Neurological diseases represent one of medicine’s greatest unmet challenges. While treatments for many conditions have advanced dramatically, neurological disorders continue to cause immense suffering with limited therapeutic options. This treatment gap stems from a fundamental limitation: current pharmacotherapies act broadly across the nervous system rather than targeting the specific neural circuits that drive disease.
To bridge this gap, we must solve two critical problems: First, we need a deeper understanding of which circuits become dysregulated and how. Second, we need precise technologies capable of modulating brain function at the circuit level.
Our research directly addresses both challenges. We use animal models to map the neural circuits underlying value coding, as their misregulation can lead to anhedonia and impaired decision-making – core features of major psychiatric disorders. Simultaneously, we develop optogenetic approaches that serve a dual purpose: creating potential therapeutic interventions while providing the neuroscience community with powerful new tools for circuit analysis.
Our experiences are fundamentally shaped by valence—the subjective sense that something feels pleasant or aversive. This basic valence assignment drives approach and avoidance behaviors, motivating us to seek rewarding stimuli and escape from threatening ones. Beyond immediate responses, our ability to assign value to anticipated future outcomes forms the foundation of our emotional lives and guides complex decision-making processes. Emotional information is integral to adaptive behavior, providing the motivational drive to select actions that bring us closer to desired goals while avoiding harmful consequences.
However, when the neural circuits underlying emotional integration become dysregulated, this adaptive system breaks down. Such dysregulation is a hallmark of psychiatric disorders, manifesting as affect dysregulation, maladaptive decision-making, and inappropriate responses to rewarding or threatening stimuli. Understanding how the brain encodes and integrates valence information is therefore crucial for comprehending both normal adaptive behavior and the pathophysiology of mental health disorders.
While many of these concepts are intuitive from an interoceptive perspective, our knowledge of the etiology and pathophysiology of these disorders is strongly limited by our understanding of the non-pathological neuronal circuits underlying emotional processing, which makes targeted intervention methods scarce.
We recently demonstrated that the basolateral amygdala (BLA) encodes stimulus-specific and adaptive value representations that are crucial for decision-making. Using two-photon calcium imaging, we demonstrated that the magnitude of the population response scales with subjective value, with different rewards recruiting distinct neuronal subpopulations. Importantly, these value representations rapidly re-scale when novel, higher-value rewards appear and are dynamically shaped by internal state—thirst selectively boosts responses to water, while aversive experiences dampen sucrose responses. These findings reveal that BLA circuits carry flexible, stimulus-specific value signals that integrate relative value with current affective and homeostatic conditions and pointing to a potentially misregulated circuit in anhedonia.
Building on this understanding of value coding, our current research is focused on characterizing the information transfer between the BLA and the prefrontal cortex within the larger brain networks of decision-making and emotional processing in the mouse. These two brain areas are critically involved in value assignment to environmental stimuli and integration of this information in decision-making processes.
We are addressing this question by monitoring and manipulating the involved neuronal circuits during decision-making using in vivo and in vitro approaches such as electrophysiological recordings, optogenetic sensor imaging, and optogenetic actuator activation
Optogenetics has revolutionized neuroscience by enabling precise circuit-level interventions, yet significant limitations in available tools continue to constrain both therapeutic development and basic research. To address these gaps, we develop next-generation optogenetic technologies that serve our dual mission.
Our previous work exemplifies this approach: we developed soma-targeted chloride channels and light-gated G-protein coupled receptors that achieved highly efficient somatic and presynaptic silencing. These completed tools now provide both potential clinical applications for circuit-specific disorders and enhanced capabilities for the broader neuroscience community’s mechanistic studies.
Building on this, we continue addressing unmet needs like pre- and post-synaptic specific interventions that still limit both therapeutic possibilities and scientific discovery. Our ongoing development of innovative optogenetic strategies aims to create the next generation of tools, with each advance bringing us closer to clinical translation while empowering researchers worldwide to decode the neural basis of disease.