Theory & Data Analysis Tools

ABSTRACT Perceptually guided behavior involves a complex and dynamic interplay between external inputs and internal states that are related, for example, to alertness, motivation, expectations and attention. A wide range of evidence suggests that the representation, processing, and flow of sensory information in the primate brain is regulated by several neuromodulatory systems. However, our understanding of the physiological and behavioral impact of neuromodulatory signals during complex behaviors in primates is quite rudimentary and is lagging behind what is known in rodents.

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.

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).

Humans make rich inferences about the relationships between entities in the world from scarce information. For example, we can find a novel destination after seeing a few street numbers, or find a page in a dictionary by glancing at a few words in other pages. Theoretical considerations suggest that the brain makes such inferences by constructing "internal models" of the relationships in the environment (relationships between actions and states of the world), and by mentally simulating those models. However, the neural substrates and mechanisms of mental simulation are not understood.

The ability to predict when external events will occur, such as anticipating the actions of a predator or the availability of food, is critical for survival. Converging computational and experimental work suggests that dynamically changing patterns of neural activity, including neural sequences, underlie temporal prediction and temporal processing.

Serotonergic neuromodulation is a crucial factor in regulating several aspects of brain function, from mood disorders to appetite, reward and motivation, and in maintaining balance of sensory perception. However, the network mechanisms by which it modulates brain dynamics are elusive. In this project, we will develop and experimentally test a mechanistic theory explaining the observed modulations of cortical activity induced by the serotonergic activation via hallucinogenic agonists.

A brief glimpse at a face quickly reveals rich multi-dimensional information about the person in front of us. How is this impressive computational feat accomplished? A recently revised neural framework for face processing suggests perception of face form information, i.e. face invariant features such as gender, age, and identity, are processed through the ventral visual pathway, comprising the occipital face area, fusiform face area, and anterior temporal lobe face area.