Overview

Neuromodulators are powerful, specialized neurotransmitters that can functionally reconfigure neural circuits. By fine‐tuning the properties of specific cells and synapses, neuromodulators mediate learning and changes in behavioral state. Compromised neuromodulation underlies many neurological disorders ranging from pain and drug addiction to Parkinson’s disease.

We are particularly interested in neuropeptides, which are specifically expressed in distinct cell types that also release GABA or glutamate. Despite their abundance and striking, evolutionarily conserved expression patterns, the physiological roles of most neuropeptides in the brain are largely unknown. 

To reveal when, where and how neuropeptides modulate neural circuits, we employ contemporary genetically-targeted neuroanatomical methods, whole-cell electrophysiology, two-photon imaging and rodent behavioral analysis, often in conjunction with optogenetic and chemical-genetic perturbations. To facilitate these efforts, we also develop novel molecular tools for observing and manipulating neuromodulatory activity with an emphasis on photoactivatable (caged) neurotransmitters, optical sensors and genetically-targeted pharmacological probes.

Current projects

Neuropeptides in the basal ganglia

Neuropeptides have long been appreciated as anatomical markers for distinct cell types in striatum. Whereas dynorphin and substance P are uniquely expressed in striatonigral neurons, striatopallidal neurons express enkephalin, and distinct interneurons specifically express somatostatin or neuropeptide Y. Furthermore, expression levels of several neuropeptides and receptors map onto striatal compartments known as patches (striosomes) and matrix, whose functional significance is poorly understood. Despite their abundance and evolutionarily conserved patterns of distribution in the basal ganglia, surprisingly little is known about the role of neuropeptides in transforming striatal output. 

We aim to uncover the contributions of striatal neuropeptides to decision making, as well as the learning and recall of goal-oriented and habitual actions. Toward these goals we take advantage of transgenic mice that enable targeted electrophysiological and optical recordings, as well as optogenetic and chemogenetic manipulation of neurons in either patch or matrix compartments, both in vivo and ex vivo. 

Central mechanisms of antinociception

Despite our inherent aversion to pain, nociception is critical for organisms to successfully navigate environments that cause physical harm and threaten survival. A great deal of sensory processing occurs within nociceptive circuits of the peripheral nervous system and spinal cord. Although the brain is able to regulate thresholds for the awareness of pain as well, the architecture of the brain circuits capable of modulating nociception are poorly defined. Similarly, although various neuromodulators, including several neuropeptides, are known to bidirectionally shift pain thresholds when applied locally in the brain, the details of how these signaling molecules interface with the brain's nociceptive circuitry have not been established.

We aim to decipher the underlying circuit mechanisms of both pharmacological analgesia and top-down pain modulation (e.g. placebo analgesia), and to understand how neuromodulators and their receptors shape nociception in these contexts. We employ a combination of genetically-targeted anatomical methods, behavioral pharmacology, chemo- and optogenetic manipulations in vivo, as well as slice electrophysiology to address these issues. In light of the current epidemic of opioid-related deaths in America, a long-term goal of this work is to develop non-addictive analgesics. 

Molecular mechanisms of neuropeptide release

In contrast to fast neurotransmitters such as glutamate and GABA that are released from small, clear synaptic vesicles in response to single action potentials, relatively little is known about the neural neural activity patterns and biochemical signals that govern the release of neuropeptides from dense-core vesicles. In general, dense-core vesicle exocytosis follows "high frequency activity," but for many peptides released from mammalian central neurons, high frequency stimulation is insufficient to produce detectable peptide release, suggesting that different peptides may be under distinct control mechanisms in different types of cells. 

We aim to understand the molecular pathways that regulate neuropeptide release from mammalian central neurons. Our efforts are currently focused on the the release of dynorphin and substance P from striatonigral neurons and enkephalin from striatopallidal neurons. To detect exocytosis, we rely on slice electrophysiology and imaging, both in slice and in vivo. Our imaging experiments are largely driven by the development of genetically-encoded optical neuropeptide sensors in our lab and by our collaborator Lin Tian at UC Davis.