The prefrontal cortex receives information from many brain regions, and captures the essence of events to extract rules for action. In an uncertain environment opportunities and dangers must also be weighed in context for flexible behavior, in functions that engage the medial prefrontal cortex (mPFC), the hippocampus and the amygdala. The roles of these structures in motivated behavior appear to be distinct and often opposing. The goal of the proposed studies is to investigate the hitherto unknown circuit mechanisms of this functionally significant network in a non-human primate animal model. The overarching hypothesis is that the hippocampus, amygdala and mPFC form a tightly linked network whose nodes differentially interface with excitatory and distinct types of inhibitory neurons, in patterns suited for weighing stimuli in context for adaptive behavior. Experiments are designed to test this hypothesis by: (1) study of interconnections of the hippocampus and amygdala and their synaptic circuits with excitatory and inhibitory neurons; (2) study of pathways from the subgenual mPFC, and hippocampus to the amygdala, which may help balance network activity via inhibitory mechanisms; (3) investigating if the limbic thalamic reuniens nucleus is a common link for the amygdala, hippocampus and subgenual mPFC, which may mediate their respective roles in vigilance, separation of memories, and behavioral context; and (4) testing if synaptic arrangements in limbic thalamic nuclei from hippocampal, amygdalar and subgenual mPFC pathways are organized like sensory pathways in the main thalamic relay nuclei. Hypotheses about pathway interactions are based on a theoretical framework on the organization of the cortex and thalamus, and principles of excitatory and inhibitory control in primates. Multiple neural pathways will be labeled with tracers, combined with multiple labeling of distinct classes of inhibitory neurons. Brain tissue will be processed to study pathway features at the level of the light, confocal, and electron microscope. Quantitative analyses on pathway features will be conducted from the system to the synapse. Circuits will be modeled to infer their complex normal interactions and perturbation in psychiatric diseases. Findings from these studies will provide the circuit basis for the role of mPFC, hippocampus and amygdala in excitatory and inhibitory control for flexible behavior and disruption in anxiety disorders.

Public Health Relevance

Three parts of the brain, the hippocampus, amygdala, and the prefrontal cortex, form a network to weigh information based on the circumstances and respond appropriately. Balance in this network is disrupted in stress and anxiety disorders. In post-traumatic stress disorder (PTSD) the amygdala is overactive and not properly regulated by the prefrontal cortex and hippocampus. The proposed research will examine how pathways from the hippocampus and the prefrontal cortex may apply brakes on the amygdala through inhibitory neurons. Information from this study will provide the foundation to develop rational therapies to combat anxiety disorders, such as PTSD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH057414-20
Application #
9900588
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Simmons, Janine M
Project Start
1999-04-10
Project End
2021-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
20
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Boston University
Department
Other Health Professions
Type
Sch Allied Health Professions
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
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García-Cabezas, Miguel Á; Joyce, Mary Kate P; John, Yohan J et al. (2017) Mirror trends of plasticity and stability indicators in primate prefrontal cortex. Eur J Neurosci 46:2392-2405
Zikopoulos, Basilis; Höistad, Malin; John, Yohan et al. (2017) Posterior Orbitofrontal and Anterior Cingulate Pathways to the Amygdala Target Inhibitory and Excitatory Systems with Opposite Functions. J Neurosci 37:5051-5064
García-Cabezas, Miguel Á; Barbas, Helen (2017) Anterior Cingulate Pathways May Affect Emotions Through Orbitofrontal Cortex. Cereb Cortex 27:4891-4910
Hilgetag, Claus C; Medalla, Maria; Beul, Sarah F et al. (2016) The primate connectome in context: Principles of connections of the cortical visual system. Neuroimage 134:685-702
Anderson, Michael C; Bunce, Jamie G; Barbas, Helen (2016) Prefrontal-hippocampal pathways underlying inhibitory control over memory. Neurobiol Learn Mem 134 Pt A:145-161

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