-VTA pathway largely affected the development of depressive symptoms caused by chronic pain.Our study thus identifies a pivotal role of the LHb-VTA pathway in coupling chronic pain with depression and highlights the activity-dependent contribution of LHbGlu-to-VTADA inhibition in depressive behavioral regulation.

Brain region-specific roles of brain-derived neurotrophic factor in social stress-induced depressive-like behavior

Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response.Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice is brain region–specific,particularly involving the corticolimbic system,including the ventral tegmental area,nucleus accumbens,prefrontal cortex,amygdala,and hippocampus.Determining how brain-derived neurotrophic factor participates in stress processing in different brain regions will deepen our understanding of social stress psychopathology.In this review,we discuss the expression and regulation of brain-derived neurotrophic factor in stress-sensitive brain regions closely related to the pathophysiology of depression.We focused on associated molecular pathways and neural circuits,with special attention to the brain-derived neurotrophic factor–tropomyosin receptor kinase B signaling pathway and the ventral tegmental area–nucleus accumbens dopamine circuit.We determined that stress-induced alterations in brain-derived neurotrophic factor levels are likely related to the nature,severity,and duration of stress,especially in the above-mentioned brain regions of the corticolimbic system.Therefore,BDNF might be a biological indicator regulating stress-related processes in various brain regions.

Research Progress on Mechanisms in Regulating Anxiety-Related Neural Circuits

Anxiety is a common disease in the modern society which significantly affects people’s daily lives and function,thus it has become an increasingly highlighted issue.Anxiety is regulated by neural circuits in the brain.Therefore,the basal mechanism of anxiety has been studied,especially research based on the related neural circuits.For a long time,due to the limitations of science and technology,there was no breakthrough in research regarding anxiety.However,in recent years,due to the progress of technology,the research on anxiety neural circuits has made great progress.For example,the interaction among various brain regions,such as the central nucleus of the amygdala(CeA),the ventral tegmental area(VTA),the ventral hippocampus(vHPC),and so on.This article focuses on three brain regions:including BLA,BNST,and VTA,and illustrate their different roles and mechanisms in regulating anxiety.On this basis,this intensive study of anxiety will further promote the progress of anxiety research and provide therapeutic targets for the related treatment.

Dopaminergic Neurons in the Ventral Tegmental–Prelimbic Pathway Promote the Emergence of Rats from Sevoflurane Anesthesia

Dopaminergic neurons in the ventral tegmental area(VTA)play an important role in cognition,emergence from anesthesia,reward,and aversion,and their projection to the cortex is a crucial part of the"bottom-up"ascending activating system.The prelimbic cortex(PrL)is one of the important projection regions of the VTA.However,the roles of dopaminergic neurons in the VTA and the VTADA–PrL pathway under sevoflurane anesthesia in rats remain unclear.In this study,we found that intraperitoneal injection and local microinjection of a dopamine D1 receptor agonist(Chloro-APB)into the PrL had an emergence-promoting effect on sevoflurane anesthesia in rats,while injection of a dopamine D1 receptor antagonist(SCH23390)deepened anesthesia.The results of chemogenetics combined with microinjection and optogenetics showed that activating the VTADA–PrL pathway prolonged the induction time and shortened the emergence time of anesthesia.These results demonstrate that the dopaminergic system in the VTA has an emergence-promoting effect and that the bottom-up VTADA–PrL pathway facilitates emergence from sevoflurane anesthesia.

Lateral habenula neurocircuits mediate the maternal disruptive effect of maternal stress: A hypothesis

Up to 20%of women experience stress-related disorders during the postpartum period;however,little is known about the specific neural circuitry by which maternal stress exerts its negative impacts on mental health and maternal caregiving behavior.Theoretically,such a circuitry should serve as an interface between the stress response system and maternal neural network,transmitting stress signals to the neural circuitry that mediates maternal behavior.In this paper,I propose that the lateral habenula(LHb)serves this interface function.Evidence shows that the LHb plays a key role in encoding stress-induced effects and in the pathophysiology of major depression and stressrelated anxiety,and thus may play a role in maternal behavior as part of the maternal brain network.I hypothesize that maternal stress acts upon the LHb and two of its major downstream targets,i.e.,ventral tegmental area(VTA)and dorsal raphe nucleus(DRN),compromising the maternal care and contributing to postpartum mental disorders.This hypothesis makes three predictions:(1)maternal stress enhances LHb neuronal activity;(2)activation of DRN-and VTA-projecting neurons in the LHb mimics the detrimental effects of maternal stress on maternal behavior;and(3)suppression of DRN-and VTA-projecting neurons in the LHb attenuates the detrimental effects of maternal stress on maternal care in stressed mothers.Confirmation of this hypothesis is expected to enhance our understanding of the neurocircuit mechanisms mediating stress effects on maternal behavior.

