Circuit Diagrams

PROJECT SUMMARY Neuromodulation, such as that mediated by the neuromodulators norepinephrine, acetylcholine, and dopamine, imposes powerful control over brain function. It regulates the excitability, synaptic plasticity, and other aspects of neuronal function. Defects in neuromodulation are associated with many neuropsychiatric diseases. Neuromodulators exert their functions by regulating intracellular signaling events via their corresponding G protein-coupled receptors (GPCRs).

ABSTRACT ‒ UG3/UH3 Deep Brain Stimulation (DBS), applied to areas like the subthalamic nucleus (STN), is a standard treatment for Parkinson Disease (PD), however, DBS has inherent surgical risks as well as potential for infections and adverse side effects. Our overarching goal is to establish novel chemogenetic neuromodulation strategies in nonhuman primates (NHPs) that utilize and build upon the strengths of DBS but resolve many DBS limitations, and ultimately to translate these to clinical therapies in humans.

Project summary The heterogeneity from the vast number of cell types in the brain presents a major challenge in our understanding of how brain works and in our treatment of neurological disorders. With the amazing advances in high throughput sequencing technology, our knowledge on the molecular makeup of the myriad cell types in the brain has reached an unprecedented level. However, tools that allow us to easily study the functions of any cell types of our choice are lagging. The goal of our proposed research is to develop technology to generate such tools.

Motivational drive is an adaptive process that helps individuals overcome obstacles to obtain essential needs and hence ensure survival. Motivation is composed of two major components. The first component is the directionality of motivation (the orientation of goal-oriented behavior), such as seek food/shelter or avoid pain. The second is the activational motivation (the energizing of goal-oriented behaviors) such as increase vigor, and persistence of these actions.

Neuromodulation is crucial for information processing throughout the brain. Neuromodulators influence neuronal function by acting through G protein-coupled receptors (GPCRs) to alter neuronal excitability and synaptic transmission, which can then affect circuit functions. GPCRs are major drug targets used to treat a variety of diseases, including neurological disorders. The causal link between in vivo subcellular signaling mechanisms and behaviors is poorly understood due to the limited tools available to monitor signaling in freely behaving animals.

The initiation and maintenance of organized movement through the basal ganglia is strongly influenced by its feed-forward and feedback inhibitory architecture. The substantia nigra pars compacta (SNc) and pedunculopontine nucleus (PPN) contribute to the overall output of the basal ganglia. Neurons in both structures degenerate in Parkinson's Disease, resulting in impaired motion.

Food consumption is fundamental to species survival and understanding the neuronal circuitry underlying feeding behaviors is of the utmost importance. Amassing evidence supports the idea that control of caloric intake is complex and involves calculations of hedonic value, reward and motivation. Thus, it requires interactions between brain regions classically implemented in feeding (such as the lateral hypothalamus; LH) and the regions modulating reward (such as the ventral striatum).

Non-invasive brain stimulation (NIBS) has attracted considerable interest in the cognitive neuroscience community, providing an important basic research tool to study brain function, with emerging clinical applications to enhance function in individuals with neurological disorders. Despite this potential, an emerging literature has highlighted concerns regarding the reliability and robustness of transcranial electric stimulation (tES), the primary NIBS method used to induce changes in brain plasticity through the application of subthreshold stimulation.

Histone modifications carry rich information of cellular memory and gene regulatory mechanisms. Single cell analysis of histone modification in conjunction with transcriptome could recover this critical layer of cell identity and help to dissect the cellular and molecular composition of complex tissues such as the brain. We recently developed an ultra-high throughput single cell multi-omics assay, Paired-Tag, that can jointly map transcriptome and histone modifications from up to a million single cells in parallel.

Brain function is regulated by molecular signaling and metabolism, however, our ability to track neurometabolic transformations deep in the brain is very underdeveloped compared to the central role of neurometabolism in neurodegenerative disease or brain function in general.