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Optical Imaging of Dopamine Dynamics and Decoding its Role in Arousal and Salience


Cho, Jounhong Ryan (2019) Optical Imaging of Dopamine Dynamics and Decoding its Role in Arousal and Salience. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/TNGA-5X08.


Dopamine (DA) is a key neuromodulator in the brain that can exert a profound impact on brain physiology and cognitive functions. There is consensus that DA plays critical roles in reward prediction error, reinforcement learning, and motor control, and that dysregulation of DA signaling is common in many neuropsychiatric diseases, such as Parkinson’s disease, drug addiction, and depression. Although the tools to study the functional roles of DA have considerably expanded with novel genetic tools and optical imaging methods, we are still limited in our ability to record or visualize DA release in vivo with long-term stability and high spatiotemporal resolution. This is an unmet need in DA research, as DA release at the post-synaptic sites can be decoupled from DA cell body firing due to local circuit interaction and influence from other afferent activities. In parallel, there is growing evidence that DA is functionally heterogeneous beyond its classically described roles for reward and movement, based on its anatomical location, projection target, electrophysiological properties, and response patterns to stimuli with motivational valence. Pharmacological and genetic studies have provided indirect evidence that DA can promote strong behavioral arousal and signal salience, but the precise neural substrates for these functions remain largely unknown. Towards this end, my thesis work has been focused on 1) developing and characterizing optical tools to visualize DA release in vivo and 2) utilizing such optical and genetic tools to study the overlooked, sparse DA populations in the dorsal midbrain, demonstrating that they are functionally unique DA cells for broadcasting arousal and salience signals to the forebrain targets.

As neuromodulatory systems exert profound influences on brain function, understanding how these systems modify the operating mode of target circuits requires spatiotemporally precise measurement of neuromodulator release. Towards this goal, in Chapter II, my colleagues and I developed dLight1, an intensity-based genetically encoded DA indicator, to enable optical recording of DA dynamics with high spatiotemporal resolution in behaving mice. We demonstrated the utility of dLight1 by imaging DA dynamics simultaneously with pharmacological manipulation, electrophysiological or optogenetic stimulation, and calcium imaging of local neuronal activity. dLight1 enabled chronic tracking of learning-induced changes in millisecond DA transients in mouse striatum. Further, we used dLight1 to image spatially distinct, functionally heterogeneous DA transients relevant to learning and motor control in mouse cortex. We also validated our sensor design platform for developing norepinephrine, serotonin, melatonin, and opioid neuropeptide indicators. Together, this tool provides a unique opportunity to optically monitor DA release dynamics in vivo with long-term stability and unprecedented spatiotemporal resolution.

In Chapter III, I have characterized the functional roles of sparse DA populations in the dorsal raphe nucleus (DRN) and discovered that these neurons play key roles in promoting behavioral arousal. I first demonstrated that DRNDA neurons are activated by diverse forms of motivationally salient stimuli, irrespective of valence. Simultaneous fiber photometry and polysomnographic recordings showed that DRNDA neuronal activity is correlated with distinct sleep-wake states, showing highest activities during wakefulness over sleep states. Optogenetic activation of DRNDA neurons was sufficient to cause immediate sleep-to-wake transitions and promote longer wakefulness upon sustained stimulation. On contrary, DRNDA inhibition via chemogenetics reduced wakefulness and promoted non-rapid eye movement sleep, even in the presence of ethologically relevant salient stimuli. Taken together, this pinpoints DRNDA neurons as the critical contributor of arousal-promoting DA system in the brain.

In Chapter IV, I further characterized the encoding dynamics of DRNDA neurons during classical conditioning tasks where mice learned the association between neutral cues and outcomes with positive or negative outcomes. DRNDA neurons developed phasic, positive responses to cues predicting both positive and negative unconditioned stimuli across learning, suggesting that these populations track motivational salience rather than valence. In addition, DRNDA neurons encoded unsigned prediction error, demonstrating higher neuronal activity to unexpected reward or punishment over fully expected outcomes. Collectively with Chapter III, these results expand on the existing literature on functionally heterogeneous roles of DA in the brain and propose that DRNDA neurons play critical roles in signaling arousal and motivational salience to the forebrain regions to coordinate appropriate behavior, depending on the nature of environmental stimuli.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Dopamine; Optical imaging; Dorsal raphe nucleus; arousal; salience
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Computation and Neural Systems
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Gradinaru, Viviana
Thesis Committee:
  • Siapas, Athanassios G. (chair)
  • Anderson, David J.
  • Oka, Yuki
  • Gradinaru, Viviana
Defense Date:23 May 2019
Non-Caltech Author Email:ryanjhcho (AT)
Record Number:CaltechTHESIS:05302019-104701860
Persistent URL:
Related URLs:
URLURL TypeDescription adapted for Chapter 2. adapted for Chapter 3.
Cho, Jounhong Ryan0000-0001-9542-716X
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:11566
Deposited By: Joun Hong Cho
Deposited On:03 Jun 2019 22:46
Last Modified:04 Nov 2021 21:30

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[img] Video (MPEG) (Supplementary Movie 1) - Supplemental Material
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[img] Video (MPEG) (Supplementary Movie 2) - Supplemental Material
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