@article {47552, title = {Near-perfect synaptic integration by Nav1.7 in hypothalamic neurons regulates body weight.}, journal = {Cell}, volume = {165}, year = {2016}, month = {2016 Jun 16}, pages = {1749-61}, abstract = {

Neurons are well suited for computations on millisecond timescales, but some neuronal circuits set behavioral states over long time periods, such as those involved in energy homeostasis. We found that multiple types of hypothalamic neurons, including those that oppositely regulate body weight, are specialized as near-perfect synaptic integrators that summate inputs over extended timescales. Excitatory postsynaptic potentials (EPSPs) are greatly prolonged, outlasting the neuronal membrane time-constant up to 10-fold. This is due to the voltage-gated sodium channel Nav1.7 (Scn9a), previously associated with pain-sensation but not synaptic integration.\ Scn9a\ deletion in AGRP, POMC, or paraventricular hypothalamic neurons reduced EPSP duration, synaptic integration, and altered body weight in mice. In\ vivo whole-cell recordings in the hypothalamus confirmed near-perfect synaptic integration. These experiments show that integration of synaptic inputs over time by Nav1.7 is critical for body weight regulation and reveal a mechanism for synaptic control of circuits regulating long term homeostatic functions.

}, doi = {10.1016/j.cell.2016.05.019}, author = {Branco, Tiago and Tozer, Adam and Magnus, Christopher J and Sugino, Ken and Tanaka, Shinsuke and Lee, Albert K and Wood, John N and Sternson, Scott M} } @article {47033, title = {Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to weight-loss.}, journal = {eLife}, volume = {4}, year = {2015}, month = {2015 Sep 2}, abstract = {

Molecular and cellular processes in neurons are critical for sensing and responding to energy deficit states, such as during weight-loss. AGRP neurons are a key hypothalamic population that is activated during energy deficit and increases appetite and weight-gain. Cell type-specific transcriptomics can be used to identify pathways that counteract weight-loss, and here we report high-quality gene expression profiles of AGRP neurons from well-fed and food-deprived young adult mice. For comparison, we also analyzed POMC neurons, an intermingled population that suppresses appetite and body weight. We find that AGRP neurons are considerably more sensitive to energy deficit than POMC neurons. Furthermore, we identify cell type-specific pathways involving endoplasmic reticulum-stress, circadian signaling, ion channels, neuropeptides, and receptors. Combined with methods to validate and manipulate these pathways, this resource greatly expands molecular insight into neuronal regulation of body weight, and may be useful for devising therapeutic strategies for obesity and eating disorders.

}, issn = {2050-084X}, doi = {10.7554/eLife.09800}, author = {Henry, Fredrick E and Sugino, Ken and Tozer, Adam and Branco, Tiago and Sternson, Scott M} }