Research

Understanding how neuropeptides regulate changes in normal and aging animals

Overview

Jennifer Garrison, PhD, is interested in understanding how neuropeptides control behavior at both the cell biological and neural circuit level. Neuropeptides comprise a large class of signaling molecules which are secreted from neurons and transmit messages within the brain and across the nervous system. The focus of her current research program includes:

Mechanisms of Neuropeptide Signaling

A major focus of the lab is to elucidate the mechanisms by which neuromodulation by neuropeptides encodes long-term changes in the brain that influence behavior and aging. Neuropeptides are the most diverse class of neuromodulators that that neurons use to communicate with each other and regulate behavior. Despite strong evidence showing essential functional roles for neuropeptides, at the cellular level a number of questions remain. To what extent does neuromodulation occur through synaptic versus extra-synaptic signaling? What distance do neuromodulators travel from their sites of release to signal? And on what timescale does this transmission occur? In the worm, we are developing tools to monitor neuromodulation at cellular resolution in an intact brain and using them to directly measure endogenous peptide release and binding to receptors on identified neurons using real-time approaches for imaging neuropeptide signaling, in order to understand the dynamics of this process in a living animal. We are using biochemistry and genetics to identify the proteins that enable neurite-specific neuropeptide localization and using cell-type-specific genetic manipulations to disable that machinery and thereby probe the behavioral function of extra-synaptic peptide signaling in specific circuits. We are also exploring the mechanisms by which long range neuropeptide signaling might be regulated. We are translating our findings from C. elegans to the mouse to systematically delineate the specific function of neuropeptide signaling in behavior.

Role of Neuropeptides in Aging

We are investigating how age-related changes in neuropeptide levels in specific neurons can influence whole organism healthspan and longevity. It is clear that neuropeptide levels in the brain change in defined ways as an organism ages but the role of neuropeptide signaling in aging has not been explored in a systematic way, in part due to a lack of tools to study these molecules. To define the relationship between neuropeptide signaling and aging, we are developing novel approaches for cell-type-specific analysis of neuropeptide signaling in the worm and the mouse. Our goal is to understand age-related differences in neuropeptide signaling, to identify specific longevity factors expressed in response to calorie restriction, and to discover novel neuropeptide genes.

Decoding Neurotransmission

Information processing in the brain is mediated by chemical communication between neurons. These chemical signals consist of both classical “fast acting” neurotransmitters such as glutamate and GABA that signal across synapses in milliseconds, as well as more than 100 diverse neuromodulators that can act on longer timescales. Neurons are typically classified according to expression of a specific transmitter (i.e. ‘oxytocin’ neurons), yet in reality most, if not all, neurons produce and use multiple transmitters. A major challenge in this area is that, while we now have powerful methods to manipulate neural circuits as a whole (such as optogenetics), we lack comparable methods to dissect the function of each of the individual neurotransmitters that are used within those circuits. We are developing a technique to define the precise role of individual neurotransmitters within defined circuits in the adult mouse brain. Our approach can be extended to examine the contribution of any neurotransmitter to the functional output of neural circuits in any region of the brain. Our goal is to understand how neuromodulators and their fast acting counterparts cooperate to generate the diverse behavioral outputs of the brain.

Garrison received her PhD from the University of California San Francisco in the laboratory of Dr. Jack Taunton, where she discovered the molecular target of a natural product and elucidated a novel mechanism by which small molecules can regulate protein biogenesis. As a postdoctoral fellow in Dr. Cori Bargmann’s lab at the Rockefeller University, she showed that the nematode C. elegans produces a neuropeptide that is an evolutionary precursor of the mammalian peptides vasopressin and oxytocin, and mapped a neural circuit by which this molecule, nematocin, modulates mating behavior.

Garrison was named an Alfred P. Sloan Research Fellow and received a Glenn Foundation Award for Research in Biological Mechanisms of Aging in 2014, and a Next Generation Leader at the Allen Institute for Brain Science in 2015. Her work is funded by the NIH National Institute of General Medical Sciences, the Glenn Foundation for Medical Research, the Alfred P. Sloan Foundation, and the Larry L. Hillblom Foundation.