My laboratory develops, disseminates, and uses multi-color, genetically encoded indicators that sense released neurotransmitters, neuromodulators, and neuropeptides. We aim to understand the complex interactions of released neurochemicals on neural activity. Using a novel high-throughput sensor engineering platform, including ligand-binding scaffolds, computational modeling, and machine learning-guided directed evolution, we create highly optimized sensors covering the full-color spectrum with enhanced chemical specificity, resolution, and depth across biological systems.

Biosensors permit chronic, direct, and precise measurements of the spatiotemporal dynamics of neurochemical release during a behavioral task. Moreover, these measurements can be combined with modern optical approaches and electrical recordings to measure and manipulate additional circuit components.

To ensure that our efforts have maximum impact, we form interdisciplinary collaborations to benchmark and cross-validate these tools in various model systems, followed by broad dissemination of our technology to end users before and after publication. We strongly believe in the open sharing of our technologies to accelerate the development of new and refined theories of neuromodulation. Published reagents are disseminated through viral cores, including UNC NeuroTools, Addgene, and the Neurophotonics platform.

In addition to sensor engineering, we apply our biotechnologies to visualize neuromodulator and peptide release dynamics across cortical and subcortical regions during naturalistic behaviors. We can achieve sub-second synchrony between brain activity recordings and behavior by using machine learning to detect precise movement epochs. A significant aspect of our research involves studying how stress impacts neurotransmitter release patterns in the brain—an essential consideration given stress’s ubiquitous presence and substantial role as a risk factor for conditions like anxiety and depression. Specifically, we are interested in how alterations in brain neurotransmitter dynamics lead to stress-induced changes in behavior (https://www.biorxiv.org/content/10.1101/2020.12.02.408526v2). Understanding how stress modifies neurotransmitter release offers deeper insights into the effects of stress on brain function and its implications for related disorders.

Astrocytes, one of the most abundant cell types in the brain, have long been thought of as primarily passive support cells. However, in the past two decades, studies leveraging modern techniques have revealed crucial roles for astrocytes in neural circuit assembly, function, and disease. Despite these advances, how astrocytes structurally and functionally integrate with neurons to sculpt circuit function and behavior remains a mystery. In order to develop a deeper mechanistic understanding of astrocytes’ roles in neural circuit operation, brain computation, and behavior, we have partnered with other researchers to study astrocyte function as part of the U19 Astrocyte-Team (A-Team) BRAIN Circuit Program (https://a-team.salk.edu/).

Astrocyte function has primarily been studied through measuring behavior-triggered intracellular calcium with genetically encoded calcium indicators (e.g., GCaMPs). However, calcium imaging alone is insufficient to reveal astrocytes’ integral and modulatory roles in neural circuits. We are developing new approaches to identify molecular, cellular, and circuit components of astrocyte-neuron interaction that contribute to behavior. This biotechnology will allow us to determine how astrocytes integrate the signals they receive from diverse types of neurons during behavior and how astrocytes convert this information into functional outputs to modulate neural circuits.

Therapeutics for depression, such as selective serotonin reuptake inhibitors (SSRIs), and psychedelic drugs alter neuromodulator release in the brain. We are using sensor biotechnology to screen how these various drugs change neuromodulator dynamics in the brain. Recently, we developed a high-throughput screening platform based on an optical serotonin receptor (5-HT2AR) sensor to screen psychedelic analogs for hallucinogenic properties, which limit their use as therapeutics.

Through this approach, we identified a non-hallucinogenic psychedelic analog that shows anti-depressant properties (Link). We are expanding this research direction to create platforms to screen novel therapeutics for the absence of unwanted properties that have previously characterized existing medications.

In addition, we integrate our optical biosensors with animal models of brain diseases and induced pluripotent stem cell (iPSC) technology to study molecular and cellular mechanisms of neurodevelopmental and neuropsychiatric disorders, including Down syndrome, Parkinson’s disease (Aligning Science Across Parkinson’s network), addiction, and depression.

We are developing novel tools to achieve cell-type and circuit-specific understanding of altered brain circuits and dynamics in animal models of disease. Using these tools, we then measure how therapeutic drugs affect and correct altered network function. We are also using cultured neural networks derived from patient-specific iPSCs to study alterations in how neurons develop their precise, guided communication patterns in patient-specific disease models and how therapeutics can correct these processes. This platform will allow us to study the patient-specific mechanistic action of therapeutic drugs, which could significantly advance personalized treatments for neurological disorders and mental health conditions.