Bidirectional electromagnetic control of the hypothalamus regulates feeding and metabolism

Sarah A. Stanley, Leah Kelly, Kaamashri N. Latcha, Sarah F. Schmidt, Xiaofei Yu, Alexander R. Nectow, Jeremy Sauer, Jonathan P. Dyke, Jonathan S. Dordick, Jeffrey M. Friedman
<span title="">2016</span> <i title="Springer Nature"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/drfdii35rzaibj3aml5uhvr5xm" style="color: black;">Nature</a> </i> &nbsp;
Targeted, temporally regulated neural modulation is invaluable in determining the physiological roles of specific neural populations or circuits. Here we describe a system for non-invasive, temporal activation or inhibition of neuronal activity in vivo and its use to study central nervous system control of glucose homeostasis and feeding in mice. We are able to induce neuronal activation remotely using radio waves or magnetic fields via Cre-dependent expression of a GFP-tagged ferritin fusion
more &raquo; ... otein tethered to the cation-conducting transient receptor potential vanilloid 1 (TRPV1) by a camelid anti-GFP antibody (anti-GFP-TRPV1) 1 . Neuronal inhibition via the same stimuli is achieved by mutating the TRPV1 pore, rendering the channel chloride-permeable. These constructs were targeted to glucose-sensing neurons in the ventromedial hypothalamus in glucokinase-Cre mice, which express Cre in glucose-sensing neurons 2 . Acute activation of glucose-sensing neurons in this region increases plasma glucose and glucagon, lowers insulin levels and stimulates feeding, while inhibition reduces blood glucose, raises insulin levels and suppresses feeding. These results suggest that pancreatic hormones function as an effector mechanism of central nervous system circuits controlling blood glucose and behaviour. The method we employ obviates the need for permanent implants and could potentially be applied to study other neural processes or used to regulate other, even dispersed, cell types. While electrode stimulation and lesioning studies suggest that hypothalamic neurons regulate blood glucose and feeding 3 , these methods affect both cells and fibres of passage 4-6 and do not define contributing cell types 7 . Previously we showed that radio waves or magnetic fields can control calcium (Ca 2+ ) entry and gene expression using ferritin nanoparticles tethered to the temperature-sensitive TRPV1 channel 1 . In this report, we tested the utility of our approach for neural activation and investigate the function of hypothalamic glucose-sensing neurons. A replication-deficient adenovirus with Cre-dependent expression of anti-GFP-TRPV1/GFP-ferritin (Ad-FLEX-anti-GFP-TRPV1/GFP-ferritin) was injected unilaterally into the ventromedial hypothalamus (VMH) of glucokinase-Cre (GK-Cre) mice, which express Cre in glucosesensing neurons 2 (Extended Data Fig. 1a) , targeting ~2,000 neurons (see Methods), similar to previous studies 8,9 . Radio frequency (RF) treatment (465 kHz) of these mice significantly increased blood glucose (change in blood glucose at 30 min: RF-treated, 48.9 ± 16.9 mg dl −1 versus untreated, −0.7 ± 12.9 mg dl −1 ; P < 0.05; at 45 min: RF-treated, 91.3 ± 28.2 mg dl −1 versus untreated, 8.7 ± 11.1 mg dl −1 ; P < 0.05) and the cumulative change in blood glucose (area under the curve (AUC; 0-90 min): RF-treated, 5,562 ± 1,977 mg dl −1 min versus untreated, 62 ± 1,184 mg dl −1 min; P < 0.05) (Fig. 1b, c) . The time course and extent of glucose changes after RF treatment were almost superimposable with those after optogenetic activation of VMH GK-Cre neurons, albeit with a slight delay (Fig. 1b, c) . RF treatment of GK-Cre mice with VMH injection of anti-GFP-TRPV1/GFP-ferritin halved plasma
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