Uncovering the Spatiotemporal Dynamic of Behavioral Flexibility
How the brain learns from Experience
For Dr. Gideon A. Sarpong, a researcher at the Neurobiology Research (Wickens) Unit of the Okinawa Institute of Science and Technology (OIST), the journey into the brain began with a fundamental curiosity: how do microscopic neurons govern complex behavior?
Dr. Sarpong is driven by the challenge of connecting disparate levels of neuroscience, linking microscopic chemical signaling to macro-level behaviors. For him, the excitement of the field lies in connecting cellular events to complex behavioral outputs.
His research focuses on the neurobiology of motivation and adaptive behaviors, with a particular interest in how the brain learns from experience. Specifically, how the interaction between the neuromodulators acetylcholine (ACh) and dopamine in the striatum shapes learning, decision-making, and motivation.
His latest work, published in Nature Communications, explores how ACh dynamics in the striatum promote the ability to switch strategies in response to changing environmental conditions.
Navigating Disappointment
Dr. Sarpong’s research focuses on behavioral flexibility—the essential survival skill of ceasing a previously rewarded action to explore new alternatives. Specifically, the study investigated the role of cholinergic interneurons (CINs) during reversal learning, a task where an established reward contingency is suddenly switched without warning. Cholinergic interneurons (CINs) are the prime source of ACh) in the striatum and are important for behavioral flexibility.
Using a genetically encoded ACh sensor and 2-photon imaging, the team visualized ACh release in the dorsal striatum of behaving mice. They discovered thae below:
- Rewarded outcomes evoke a phasic decrease (a "dip") in acetylcholine levels.
- Unexpected non-rewards (disappointment) trigger widespread increases in ACh.
- The magnitude of this ACh increase predicts lose-shift behavior, where the animal successfully switches its choice on the subsequent trial.
When you expect something and don’t get it – that’s when ACh is released in the striatum. Importantly, the magnitude of the increase predicts subsequent behavioral adaptation.
Virtual Reality and Precision
To achieve the high level of experimental control required for this study, Dr. Sarpong utilized the PhenoSys Jet Ball system. This virtual reality (VR) setup allows head-fixed mice to navigate a two-dimensional linear corridor—in this case, a VR Y-maze—while remaining stable enough for high-resolution imaging.
The success of this work was largely due to the virtual reality system. It provides very precise experimental control over sensory inputs, as well as the timing of cues, and rewards.
By using the JetBall the team achieved the below.
- Synchronize 2-photon imaging with behavioral events in real-time.
- Observe naturalistic behavior in a head-fixed animal, ensuring the mice could perform the task intuitively.
- Implement flexible task designs, including complex reversal paradigms using the PhenoSoft Schedule software.
The PhenoSys Experience: More Than Just a Tool
Dr. Sarpong notes that the technical support provided by the PhenoSys was instrumental in integrating the VR system with their existing 2-photon setup. This transition was made seamless through the provision of specialized templates and ongoing guidance, which allowed a neuroanatomist to adopt VR-based behavioral paradigms without technical friction.
Furthermore, Dr. Sarpong highlighted the team’s exceptional responsiveness; their willingness to assist with software re-installations across different time zones proved vital in maintaining the continuity of long-term experiments.
Looking Ahead: A Teaching Signal for the Brain
Dr. Sarpong and his colleagues’ work provides a unique insight into the mechanisms underlying inflexible habits. He anticipates that these findings will serve as a foundational step for future translational approaches aimed at mitigating maladaptive behavioral inflexibility—translating basic research into practical solutions. Ultimately, the goal is to build a more complete picture of how the brain supports flexible behaviors, and how disruptions in these systems may contribute to maladaptive behaviors central to addiction, OCD, and other neuropsychiatric disorders.
His advice for the next generation of neuroscientists is to stay grounded.
Stay focused on the question, not just the method. Be comfortable with uncertainity and ambiguity; progress comes from learning how you navigate those uncertainities.
