Imaging a dopaminergic reward-seeking state and its modulation by prefrontal cortex using optogenetic functional magnetic resonance imaging
Abstract/Contents
- Abstract
- The anticipation and experience of reward drives many behaviors across the animal kingdom and is an important determinant of mental health in humans. The loss of the capacity to experience reward or enjoyment is termed anhedonia, a symptom that is manifest in a number of psychiatric diseases, including depression and schizophrenia. We optimized optogenetic functional MRI (ofMRI) to manipulate and image dopaminergic reward circuits in awake rodents and determine the contribution of dopamine to reward-related neuroimaging signals commonly observed in humans. We also sought to investigate the role of the medial prefrontal cortex in modulating dopaminergic signaling and reward-seeking behavior. The influence of phasic midbrain dopamine firing on brainwide BOLD activity was assessed by expressing a Cre-dependent channelrhodopsin (ChR2) in the dopaminergic midbrain of transgenic tyrosine hydroxylase (TH-cre) rats. Phasic stimulation of the midbrain with blue light supported self-stimulation in an operant chamber. During fMRI scanning, this phasic stimulation generated robust increases in BOLD activity, particularly in the striatum (in a manner that correlated with individual rats' self-stimulation behavior), as well as other regions including the retrosplenial cortex and thalamus. The BOLD activity increases were sensitive to post-synaptic dopamine (D1 and D2) receptor antagonists. In addition, we directly visualized the impact of suppressing dopaminergic neuron firing on BOLD activity using the inhibitory optogenetic tool, halorhodopsin (eNpHR3.0). We next assessed whether focal excitability changes in medial prefrontal cortex (mPFC) could modulate reward-seeking, using optogenetically-triggered shifts in mPFC excitability with a stable step-function opsin (SSFO, expressed in predominantly glutamatergic neurons) during natural appetitive behaviors. Notably, we observed a suppression of typical reward-seeking behavior (a preference for sucrose-containing water and social interaction with a same-sex juvenile) in optogenetically-stimulated rats compared to controls. In the fMRI scanner, elevated mPFC excitability provoked changes in spatiotemporal correlations in BOLD activity across a number of brain regions, and the strength of correlations between specific regions was associated with the observed reduction in sucrose preference at the individual level. To directly test the hypothesis that elevated mPFC excitability negatively influences subcortical responses to reward, we expressed a red-shifted channelrhodopsin variant, C1V1, in midbrain dopaminergic neurons and SSFO in mPFC glutamatergic neurons of TH-Cre rats. Phasic C1V1 stimulation of dopamine neurons generated robust striatal BOLD activity in the fMRI scanner, however in the presence of superimposed SSFO activation of mPFC, this striatal BOLD activity was suppressed. Behaviorally, the tendency for rats to seek out a location in which they received C1V1 stimulation was abolished in the presence of mPFC activation by SSFO. These findings inform theories about how specific neurochemical projections interact to promote or modulate reward processing and neuroimaging signals, with a direct bridge between animal and human research. This may help further our understanding of cortical-subcortical interactions in the diagnosis, pharmacology and treatment of symptoms related to altered reward processing in neuropsychiatric disorders.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2015 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Ferenczi, Emily Anne | |
|---|---|---|
| Associated with | Stanford University, Neurosciences Program. | |
| Primary advisor | Deisseroth, Karl | |
| Thesis advisor | Deisseroth, Karl | |
| Thesis advisor | Glover, Gary H | |
| Thesis advisor | Huguenard, John | |
| Thesis advisor | Knudsen, Eric I | |
| Advisor | Glover, Gary H | |
| Advisor | Huguenard, John | |
| Advisor | Knudsen, Eric I |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Emily Anne Ferenczi. |
|---|---|
| Note | Submitted to the Program in Neuroscience. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2015. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2015 by Emily Anne Ferenczi
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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