Flexible behavioral change in response to environmental changes is one of the hallmarks of intelligence. The process through which these changes manifest is called learning. Learning can happen at a wide range of timescales with different underlying neural processes: from rapid changes in synaptic efficacy to Hebbian learning and incremental changes in the structural composition of neurons, neural circuits, and signaling pathways. Psychological states such as arousal, stress, and motivation, however, evolve at a timescale in between these extremes and can affect the performance in cognitively demanding tasks. These slowly evolving states are under the influence of ascending neurotransmitter systems such as Dopamine (DA), Acetylcholine (ACh), Norepinephrine (NE), Serotonin (5-HT), etc. The working hypothesis of my research program is that such neuromodulators influence the way that local circuits encode and process incoming information and contribute to decisions.
Dopaminergic Modulation of Prefrontal Cortex During Working Memory
(NIMH K01 award, 2021-2024)
Motivation: Disruption of DA signaling in the prefrontal cortex (PFC) has been proposed to underlie cognitive deficits in major mental disorders, including schizophrenia and attention-deficit hyperactivity disorder (ADHD). Working memory (WM) is an essential cognitive process for temporarily holding and manipulating goal-directed information that depends on DA in the PFC. Yet despite decades of investigation, the key circuit mechanisms underlying dopaminergic modulation of PFC cells during WM remain poorly understood. In turn, this gap in knowledge has limited our ability to gain better insights into the pathophysiology of such mental disorders. The overall goal of this study is to use multiple complementary state-of-the-art techniques to investigate DA signaling in PFC during a well-established parametric WM task. Technical limitations have hindered our ability to measure rapidly-evolving DA signals in the PFC reliably. This is now changing. I will use retrograde viral infection tools to distinguish PFC-projecting from striatal-projecting DA cells in VTA optogenetically. I will test the hypothesis that PFC-projecting DA cells encode a cue saliency signal, gating information flow to PFC. Using a novel optical DA sensor, I will characterize the DA dynamics in subregions of medial PFC and test the hypothesis that DA transiently increases during the delay period and that the magnitude of this increase is linked to WM performance. Finally, using head-mounted microendoscopes, I will optogenetically manipulate PFC DA release while simultaneously monitoring distinct subpopulations of PFC neurons. If successful, this project will provide a novel window onto dopaminergic modulation of PFC during cognitive processes.
Approach: 1) Fiber photometry, 2) in vivo electrophysiology, 3) head-fixed 2-p imaging
Nicotinic Modulation of Dopamine Release in Nucleus Accumbens
(NARSAD Young Investigator Award, BBRF, 2021-2023)
Motivation: Nicotine (found in tobacco leaves and smoked in cigarettes) acts as a primary reinforcer in the brain. However, in addition to primary reinforcer effects, nicotine enhances the motivational effects of accompanying stimuli. For example, the co-use of tobacco with other drugs such as alcohol has synergistic effects2. But how exactly does nicotine acts as a reinforcer and also a motivational enhancer? Both DA cell bodies in the midbrain and DA terminals in the nucleus accumbens have nicotinic acetylcholine receptors (nAChR) that cause rapid depolarization. Building upon my previous findings of dissociable DA dynamics for learning and motivation, I will test the hypothesis that the reinforcing and motivational enhancing of the nicotine effects are exerted via different brain regions. Specifically, nAChRs in the midbrain are related to primary reinforcing effects, while the forebrain nAChR locally modulates DA release, leading to motivational enhancement.
Approach: 1) Using two-color photometry to monitor ACh and DA dynamics in nucleus accumbens simultaneously. 2) Using pharmacological and chemogenetic manipulation of nicotinic receptors at various targets of DA action along the midbrain-forebrain axis and study the interaction between ACh and DA during motivated behavior.
Dissociable Dopamine Dynamics for Learning and Motivation
Dopamine (DA) is a key modulator of brain activity. DA signals are involved in learning (changes in future behavior based on experienced outcomes) and invigorating actions (motivation). Following reward delivery, DA cells fire a burst of action potentials, the magnitude of which is proportional to reward prediction error (RPE). This narrative, however, does not explain the role of DA in motivation. One influential model suggests that slow ‘tonic’ changes in DA cell firing mediate the motivational functions. We speculated that the presumed slow nature of tonic changes might be due to using different tasks and measurement techniques. We trained rats on a reinforcement learning task (two-armed bandit) and directly compared the firing of optogenetically identified midbrain DA cells with forebrain DA release patterns. We used three different techniques with different time resolutions to measure DA release: fast microdialysis, fast scan voltammetry, and ultrafast photometry imaging of the biosensor dLight. We found that DA release increases with reward expectation and as the rats approach a port to initiate a trial, enhancing the animals’ willingness to expend effort. However, we found no correspondence between the ramp in DA release and changes in DA cell firing. Instead, this motivational aspect of dopamine release seems to be locally controlled within forebrain subregions. We found specific “hotspots” in both the striatum and cortex, where dopamine release covaried with reward expectation. These spatial foci contrast the canonical concept of dopaminergic reward prediction errors being “broadcast” throughout the forebrain. Consequently, we suggested a model in which motivational aspects of the DA signal are presynaptically sculpted. Our follow-up studies in which we monitored changes in the cholinergic activity during the same task suggest that acetylcholine (ACh) also ramps up during the motivated approach. This coincidence ramp in DA and ACh supports the hypothesis that the motivational DA signal is locally generated in the ventral striatum.