AMP-activated protein kinase (AMPK), an evolutionarily conserved serine/threonine kinase stimulated by both decreased cellular energy status and increased calcium, is an important player acting at the interface between metabolism and brain function. In addition to metabolic diseases like obesity and diabetes, abnormal AMPK activities have been implicated in a variety of neurological disorders with dysfunctional neurotransmission. The neurobiological mechanisms of AMPK responsible for these effects, however, are largely unknown. Recent studies have suggested that agouti-related peptide (AgRP)-expressing neurons in the hypothalamus, a master controller of feeding and energy balance, receive intense glutamatergic input and their excitatory synaptic plasticity plays an essential role in regulating AgRP neuron firing and related feeding. Importantly, our prior findings demonstrate that fasting significantly induces dendritic spinogenesis, glutamatergic synaptogenesis, and firing in AgRP neurons, and this fasting-induced plasticity requires postsynaptic NMDA receptors on AgRP neurons and contributes essentially to their fasting-induced activation. The neurobiological mechanism that underlies fasting-induced plasticity in AgRP neurons, however, is left unknown. In this context, AMPK in the hypothalamus is activated by fasting and manipulation of AMPK activity in this region affects feeding. In addition, when stimulated pharmacologically in brain slices, AMPK increases glutamatergic input to AgRP neurons. These findings suggest that AMPK likely trigger this fasting-induced plasticity. However, given the wide expression of AMPK in the brain and its multi-faceted roles in cellular biology, whether AMPK in AgRP neurons mediates fasting-induced feeding is still in debate. How fasting modulates AMPK dynamics is also unclear. By employing a battery of neuron-specific approaches, including neuron-specific transgenic and knockout mouse lines, cre-dependent AAV viral vectors, 2-photon laser scanning microscopy (2PLSM) combined with whole cell patch-clamp electrophysiology, and particularly 2PLSM-based fluorescence lifetime imaging (FLIM), this proposal aims to provide a unique, multi-faceted study to understand AMPK signaling and its physiology in the neurotransmission of AgRP neurons. Based on our compelling preliminary findings, we hypothesize that a postsynaptic pathway engaged by AMPK in AgRP neurons drives fasting induced excitatory synaptic plasticity and the plasticity brought about by this pathway accounts for the effects of AMPK on energy balance (Aim 1). We further hypothesize that AMPK functions as a critical integrator of diverse inputs (such as fasting, ghrelin, and leptin) of AgRP neurons and mediates both synaptic and cellular changes (Aim 2). Our novel findings on synaptic plasticity and AMPK will provide innovative knowledge in the feeding circuits. Given the wide distribution of AMPK and its substrates, the uncovered pathway engaged by AMPK in AgRP neurons will likely operate both within and beyond the hypothalamus, and have important implications for many processes where synaptic plasticity plays a key regulatory role.
AMPK is a critical sensor and regulator of cellular metabolism and has been implicated in various metabolic and neurological diseases. The regulatory mechanism of AMPK in neurons and synaptic transmission is still unclear. By focusing on a group of neurons in the hypothalamus and their related feeding behavior, we will employ multiple advanced technologies with both neuron-specificity and high spatiotemporal resolution to investigate AMPK signaling in neurotransmission and its physiological function in controlling feeding.
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