Advanced Optical and Sono-Chemogenetic Systems for Probing Dopamine Dynamics in the Non-Human Primate Brain

About This Grant

PROJECT SUMMARY Cell-type specific recording and manipulations are powerful methods for targeting categories of neurons that have a particular behavior or disease relevance. Cutting-edge genetic engineering approaches, such as optogenetics, enable interactions with neurons in a cell type-specific manner. However, these approaches have by and large been relegated to smaller animal models, with limited success in larger animals such as nonhuman primates. This proposal seeks to address this major gap in methodology by establishing tools for interfacing with dopamine circuitry in the macaque animal model. Dopamine is a critical neurotransmitter for a suite of cognitive processes and is implicated in many neurological and neuropsychiatric conditions, making it of clear interest for neuroscientific studies and the development of neurotherapeutics. Nonhuman primates are important preclinical animal models and it is essential to develop tools and technologies that continue to advance our capabilities to interface with the nervous system in this model system. In this work we will establish and characterize the dLight sensor, a genetically encoded fluorescent dopamine indicator, in the macaque model system. We will also develop a sono-chemogenetic approach to selectively modulate signaling in this neural population. Chemogenetics has emerged as a less invasive alternative to achieve similar manipulation of neural signaling to optogenetics. However, current chemogenetic approaches typically rely on systemic drug administration, which limits the temporal and tunable control of the manipulation. Sono-chemogenetics is an innovative new area that leverages ultrasound-programmable nanoparticles for drug delivery. This approach is non-invasive and facilitates precise manipulation of specific cells and overcomes barriers of previous optogenetic and chemogenetic methods. In Aim 1, we will characterize the in vivo sensitivity of the dLight sensor to targeted interventions and behavior. We will use pharmacological techniques and electrical stimulation to mediate dopamine release to validate functional changes in the recorded fluorescent signal. Additionally, we will establish the sensitivity of the sensor to natural variations in dopamine levels during behavior. In Aim 2, we will determine the timescale over which dopamine signals are stable. These longitudinal studies are critical to verify the longevity of this methodology, which is relevant to chronic studies. In Aim 3, we establish the sono-chemogenetic approach to mediate signaling in dopamine neurons and verify the functional effects in a relevant behavioral paradigm. Together these aims will take critical steps toward refining and optimizing these tools for use in a large animal model which is a valuable platform for developing therapies and treatments for human conditions.