Deletion ofStim1in Hypothalamic Arcuate Nucleus Kiss1 Neurons Potentiates Synchronous GCaMP Activity and Protects against Diet-Induced Obesity
| Autor: | Jian Qiu, Martin J. Kelly, Ashley M. Connors, Stefanie Kaech Petrie, Todd L. Stincic, Oline K. Rønnekleiv, Martha A. Bosch |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | The Journal of Neuroscience. 41:9688-9701 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | Kisspeptin (Kiss1) neurons are essential for reproduction, but their role in the control of energy balance and other homeostatic functions remains unclear. High-frequency firing of hypothalamic arcuate Kiss1 (Kiss1ARH) neurons releases kisspeptin into the median eminence, and neurokinin B (NKB) and dynorphin onto neighboring Kiss1ARHneurons to generate a slow EPSP mediated by TRPC5 channels that entrains intermittent, synchronous firing of Kiss1ARHneurons. High-frequency optogenetic stimulation of Kiss1ARHneurons also releases glutamate to excite the anorexigenic proopiomelanocortin (POMC) neurons and inhibit the orexigenic neuropeptide Y/agouti-related peptide (AgRP) neurons via metabotropic glutamate receptors. At the molecular level, the endoplasmic reticulum (ER) calcium-sensing protein stromal interaction molecule 1 (STIM1) is critically involved in the regulation of neuronal Ca2+signaling and neuronal excitability through its interaction with plasma membrane (PM) calcium (e.g., TRPC) channels. Therefore, we hypothesized that deletion ofStim1in Kiss1ARHneurons would increase neuronal excitability and their synchronous firing, which ultimately would affect energy homeostasis. Using optogenetics in combination with whole-cell recording and GCaMP6 imaging in slices, we discovered that deletion ofStim1in Kiss1 neurons significantly increased the amplitude and duration of the slow EPSP and augmented synchronous [Ca2+]i oscillations in Kiss1ARHneurons. Deletion ofStim1in Kiss1ARHneurons amplified the actions of NKB and protected ovariectomized female mice from developing obesity and glucose intolerance with high-fat dieting (HFD). Therefore, STIM1 appears to play a critical role in regulating synchronous firing of Kiss1ARHneurons, which ultimately affects the coordination between energy homeostasis and reproduction.SIGNIFICANCE STATEMENTHypothalamic arcuate kisspeptin (Kiss1ARH) neurons are essential for stimulating the pulsatile release of gonadotropin-releasing hormone (GnRH) and maintaining fertility. However, Kiss1ARHneurons appear to be a key player in coordinating energy balance with reproduction. The regulation of calcium channels and hence calcium signaling is critically dependent on the endoplasmic reticulum (ER) calcium-sensing protein stromal interaction molecule 1 (STIM1), which interacts with the plasma membrane (PM) calcium channels. We have conditionally deletedStim1in Kiss1ARHneurons and found that it significantly increased the excitability of Kiss1ARHneurons and protected ovariectomized female mice from developing obesity and glucose intolerance with high-fat dieting (HFD). |
| Databáze: | OpenAIRE |
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