The experience-dependent modification of synapses in the brain is thought to underlie the ability of animals to learn new behaviors and form memories. A great deal is known about the mechanisms that regulate synapses that signal via fast, classical neurotransmitters such as glutamate and GABA. However, the brain also contains a diverse and wide-spread system of synapses that signal through the release of short peptides called neuropeptides. Despite the importance of neuropeptides and neuropeptide receptors in modulating mammalian behavior and their known role in the pathogenesis of human disease, relatively little is known at a cellular level about the physiological consequences of peptidergic signaling. Similarly, neither the stimuli that trigger neuropeptide release nor its modulatory effects on classical synaptic transmission in the mammalian brain are well understood. We propose that neuropeptides rapidly regulate neurons and synapses with high temporal and spatial precision. We will examine this hypothesis using novel tools that allow the precisely-timed and spatially-delimited delivery of neuropeptides within brain tissue. We will use this approach in conjunction with optical and electrophysiological analysis of glutamatergic and GABAergic synapses to determine the modulatory effects of neuropeptides on cellular and synaptic physiology within the mammalian brain. We will initially focus on the actions of Tachykinin and Opioid family peptides and hope to eventually include Vasopressin, Oxytocin, and other neuropeptides. The action of these peptides will be examined in the hippocampus and basal ganglia, brain regions that have established relevance in human disease and behavior and with which the laboratory is familiar. In summary, we will use innovative approaches to study fundamental and relatively unexplored aspects of neurophysiology. These studies will advance our basic understanding of the mammalian brain and begin to lay the groundwork necessary to eventually understand the contribution of perturbed peptidergic signaling to neurological diseases.

Public Health Relevance

Neurons in the mammalian brain use peptides to send signals and modulate brain function. Although perturbations of these """"""""neuropeptide"""""""" signaling systems contribute to human neurological and psychiatric diseases, how they regulate neuron function is largely unknown. Here we propose to generate tools to rapidly activate neuropeptide signaling systems and to use these to understand how neuropeptides regulate neurons and synapses in the mammalian brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH085498-04
Application #
8113436
Study Section
Special Emphasis Panel (ZNS1-SRB-P (44))
Program Officer
Asanuma, Chiiko
Project Start
2008-08-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$335,610
Indirect Cost
Name
Harvard University
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Banghart, Matthew Ryan; Neufeld, Shay Quentin; Wong, Nicole Christine et al. (2015) Enkephalin Disinhibits Mu Opioid Receptor-Rich Striatal Patches via Delta Opioid Receptors. Neuron 88:1227-39
Banghart, Matthew R; Williams, John T; Shah, Ruchir C et al. (2013) Caged naloxone reveals opioid signaling deactivation kinetics. Mol Pharmacol 84:687-95
Olson, Jeremy P; Banghart, Matthew R; Sabatini, Bernardo L et al. (2013) Spectral evolution of a photochemical protecting group for orthogonal two-color uncaging with visible light. J Am Chem Soc 135:15948-54
Banghart, Matthew R; Sabatini, Bernardo L (2012) Photoactivatable neuropeptides for spatiotemporally precise delivery of opioids in neural tissue. Neuron 73:249-59