Neuroscience Graduate Program at UCSF
Neural circuits for homeostatic behaviors
We study neural circuits in the mouse that control feeding and other motivated behaviors central to survival. Our goal is to understand how these circuits are able to sense the needs of the body and then generate specific behavioral responses that restore homeostasis. A major challenge in this field is that these homeostatic circuits are embedded within brain structures such as the hypothalamus that contain a vast diversity of neural cell types. As a result we know remarkably little about the specific cell types, interconnections, and activity dynamics that drive these fundamental behaviors. To address this challenge we develop genetic tools that enable the use of RNA sequencing to identify molecular markers for functional populations of neurons in these brain regions (Knight et al, Cell, 2012; Ekstrand et al., Cell, 2014). We then use these molecular markers as entry points to visualize and manipulate the underyling cells, using a range of modern approaches in neuroscience including optogenetics, in vivo calcium imaging, slice electrophysiology, and viral tracing. Our long-term goal is to eludicate the structure and dynamics of these homeostatic circuits, so that we can begin to understand how they give rise to goal-directed behaviors and further how they become dysregulated in conditions such as obesity.
We recently reported the first in vivo recordings of the activity of AgRP and POMC neurons, the two most widely studied cell types in the mouse brain that control hunger (Chen et al., Cell, 2015). These experiments unexpectedly revealed that AgRP and POMC neurons are potently regulated by the sensory detection of food – that is, the mere sight and smell of food is sufficient to rapidly “reset” the activation state of these neurons induced by food deprivation. This discovery suggests that AgRP and POMC neurons function primarily to control appetitive behaviors, such as foraging, that promote the discovery of food. An ongoing interest of the lab is to understand how these and other homeostatic circuits integrate sensory information from the outside world with internal signals arising from the body in order to generate and shape goal-directed behaviors such as feeding.
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Chris Zimmerman, Neuroscience Graduate Student
Yiming Chen, Neuroscience Graduate Student
Tzu-Wei Kuo, Neuroscience Graduate Student
David Leib, Neuroscience Graduate Student
Chan Lek Tan, Postdoctoral Fellow
Dina Faddah, Postdoctoral Fellow
Daniel Estandian, Specialist
Elizabeth Cooke, Specialist
Yen-Chu Lin, Specialist
Alissa Gee, Adminstrative Assistant
Chen, Y., Lin,Y.C., Kuo,T.W., and Knight, Z.A. Sensory detection of food rapidly modulates arcuate feeding circuits. Cell. 2015, February 26; 160(5)
Ekstrand M.I., Nectow A.R., Knight Z.A., Friedman, J.M., Latcha K.N., Pomeranz, LE., and Friedman J.M., Molecular profiling of neurons based on connectivity, Cell. 2014, May 22; 157(5):1230-42
Knight, Z.A., Tan, K., Birsoy, K., Schmidt, S., Garrison, J.L., Wysocki, R.W., Emiliano, A., Ekstrand, M.I., Friedman, J.M., Molecular profiling of activated neurons by phosphorylated ribosome capture, Cell. 2012, November 21; 151(5): 1126-37.
Tan, K.., Knight, Z.A., Friedman, J.M. Ablation of AgRP neurons impairs the adaptation to restricted feeding, Molecular Metabolism. 2014, July 10; ;3(7):694-704
Knight, Z.A., Hannan, K.S., Greenberg, M., and Friedman, J.M., Hyperleptinemia is required for the development of leptin resistance, Plos One. 2010 Jun 29; 5(6):e11376.