Project Summary Electrical stimulation of deep brain structures is an essential tool for the causal investigation of neural systems that regulate learning and decision making. Deep brain electrical stimulation is also a valuable tool for treating neurological disorders such as Parkinson's disease and tremor, and recent data suggests that electrical brain stimulation may effectively treat epilepsy and severe depression. Despite its scientific and translational applications, little is known about how electrical stimulation affects the ongoing activities of neurons or the release of neuromodulators such as dopamine. Understanding how electrical stimulation affects dopamine release is particularly important given dopamine's involvement in learning, motor control, decision making, and neuroplasticity. There is considerable evidence that dopamine's function is determined by the time course of release. For example, fast, “phasic” release (~1-2 seconds) is involved in neuroplasticity and reward-guided learning while slow, “tonic” release (tens of seconds) is involved in motor control and motivation. Little is known about how the brain selectively regulates tonic and phasic release, and few methods exist for controlling the time course of dopamine release. Developing such methods could result in 1) new experimental approaches for the causal investigation of the roles phasic and tonic release play in motivation and motor control, and 2) translational tools to correct disrupted patterns of dopamine release in disorders such as Parkinson's disease, schizophrenia, addiction, and depression. Towards these goals, evidence from our group suggests that the frequency and duration of electrical brain stimulation allows selective control of the time course of dopamine release. Our general objective is to characterize how parameters of brain stimulation such as stimulation frequency, variability, and the brain region targeted impacts the time-course of dopamine release and dopamine's role in reward-guided learning. Our experimental objectives are to determine (1) how the frequency and variability of the sequence of pulses delivered during brain stimulation affects phasic and tonic dopamine release, (2) how brain stimulation and tonic and phasic signaling interact to affect reward-driven learning, and (3) and how tonic and phasic signaling affect interactions between neurons and shape neuroplasticity. Our experimental approaches involve voltammetry for dopamine measurement, neural ensemble recordings for measurement of neural coordination, optogenetics, and on-line optimization of dopamine release in anesthetized and behaving rats. Our computational objective is to use data collected to develop multi-scale systems and cellular models that describe how stimulation frequency and variance affect the time course of dopamine release. We predict that multi-scale models will outperform current synaptic models and improve the capacity of scientists and clinicians to control dopamine release in experimental and therapeutic settings. These models may also explain clinical effects such as recent data from human patients suggesting that electrical stimulation of deep brain regions reduces depression.

NARRATIVE The proposed research is relevant to public health as its goal is to develop new ways to use electrical deep brain stimulation for the precise control of tonic (slow) and phasic (fast) dopamine release in the brain. Disrupted tonic and phasic dopamine release underlies addiction, depression, Parkinson's disease, and schizophrenia, and improved control would therefore be relevant to translational research as new stimulation technologies could potentially treat these conditions. Thus, the proposed research is relevant to the NIH's mission to develop fundamental knowledge that can be applied to reduce human disability.