Dopamine Modulation of Prefrontal Cortex Activity Is Manifold and Operates at Multiple Temporal and Spatial Scales.

Although the function of dopamine in subcortical structures is largely limited to reward and movement, dopamine neurotransmission in the prefrontal cortex (PFC) is critical to a multitude of temporally and functionally diverse processes, such as attention, working memory, behavioral flexibility, action planning, and sustained motivational and affective states. How does dopamine influence computation of these temporally complex functions? We find causative links between sustained and burst patterns of phasic dopamine neuron activation and modulation of medial PFC neuronal activity at multiple spatiotemporal scales. These include a multidirectional and weak impact on individual neuron rate activity but a robust influence on coordinated ensemble activity, gamma oscillations, and gamma-theta coupling that persisted for minutes. In addition, PFC network responses to burst pattern of dopamine firing were selectively strengthened in behaviorally active states. This multiplex mode of modulation by dopamine input may enable PFC to compute and generate spatiotemporally diverse and specialized outputs.

Burst activation of dopamine neurons produces prolonged post-burst availability of actively released dopamine.

Both phasic and tonic modes of neurotransmission are implicated in critical functions assigned to dopamine. In learning, for example, sub-second phasic responses of ventral tegmental area (VTA) dopamine neurons to salient events serve as teaching signals, but learning is also interrupted by dopamine antagonists administered minutes after training. Our findings bridge the multiple timescales of dopamine neurotransmission by demonstrating that burst stimulation of VTA dopamine neurons produces a prolonged post-burst increase (>20 min) of extracellular dopamine in nucleus accumbens and prefrontal cortex. This elevation is not due to spillover from the stimulation surge but depends on impulse flow-mediated dopamine release. We identified Rho-mediated internalization of dopamine transporter as a mechanism responsible for prolonged availability of actively released dopamine. Thus, a critical consequence of burst activity of dopamine neurons may be post-burst sustained elevation of extracellular dopamine in terminal regions via an intracellular mechanism that promotes dopamine transporter internalization. These results demonstrate that phasic and tonic dopamine neurotransmission can be a continuum and may explain why both modes of signaling are critical for motivational and cognitive functions associated with dopamine.

Enabling breakthroughs in Parkinson's disease with wearable technologies and big data analytics.

Parkinson's disease (PD) is a progressive, degenerative disorder of the central nervous system that is diagnosed and measured clinically by the Unified Parkinson's Disease Rating Scale (UPDRS). Tools for continuous and objective monitoring of PD motor symptoms are needed to complement clinical assessments of symptom severity to further inform PD therapeutic development across several arenas, from developing more robust clinical trial outcome measures to establishing biomarkers of disease progression. The Michael J. Fox Foundation for Parkinson's Disease Research and Intel Corporation have joined forces to develop a mobile application and an Internet of Things (IoT) platform to support large-scale studies of objective, continuously sampled sensory data from people with PD. This platform provides both population and per-patient analyses, measuring gait, activity level, nighttime activity, tremor, as well as other structured assessments and tasks. All data collected will be available to researchers on an open-source platform. Development of the IoT platform raised a number of engineering considerations, including wearable sensor choice, data management and curation, and algorithm validation. This project has successfully demonstrated proof of concept that IoT platforms, wearable technologies and the data they generate offer exciting possibilities for more robust, reliable, and low-cost research methodologies and patient care strategies.

Ventral tegmental area and substantia nigra neural correlates of spatial learning.

The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) may provide modulatory signals that, respectively, influence hippocampal (HPC)- and striatal-dependent memory. Electrophysiological studies investigating neural correlates of learning and memory of dopamine (DA) neurons during classical conditioning tasks have found DA neural activity in VTA and SNc to be tightly coupled with reinforcement expectations. Also, VTA integrity and DA in HPC have been found to regulate the encoding of HPC-dependent memories. Therefore, to determine the nature of the neural code HPC may receive from midbrain DA regions, the present study investigated VTA and SNc neural activity as navigating rats engaged in new spatial learning and experienced changes in expected goal locations. VTA and SNc cells were differentially engaged during training to a series of three novel goal locations. During task acquisition, the peak firing rates of VTA neurons decreased at the time of reward and shifted to time points before reward retrieval, whereas the peak firing rates of SNc neurons remained elevated at the time of reward during training to all three goal locations. Both VTA and SNc egocentric coding was strongest during training to the first goal location, which coincided with the time subjects learned the behavioral rules specific to the task. These data imply that VTA and SNc play complementary yet distinct roles in spatial learning to optimize adaptive behavior.

Ventral tegmental area disruption selectively affects CA1/CA2 but not CA3 place fields during a differential reward working memory task.

Hippocampus (HPC) receives dopaminergic (DA) projections from the ventral tegmental area (VTA) and substantia nigra. These inputs appear to provide a modulatory signal that influences HPC dependent behaviors and place fields. We examined how efferent projections from VTA to HPC influence spatial working memory and place fields when the reward context changes. CA1 and CA3 process environmental context changes differently and VTA preferentially innervates CA1. Given these anatomical data and electrophysiological evidence that implicate DA in reward processing, we predicted that CA1 place fields would respond more strongly to both VTA disruption and changes in the reward context than CA3 place fields. Rats (N = 9) were implanted with infusion cannula targeting VTA and recording tetrodes aimed at HPC. Then they were tested on a differential reward, win-shift working memory task. One recording session consisted of 5 baseline and 5 manipulation trials during which place cells in CA1/CA2 (N = 167) and CA3 (N = 94) were recorded. Prior to manipulation trials rats were infused with either baclofen or saline and then subjected to control or reward conditions during which the learned locations of large and small reward quantities were reversed. VTA disruption resulted in an increase in errors, and in CA1/CA2 place field reorganization. There were no changes in any measures of CA3 place field stability during VTA disruption. Reward manipulations did not affect performance or place field stability in CA1/CA2 or CA3; however, changes in the reward locations "rescued" performance and place field stability in CA1/CA2 when VTA activity was compromised, perhaps by trigging compensatory mechanisms. These data support the hypothesis that VTA contributes to spatial working memory performance perhaps by maintaining place field stability selectively in CA1/CA2.

Context dependent effects of ventral tegmental area inactivation on spatial working memory.

Rats were tested on a hippocampus dependent win-shift working memory task in familiar or novel environments after receiving bilateral ventral tegmental area infusions of baclofen. Baclofen infusion disrupted working memory performance in both familiar and novel environments. In addition, baclofen infusion selectively disrupted short-term working memory in the novel environment. This experiment confirms selective ventral tegmental area support of accurate performance during a context dependent spatial navigation task.

Basal ganglia contributions to adaptive navigation.

The striatum has long been considered to be selectively important for nondeclarative, procedural types of memory. This stands in contrast with spatial context processing that is typically attributed to hippocampus. Neurophysiological evidence from studies of the neural mechanisms of adaptive navigation reveals that distinct neural systems such as the striatum and hippocampus continuously process task relevant information regardless of the current cognitive strategy. For example, both striatal and hippocampal neural representations reflect spatial location, directional heading, reward, and egocentric movement features of a test situation in an experience-dependent way, and independent of task demands. Thus, continual parallel processing across memory systems may be the norm rather than the exception. It is suggested that neuromodulators, such as dopamine, may serve to differentially regulate learning-induced neural plasticity mechanisms within these memory systems such that the most successful form of neural processing exerts the strongest control over response selection functions. In this way, dopamine may serve to optimize behavioral choices in the face of changing environmental demands during navigation.