Illuminating the function of dopaminergic neurons in reward
- This thesis examines a neural substrate (i.e. dopaminergic signaling) of reward, by integrating techniques designed to manipulate and quantify changes in behavior, neural activity, and neurotransmitter release in freely-moving animals. Dopaminergic signaling is essential to the brain's reward system. The majority of dopaminergic neurons reside in the ventral tegmental area (VTA) and project to diverse brain regions including the nucleus accumbens (NAc), one of the major integrative hubs of reward signals. Dopaminergic neurons are known to fire in two distinct modes (phasic, > 15Hz; tonic, < 10Hz) under different behavioral conditions. Both firing modes are known to be involved in multiple reward-related behaviors in normal and neuropsychiatric conditions. However, the casual role of dopaminergic neuron activity in reward-related behaviors remains unclear, largely due to a lack of technologies to selectively control dopaminergic neuron signaling in freely-moving animals during reward-related behavioral tasks. To solve this problem, we first developed a set of optogenetic technologies to selectively control dopaminergic neuron activity in vivo. By targeting a light-sensitive microbial opsin, channelrhodopsin-2 (ChR2), to the VTA dopaminergic neurons we were able to modulate dopaminergic neuron activity in freely-moving mice during behavioral tasks. We accomplished this using a thin optical fiber to deliver precisely-timed trains of light flashes directly into the VTA. We found that phasic and not tonic firing evoked by light in dopaminergic neurons is sufficient to mediate a strong conditioned place preference in rodents in the absence of other reward. Similarly, phasic dopaminergic neuron firing reinforces the lever-pressing behavior during an operant conditioning task. Phasic firing also induced substantial transient dopamine release in NAcc, as measured by fast scan cyclic Voltammetry (FSCV). Together, our behavioral and electrochemical data demonstrate a causal role of phasic dopaminergic neuron firing in behavioral conditioning. The integration of cell-specific targeting techniques with electrophysiological, behavioral, and biochemical readout methods proves to be a powerful approach to studying the role of dopaminergic signaling in the brain reward system and is likely to prove effective in the study of neuropsychiatric disorders such as depression and addiction.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|2010, c2011; 2010
|Stanford University, Department of Neurosciences.
|Malenka, Robert C
|Malenka, Robert C
|Statement of responsibility
|Submitted to the Department of Neurosciences.
|Ph.D. Stanford University 2011
- © 2011 by Hsing-Chen Tsai
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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