The goal of this grant renewal is to develop theory and large-scale circuit modeling of the primate cortex with many interconnected areas, for distributed working memory and flexible decision processes as well as its dopamine modulation. This research program is designed to meet the challenge of understanding cognition beyond local circuits towards the complex global brain. The proposed work is now feasible thanks to recently available mesoscopic directed- and weighted data for inter-areal connections of macaque cortex. We have already published several papers on the development of a large-scale, multi-regional dynamical cortical circuit model of macaque monkey, including a population rate model endowed with a laminar cortical structure and a spiking network model. Our computational work will be undertaken in collaborations with five experimental labs working on macaque monkeys (Earl Miller (MIT), John Duncan (Oxford University, UK), Stefan Everling (Western University, Ontario, Canada), Henry Kennedy (ISERM, Lyon, France) and Karl Zilles (Jlich University, Germany)).
Specific Aim 1 will be to build a large-scale cortical circuit model of macaque monkey for distributed working memory. Hypothesis: distributed self-sustained activity patterns underlying working memory depend on a combination of the mesoscopic inter-areal connection properties and gradients of circuit properties across a brain?s hierarchy.
Specific Aim 2 will be to investigate high-dimensional dynamics of persistent activity underlying a high degree of temporal variations. Hypothesis: NMDA/AMPA receptor ratio is higher at top-down projections than bottom-up ones, and there is a macroscopic gradient of short-term plasticity. The two combined contribute to complex spatiotemporal mnemonic neural population activity that is better described by trajectories in a high-dimensional state space.
Specific Aim 3 will be to expand the model to simulate decision- making and rule-based flexible sensorimotor behavior. Hypothesis: the same model endowed with different representations (spatial location, object features such as color and motion direction, rule encoding, respectively) in different cortical areas can be used to simulate rule-based flexible decision tasks as well as working memory tasks.
Specific Aim 4 will be to study of neuromodulation and NMDA deficits of this large-scale primate cortical model. Hypothesis: dopamine modulation displays a macroscopic gradient along the cortical hierarchy, and impairment of NMDA receptors preferentially affects top-down rather than bottom-up signaling in the global brain. Taken together, the proposed research will shed fundamental insights into complex dynamics and cognitive functions in the global brain. It will also yield a pioneering and powerful computational platform for basic research on large-scale brain systems of the primates, as well as cross-level circuit mechanistic studies of psychiatric disorders like Schizophrenia.

Public Health Relevance

The proposed research aims at the development of a large-scale circuit model of the macaque monkey cortex capable of distributed working memory and rule-based flexible decisions, in collaborations with five top monkey experimental laboratories. A central idea is macroscopic gradients of circuit properties across the primate cortical hierarchy, including the strength of excitatory inputs, short-term plasticity and dopamine modulation. The proposed research will shed fundamental insights into complex dynamics and cognitive functions in the global brain, and yield an openly accessible computational platform for basic research as well as cross-level circuit mechanistic studies of psychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH062349-17
Application #
9791200
Study Section
Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section (SPC)
Program Officer
Ferrante, Michele
Project Start
2001-09-22
Project End
2023-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
17
Fiscal Year
2019
Total Cost
Indirect Cost
Name
New York University
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
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Garcia Del Molino, Luis Carlos; Yang, Guangyu Robert; Mejias, Jorge F et al. (2017) Paradoxical response reversal of top-down modulation in cortical circuits with three interneuron types. Elife 6:
Murray, John D; Jaramillo, Jorge; Wang, Xiao-Jing (2017) Working Memory and Decision-Making in a Frontoparietal Circuit Model. J Neurosci 37:12167-12186
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Kim, Yongsoo; Yang, Guangyu Robert; Pradhan, Kith et al. (2017) Brain-wide Maps Reveal Stereotyped Cell-Type-Based Cortical Architecture and Subcortical Sexual Dimorphism. Cell 171:456-469.e22
Murray, John D; Bernacchia, Alberto; Roy, Nicholas A et al. (2017) Stable population coding for working memory coexists with heterogeneous neural dynamics in prefrontal cortex. Proc Natl Acad Sci U S A 114:394-399
Starc, Martina; Murray, John D; Santamauro, Nicole et al. (2017) Schizophrenia is associated with a pattern of spatial working memory deficits consistent with cortical disinhibition. Schizophr Res 181:107-116
Lo, Chung-Chuan; Wang, Xiao-Jing (2016) Conflict Resolution as Near-Threshold Decision-Making: A Spiking Neural Circuit Model with Two-Stage Competition for Antisaccadic Task. PLoS Comput Biol 12:e1005081
Wei, Wei; Wang, Xiao-Jing (2016) Downstream Effect of Ramping Neuronal Activity through Synapses with Short-Term Plasticity. Neural Comput 28:652-66
Sarma, Arup; Masse, Nicolas Y; Wang, Xiao-Jing et al. (2016) Task-specific versus generalized mnemonic representations in parietal and prefrontal cortices. Nat Neurosci 19:143-9

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