Brain regional changes of guanine nucleotide binding protein-inhabitant 2 in acute and chronic morphine-tolerant and-dependent rats

BACKGROUND： Drug addiction involves two main central nervous systems, namely the dopamine and noradrenaline systems. These systems are primarily distributed in five brain regions： the ventral tegmental area, the nucleus accumbens, the prefrontal cortex, the hippocampus, and the locus coeruleus. OBJECTIVE： To investigate regional changes of guanine nucleotide binding protein-inhabitant 2 （Gi2） in dopaminergic and noradrenergic neurons in brains of morphine-tolerant and -dependent rats. DESIGN, TIME, AND SETTING： A randomized control study was performed at the Department of Neurobiology in the Second Military Medical University of Chinese PLA （Shanghai, China） between September 2002 and March 2004. MATERIALS： Thirty-six, healthy, male, Sprague-Dawley （SD） rats were used to establish morphine-dependent models. Morphine hydrochloride was a product of Shenyang First Pharmaceutical Factory （China）; naloxone hydrochloride was a product of Beijing Four-Ring Pharmaceutical Factory （China）; and α subunit of Gi2 antibody was offered by Santa Cruz Biotechnology, lnc （USA）. METHODS： Thirty-six SD rats were randomly divided into six groups （n = 6）： （1） acute morphine-dependent group, （2） acute abstinent group, （3） acute control group, （4） chronic morphine-dependent group, （5） chronic abstinent group, and （6） chronic control group. Rats in the acute morphine-dependent and the acute groups were injected with morphine （5 mg/kg）, one injection every two hours, for a total of eight injections. In the acute and chronic morphine-dependent rat models, morphine withdrawal syndrome was precipitated by an injection of naloxone （5 mg/kg）. Rats in the acute control group were given a peritoneal injection of physiological saline at the same administration time as the above two groups. Rats in the chronic morphine-dependent and chronic abstinent groups were injected with morphine three times per day. The administration dose on day 1 was initially 5 mg/kg at 20：00, which increased by 5 mg/kg at 8：00, 12：00, and 20：00 until day 7. On day 13, the dose continuously increased by 10 mg/kg until a chronic morphine-dependent rat model was successfully induced. Afterwards, the rats presented with withdrawal syndromes on naloxone （5 mg/kg） at 8：00 on the same day. Rats in the chronic control group were injected with physiological saline at the same time of the two chronic groups. MAIN OUTCOME MEASURES： The concentration of Gi2 protein in the five brain regions （ventral tegmental area, nucleus accumbens, prefrontal cortex, locus coeruleus, and hippocampus） was detected by immunohistochemistry. RESULTS： In the acute morphine-dependent and acute abstinent groups, Gi2 protein concentration was significantly decreased in the nucleus accumbens, compared to the acute control group （P 〈 0.01）, while no obvious changes were detected in other brain regions. In the chronic morphine-dependent and chronic abstinent groups, Gi2 protein concentration was significantly decreased in the nucleus accumbens, but significantly increased in the locus coeruleus （P 〈 0.01 ） compared to the chronic control group. CONCLUSION： Morphine dependence and tolerance may induce obvious reductions of Gi2 protein levels in the nucleus accumbens of rats. Chronic morphine dependence desensitizes the homologous neurons.

Effects of Melatonin Levels on Neurotoxicity of the Medial Prefrontal Cortex in a Rat Model of Parkinson＇s Disease

