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Novel Methods for Examining Prefrontal Interactions with Cortical and Subcortical Systems that Support Complex Mental Function

NAMHC Concept Clearance

NAMHC Concept Clearance — May 11, 2007

Presenter

Kathleen C. Anderson, Ph.D.
Program Chief, Neural Bases of Cognition Program
Behavioral Sciences and Integrative Neuroscience Research Branch
Division of Neuroscience and Basic Behavioral Science

Goal

To stimulate research on how prefrontal cortical regions interact with other cortical and subcortical systems to give rise to sophisticated behavior and cognitive function using state-of-the-art electrophysiological and molecular techniques.

Rationale

During the past 30 years, lesion, single-unit electrophysiological and functional imaging studies have provided a great deal of information about the function and properties of the prefrontal cortex. However, these studies have not yet provided significant insights into how the prefrontal cortex interacts with other cortical and subcortical systems to give rise to specific functions critical for mental health (cognition, emotion, and motivation). Recent findings from a range of studies suggest that regions within the prefrontal cortex can exert a significant and surprisingly strong influence on the generation or cessation of behaviors relevant to mental health and disease. For example, fear extinction studies in rats point to infralimbic (prefrontal cortex) modulation of the amygdala; studies on learned helplessness and resilience in rats points to the role of the same infralimbic regions in modulating the function of the dorsal raphe nucleus. Recent work in humans suggests that electrical stimulation of medial prefrontal cortex (subgenual anterior cingulate cortex) can result in relief from severe depression in some patients. Finally, research using non-human primates points to a network of neocortical systems, including prefrontal cortex that is involved in categorical decision-making. It is clear that network interactions have significant effects on the generation of highly complex behaviors, and these and other findings highlight the need to fully understand how interactions between these networks give rise to these behaviors. Understanding the flow of information between these systems and in particular how regions within the prefrontal cortex influence the function of other brain regions requires a detailed understanding of the anatomical targets of prefrontal cortical neurons, how their output influences the physiological properties of neurons within these regions, and the development of these neural circuits.

Studies to be supported

The goal of this initiative is to move beyond studies of individual brain regions and to adopt a systems-wide approach to understanding the development and function of the prefrontal cortex in the context of other brain regions that regulate cognition, emotion, reward and motivation (e.g., PFC-hippocampus, PFC-striatum, PFC-limbic). Innovative technologies to be supported include multi-site simultaneous electrophysiological recording and imaging in animals engaged in complex behaviors, the effects of genetically or pharmacologically enabled cell inactivation on cognitive function, and the use of molecular and genetic tracers and activity sensors (e.g., viral vectors and florescent protein tags) to map (spatially and developmentally) specific circuits and sub circuits that support PFC-mediated behaviors. It is expected that studies funded under this initiative would use non-human primates where the anatomical and functional homology of the PFC with humans has been relatively well established and invasive studies of complex cognitive function are possible. Innovative studies using other preparations would be considered if they could provide novel information on how regions within the PFC are connected to and functionally interact with other systems. Given the complexity of the data likely to be generated, it is expected that all applications will include the use of sophisticated analytical and/or computational techniques to understand the dynamic interactions between different regions as well as the relationship between neural activity at the systems level and behavior.

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