Hunger States Switch a Flip-Flop Memory Circuit via a Synaptic AMPK-dependent Positive Feedback Loop

Cell. 2011 Sep 16;146(6):992-1003. doi: 10.1016/j.cell.2011.07.039.

Abstract

Synaptic plasticity in response to changes in physiologic state is coordinated by hormonal signals across multiple neuronal cell types. Here, we combine cell-type-specific electrophysiological, pharmacological, and optogenetic techniques to dissect neural circuits and molecular pathways controlling synaptic plasticity onto AGRP neurons, a population that regulates feeding. We find that food deprivation elevates excitatory synaptic input, which is mediated by a presynaptic positive feedback loop involving AMP-activated protein kinase. Potentiation of glutamate release was triggered by the orexigenic hormone ghrelin and exhibited hysteresis, persisting for hours after ghrelin removal. Persistent activity was reversed by the anorexigenic hormone leptin, and optogenetic photostimulation demonstrated involvement of opioid release from POMC neurons. Based on these experiments, we propose a memory storage device for physiological state constructed from bistable synapses that are flipped between two sustained activity states by transient exposure to hormones signaling energy levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Agouti-Related Protein / metabolism
  • Analgesics, Opioid / metabolism
  • Animals
  • Calcium / metabolism
  • Chromosome Pairing*
  • Feedback, Physiological*
  • Ghrelin / metabolism
  • Hunger*
  • Memory*
  • Mice
  • Mice, Transgenic
  • Neuronal Plasticity
  • Neurons / metabolism*
  • Pro-Opiomelanocortin / metabolism
  • Ryanodine / metabolism
  • Signal Transduction

Substances

  • Agouti-Related Protein
  • Analgesics, Opioid
  • Ghrelin
  • Ryanodine
  • Pro-Opiomelanocortin
  • AMP-Activated Protein Kinases
  • Calcium