My colleagues and I want to know (1) how the nervous system makes decisions at the level of individual neurons and of neuronal circuits and (2) how the decision-making process is affected by life experiences. We ask these questions in an exquisitely approachable nervous system, that of the medicinal leech. Using voltage- sensitive dyes, we record activity in much of the animal's nervous system simultaneously as it decides whether to crawl, swim, feed, or bend. We also use photosensitive dyes that can activate or inactivate small groups of neurons to determine their contribution to decisions. We will first correlate activity in single neurons with particular choices, then activate or silence candidate decision-making neurons while they are make decisions. Having found neurons involved in these choices, we will now focus on three aspects of decision-making: 1. Do neuromodulators affect choice? These substances can modify the strengths of synapses, thus functionally rewiring a neuronal circuit. We will ask how the neuromodulators serotonin and dopamine affect decision-making. 2. Does the dynamical state of interactions among a set of neurons affect choice? One set of interconnected neurons could produce different stable activity states depending upon how the system is activated. 3. Does making a choice depend on increasing the gain in a particular behavioral circuit? Modifying gain might modify decision-making in a way that depends on """"""""mood"""""""" or metabolic state: in the same circumstances, a hungry, excited animal will choose differently than a sated, relaxed one. Serotonin and dopamine have been strongly implicated in such changes in behavioral state, and we will determine how they modify the responsiveness of the decision-making neurons. Understanding the decision-making process is important;people who consistently make bad choices can end up in the hospital, in jail, or dead. The need for basic research about these processes is made clear from a recent quotations from the on-line textbook, Neuropsychopharmacology: The Fifth Generation of Progress: """"""""Serotonin...has been implicated in almost every conceivable physiologic or behavioral function-affect, aggression, appetite, cognition, emesis, endocrine function, gastrointestinal function, motor function, neurotropism, perception, sensory function, sex, sleep and vascular function. Moreover, most drugs that are currently used for the treatment of psychiatric disorders (e.g., depression, mania, schizophrenia, autism, obsessive-compulsive disorder, anxiety disorders) are thought to act, at least partially, through serotonergic mechanisms."""""""" (GK Aghajanian, AE Sanders-Bush Serotonin). Malfunctions in the dopamine system lead to horrors like addiction, psychosis, and Parkinson's Disease. Basic research using a powerful model system will allow us to sort out the many roles of serotonin and dopamine, and to determine how they affect decision-making.

Public Health Relevance

I propose to find out, at the level of individual neurons, how a brain operates: how it makes generates behaviors, how it makes decisions, and how those decisions are modified by the state of the animal. My laboratory uses a model system-the brain of a simple worm-because we can hope to answer these questions in rigorous ways. The comparative approach has a long and fruitful history: questions answered in simple animals provide information and inspiration for asking the same questions in more complex animals, like rats, monkeys, and eventually humans.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Sensorimotor Integration Study Section (SMI)
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Glanzman, Dennis L
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University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
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Pipkin, Jason E; Bushong, Eric A; Ellisman, Mark H et al. (2016) Patterns and distribution of presynaptic and postsynaptic elements within serial electron microscopic reconstructions of neuronal arbors from the medicinal leech Hirudo verbana. J Comp Neurol 524:3677-3695
Woodford, Clifford R; Frady, E Paxon; Smith, Richard S et al. (2015) Improved PeT molecules for optically sensing voltage in neurons. J Am Chem Soc 137:1817-24
Palmer, Chris R; Barnett, Megan N; Copado, Saul et al. (2014) Multiplexed modulation of behavioral choice. J Exp Biol 217:2963-73
Miller, Evan W; Lin, John Y; Frady, E Paxon et al. (2012) Optically monitoring voltage in neurons by photo-induced electron transfer through molecular wires. Proc Natl Acad Sci U S A 109:2114-9
Gaudry, Quentin; Kristan Jr, William B (2012) Decision points: the factors influencing the decision to feed in the medicinal leech. Front Neurosci 6:101
Palmer, Chris R; Kristan Jr, William B (2011) Contextual modulation of behavioral choice. Curr Opin Neurobiol 21:520-6
Todd, Krista L; Kristan Jr, William B; French, Kathleen A (2010) Gap junction expression is required for normal chemical synapse formation. J Neurosci 30:15277-85
Baltzley, Michael J; Gaudry, Quentin; Kristan Jr, William B (2010) Species-specific behavioral patterns correlate with differences in synaptic connections between homologous mechanosensory neurons. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 196:181-97
Gaudry, Q; Ruiz, N; Huang, T et al. (2010) Behavioral choice across leech species: chacun a son gout. J Exp Biol 213:1356-65
Wagenaar, Daniel A; Gonzalez, Ruben; Ries, David C et al. (2010) Alpha-conotoxin ImI disrupts central control of swimming in the medicinal leech. Neurosci Lett 485:151-6

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