Disinhibition of Mesolimbic Dopamine Circuit by the Lateral Hypothalamus Regulates Pain Sensation.

Our recent study demonstrated the critical role of the mesolimbic dopamine (DA) circuit and its brain-derived neurotropic factor (BDNF) signaling in mediating neuropathic pain. The present study aims to investigate the functional role of GABAergic inputs from the lateral hypothalamus (LH) to the ventral tegmental area (VTA; LHGABA→VTA) in regulating the mesolimbic DA circuit and its BDNF signaling underlying physiological and pathologic pain. We demonstrated that optogenetic manipulation of the LHGABA→VTA projection bidirectionally regulated pain sensation in naive male mice. Optogenetic inhibition of this projection generated an analgesic effect in mice with pathologic pain induced by chronic constrictive injury (CCI) of the sciatic nerve and persistent inflammatory pain by complete Freund's adjuvant (CFA). Trans-synaptic viral tracing revealed a monosynaptic connection between LH GABAergic neurons and VTA GABAergic neurons. Functionally, in vivo calcium/neurotransmitter imaging showed an increased DA neuronal activity, decreased GABAergic neuronal activity in the VTA, and increased dopamine release in the NAc, in response to optogenetic activation of the LHGABA→VTA projection. Furthermore, repeated activation of the LHGABA→VTA projection was sufficient to increase the expression of mesolimbic BDNF protein, an effect seen in mice with neuropathic pain. Inhibition of this circuit induced a decrease in mesolimbic BDNF expression in CCI mice. Interestingly, the pain behaviors induced by activation of the LHGABA→VTA projection could be prevented by pretreatment with intra-NAc administration of ANA-12, a TrkB receptor antagonist. These results demonstrated that LHGABA→VTA projection regulated pain sensation by targeting local GABAergic interneurons to disinhibit the mesolimbic DA circuit and regulating accumbal BDNF release.SIGNIFICANCE STATEMENT The mesolimbic dopamine (DA) system and its brain-derived neurotropic factor (BDNF) signaling have been implicated in pain regulation, however, underlying mechanisms remain poorly understood. The lateral hypothalamus (LH) sends different afferent fibers into and strongly influences the function of mesolimbic DA system. Here, utilizing cell type- and projection-specific viral tracing, optogenetics, in vivo calcium and neurotransmitter imaging, our current study identified the LHGABA→VTA projection as a novel neural circuit for pain regulation, possibly by targeting the VTA GABA-ergic neurons to disinhibit mesolimbic pathway-specific DA release and BDNF signaling. This study provides a better understanding of the role of the LH and mesolimbic DA system in physiological and pathological pain.

Breast milk lead and cadmium levels in suburban areas of Nanjing, China.

OBJECTIVE: To evaluate levels of lead (Pb) and cadmium (Cd) in the breast milk in the second postpartum month, to investigate the relationship between Pb/Cd levels in breast milk and some sociodemographic parameters, and to explore whether these levels affect the infants' physical status or the mothers' psychological status (postpartum depression). METHODS: A cross-sectional study was conducted between November 2009 and December 2010. Altogether 170 healthy mothers were enrolled from Nanjing Maternity and Child Health Care Hospital. The inclusion criteria were: voluntary to participate in this study, healthy, with no chronic disease, breastfeeding in the second postpartum month, living in a suburban but not non-industrial area of Nanjing, and not occupationally exposed to toxic metals. All the mothers completed a questionnaire and were evaluated based on the Edinburgh Postpartum Depression Scale (EPDS) to identify the risk of postpartum depression. Pb and Cd levels in breast milk were determined by inductively coupled plasma mass spectroscopy. The infants of these mothers were examined for their z scores of weight for age, length for age, head circumference for age, and body mass index for age. RESULTS: The median breast milk levels of Pb and Cd were 40.6 µg/L and 0.67 µg/L, respectively. In 164 (96.5%) of the 170 samples, Pb levels were higher than the limit reported by the World Health Organization (> 5 µg/L). Breast milk Cd level was > 1 µg/L in 54 (31.8%) mothers. The mothers with a history of anemia had a higher breast milk Pb level than those without a history of anemia (41.1 µg/L vs. 37.9 µg/L, P = 0.050). The median breast milk Cd level in those who were active and passive smokers during pregnancy was significantly higher than that in non-smokers (0.88 µg/L vs. 0.00 µg/L, P = 0.025). The breast milk Cd level in the mothers not taking iron and vitamin supplements for 2 months postpartum was higher than in those taking the supplements (iron supplement: 0.74 µg/L vs. 0.00 µg/L, P = 0.025; vitamin supplement: 0.78 µg/L vs. 0.00 µg/L, P = 0.005). Breast milk Cd level at the second postpartum month was negatively correlated with the z scores of head circumference (r = - 0.248, P = 0.042) and weight for age at birth (r =- 0.241, P = 0.024) in girls. No correlation was found between the breast milk Pb/Cd levels and the EPDS scores. CONCLUSION: Considering the high levels of Pb and Cd in breast milk in this study, breast milk monitoring programs are necessary.

[Professor XU Rui-Zheng's experience in clinical diagnosis and treatment of auricular acupuncture].

Professor XU Rui-Zheng's experience in clinical diagnosis and treatment of auricular acupuncture are introduced. He is good at using auricular acupuncture to treat various diseases and symptoms, and he has rich experience in treatment of difficult and complicated cases, reflecting both syndrome differentiation treatment and an organic conception of the human body in treatment, with obviously clinical effect. He sums up clinical experience of many years, attaining the experience of ten wards, i.e. observation, touching, searching, detection, questioning, treatment program, pressing, treatment, regulation, advance.