Neuroscience
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Previous studies have shown that leptin resistance is a key feature that leads to gestational metabolic adaptions. We hypothesized that leptin sensitivity in the ventromedial nucleus of the hypothalamus (VMH) plays a critical role regulating gestational metabolic changes. In the present study, we generated a mouse model carrying ablation of the suppressor of cytokine signaling 3 (SOCS3) in steroidogenic factor-1 (SF1) cells, which include the VMH, in order to investigate whether increased leptin sensitivity in this neuronal population prevents at least part of the metabolic changes typically observed during gestation and lactation. ⋯ Unexpectedly, SF1 SOCS3 KO mice exhibited glucose intolerance during pregnancy. SF1 SOCS3 KO mice also presented a lower body weight (-3%; p < 0.05) during mid and late lactation, although food intake, litter size and offspring growth were not affected. Our findings suggest that increased leptin sensitivity in the VMH causes modest metabolic effects and is not sufficient to prevent major metabolic adaptations of pregnancy and lactation.
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The primary sensory cortex exhibits neuroplastic changes responding to sensory disturbances, and GABAergic synaptic transmission plays a critical role in the regulation of plasticity. The insular cortex (IC) integrates orofacial nociceptive signals conveyed via myelinated Aδ- and unmyelinated C-fibers. However, it has been unknown whether a disturbance of nociceptive inputs, such as a deletion of the peripheral nerves, alters GABAergic local circuit in IC. ⋯ These results suggest that capsaicin treatment depresses IPSCs via a postsynaptic mechanism. To confirm this possibility, the variance-mean analysis of unitary IPSCs was employed and we found that quantal size of GABAergic synaptic transmission was smaller in capsaicin-treated rats than in sham-treated rats. These results suggest that ablation of C-fibers induces plastic changes in GABAergic synaptic transmission by decreasing postsynaptic GABAA receptor-mediated conductance, which is a possible mechanism of the facilitative excitation in IC of capsaicin-treated rats.
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Bumetanide is a selective inhibitor of the Na+-K+-Cl--co-transporter 1(NKCC1). We studied whether bumetanide could affect axonal growth and behavioral outcome in stroke rats. Adult male Wistar rats were randomly assigned to four groups: sham-operated rats treated with vehicle or bumetanide, and ischemic rats treated with vehicle or bumetanide. ⋯ Bumetanide treatment also decreased the expressions of NKCC1 and Nogo-A, increased the expressions of KCC2 and BDNF in the perilesional cortex and enhanced the synaptic plasticity in the denervated cervical spinal cord after cerebral ischemia. The behavioral performance of ischemic rats was significantly improved by bumetanide. In conclusion, bumetanide promoted post-stroke axonal sprouting together accompanied by an improved behavioral outcome possibly through restoring and maintaining neuronal chloride homeostasis and creating a recovery-promoting microenvironment by overcoming the axonal growth inhibition encountered after cerebral ischemia in rats.
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GLT-1 is mainly expressed in astrocytes and has a crucial role in glutamate uptake. Sonic hedgehog (SHH) can inhibit glutamate uptake and its pathway is activated in many brain diseases related with glutamate excitotoxicity. However, whether SHH regulates GLT-1 to affect glutamate uptake is not clear. ⋯ The reduction of GLT-1 and inhibition of aspartate current are not observed when staurosporine (STP) and BisindolylmaleimideII (BisII), agents known as PKC inhibitors, are present. Further, when PKCδ is knocked down in astrocytes, SHH cannot reduce GLT-1 protein levels. Therefore, SHH induces degradation of GLT-1 through PKCδ to regulate its activities.
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Minimal hepatic encephalopathy (MHE) is induced by elevated intracranial dopamine (DA). Glutamate (Glu) toxicity is known to be involved in many neurological disorders. In this study, we investigated whether DA increased Glu levels and collaborated with Glu to impair memory. ⋯ DA activated TAAR1 to downregulate EAAT2 and increase extracellular Glu levels in MHE. Additionally, DA together with Glu caused decreased production of neuronal BDNF/NT3 and memory impairment through the activation of CaN/NFAT signaling in MHE. From these findings, we conclude that DA increases Glu levels via interaction with TAAR1 and disruption of EAAT2 signaling in astrocytes, and DA interacting with TAAR1 and Glu interacting with AMPAR synergistically decreased the production of BDNF by activation of CaN/NFAT signaling to impair memory in MHE rats.