Background： Damage of the medial prefrontal cortex （mPFC） results in similar characteristics to the cognitive deficiency seen with the progress of Parkinson＇s disease （PD）. Since the course of mPFC damage is still unclear, our study aimed to investigate the effects of melatonin （MT） on neurotoxicity in the mPFC of a rat model of PD. Methods： One hundred and fifty-four normal, male Wistar rats were randomly divided into the following five groups： normal ＋ normal saline （NS）, normal ＋ 6-hydroxydopamine （6-OHDA）, sham pinealectomy （PX） ＋ 6-OHDA, PX ＋ 6-OHDA, and MT ＋ 6-OHDA. 6-OHDA was injected into the right substantia nigra pars compacta （SNc） and ventral tegmental area （VTA） of each group, except normal ＋ NS, 60 days after the PX. In the MT treatment group, MT was administered immediately after the intraperitoneal injection at 4 p.m. every day, for 14 days. Neuronal apoptosis in the mPFC was exalnined using the TUNEL method, while the expression oftyrosine hydroxylase （TH）, Bax, and Bcl-2 in this region was measured using immunohistochemistry. The concentration of malondialdehyde （MDA） in the mPFC was examined using the thioharbituric acid method. Results： Rats in the normal ＋ 6-OHDA and sham PX ＋ 6-OHDA groups were combined into one group （Group N ＋ 6-OHDA） since there was no significant discrepancy between the groups for all the detected parameters. Apoptosis of cells in the NS, MT ＋ 6-OHDA, N ＋ 6-OH DA, and PX ＋ 6-OHDA groups was successively significantly increased （Hc = 256.25, P 〈 0.001 ）. The gray value of TH （＋） fibers in the NS, MT ＋ 6-OHDA, N ＋ 6-OHDA, and PX ＋ 6-OHDA groups was also successively significantly increased （F= 99.33, P 〈 0.001 ）. The staining intensities of Bax and Bcl-2 were as follows： Group NS ＋/＋, Group MT ＋ 6-OHDA ＋＋/＋, Group N ＋ 6-OHDA ＋＋/＋, and PX ＋ 6-OHDA ＋＋＋/＋. The concentrations of MDA in the NS, MT ＋ 6-OHDA, N ＋ 6-OHDA, and PX ＋ 6-OHDA groups were significantly increased in sequence （Hc = 296.309, P 〈 0.001 ）. Conclusions： Neuronal damage of the VTA by 6-OHDA might induce VTA-mPFC nerve fibers to undergo anterograde nerve damage, in turn inducing transneuronal damage of the mPFC. PX significantly exacerbated the neurotoxicity in the mPFC, which was induced by the neuronal injury of the VTA. However, MT replacement therapy significantly alleviated the neurotoxicity in the mPFC.

KCNQ Channels in the Mesolimbic Reward Circuit Regulate Nociception in Chronic Pain in Mice

Mesocorticolimbic dopaminergic(DA) neurons have been implicated in regulating nociception in chronic pain, yet the mechanisms are barely understood. Here, we found that chronic constructive injury(CCI) in mice increased the firing activity and decreased the KCNQ channel-mediated M-currents in ventral tegmental area(VTA) DA neurons projecting to the nucleus accumbens(NAc). Chemogenetic inhibition of the VTA-to-NAc DA neurons alleviated CCI-induced thermal nociception.Opposite changes in the firing activity and M-currents were recorded in VTA DA neurons projecting to the medial prefrontal cortex(mPFC) but did not affect nociception. In addition, intra-VTA injection of retigabine, a KCNQ opener, while reversing the changes of the VTA-to-NAc DA neurons, alleviated CCI-induced nociception, and this was abolished by injecting exogenous BDNF into the NAc.Taken together, these findings highlight a vital role of KCNQ channel-mediated modulation of mesolimbic DA activity in regulating thermal nociception in the chronic pain state.

Volume Gain of Brainstem on Medication-Overuse Headache Using Voxel-Based Morphometry

Background： Histopathology identified the anatomical and molecular abnormalities ofbrainstem nuclei in migraine patients. However, the exact whole brainstem structural changes in vivo have not yet been identified in medication-overuse headache （MOH） transformed from migraine. The aim of this study was to investigate the regional volume changes over the whole brainstem in the MOH patients using voxel-based morphometry （VBM） in vivo.Methods： High-resolution three-dimensional structural images were obtained using a 3.0-Tesla magnetic resonance system from 36 MOH patients and 32 normal controls （NCs） who were consecutively recruited from the International Headache Center, Chinese People＇s Liberation Army General Hospital, from March 2013 to June 2016. VBM was used to assess the brainstem structural alteration in the MOH patients, and voxel-wise correlation was performed to evaluate the relationship with the clinical characteristics.Results： The brainstem region with increased volume located in the left ventrolateral periaqueductal gray （MNI coordinate： -1, -33, -8）, ventral tegmental area （MNI coordinate： 0, -22, - 12）, bilateral substantia nigra （MNI coordinate： -8, - 16, - 12, 9, - 16, - 12）, and trigeminal root entry zone （MNI coordinate： -19, -29, -31; 19, -32, -29） in MOH patients compared with NCs. The headache visual analog scale score was positively related with the left rostral ventromedial medulla （RVM） （MNI coordinate： -1, -37, -56; cluster size： 20; r = 0.602） in the MOH patients.Conclusions： The regional volume gain ofbrainstem could underlie the neuromechanism of impaired ascending and descending pathway in the MOH patients, and the left RVM volume alteration could imply the impaired tolerance ofnociceptive pain input and could be used to assess the headache disability in the MOH patients.