The ability to learn associations between a specific sensory stimulus and an outcome such as re- ward or punishment is a basic requirement for flexible behaviors. Malfunctions of this associative process may underlie various disorders such as drug addiction and binge eating. Rodents can learn novel stimulus-response associations after only a few repetitions, but the circuits that are modified during learning are largely unknown. The olfactory tubercle (OT), a part of the ventral stri- atum, is located at the interface between sensory and reward centers, receiving strong olfactory sensory input as well as dopaminergic innervation from the ventral tegmental area (VTA). It has been implicated in reward and is a recognized ?hot spot? for cocaine self-administration. These ob- servations suggest that the OT is the site of heterosynaptic plasticity to establish valence represen- tation associated with odors. The PIs have developed a behavioral paradigm in mice that allows rapid and flexible association of arbitrary odor cues with reward or aversion. Using this behavior, they have found evidence for an explicit representation of reward in the OT. In this project, the PIs will test the hypothesis that neural activity in the OT is modified during learning to reflect the va- lence of stimuli, and that dopaminergic signals from the VTA play a key role in this learning.
Aim 1 : To determine whether OT neurons signal explicit (odor-independent) valence signals after learn- ing. Mice will be trained to learn the arbitrarily assigned valence of a panel of odors and record spiking activity using tetrodes from the OT in behaving animals. The hypothesis tested is that there is an explicit valence representation in the activity of OT neurons and this representation emerges rapidly when novel odor associations are learned.
Aim 2 : To determine how reward and aversion are represented in the OT. The PIs will use aversive and rewarding stimuli to ask whether OT neu- rons represent true valence signals, or if they signal motivational salience. The hypothesis is that OT activity will be modulated in opposite directions for rewarding and aversive cues, signaling ex- plicit valence, with potential heterogeneity across OT cell types and subregions.
Aim 3 : To deter- mine whether dopaminergic axons targeting OT carry valence related signals that evolve during learning. The PIs will use fiber photometry and microendoscopy to record valence-related activity of dopaminergic axons in the OT and optogenetics to stimulate these axons in behaving mice. The hypothesis is that the OT receives dopamine inputs that represent value prediction errors that can shape the valence-related activity of OT neurons. The research proposed has broad relevance for neuroscience because it will shed light on how reward-predicting signals are learnt and represent- ed in the brain, which could help devise treatments in abnormal conditions such as addiction.

Public Health Relevance

The research proposed has broad relevance for neuroscience because it will shed light on how reward- predicting signals are learnt and represented in the brain. Understanding these basic processes in the normal brain could help devise specific and efficacious treatments in abnormal conditions such as drug addiction and binge eating.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Neurobiology of Learning and Memory Study Section (LAM)
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Sullivan, Susan L
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Harvard University
Schools of Arts and Sciences
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