Behavioral and physiologic studies suggest that the prefrontal cortex selects relevant signals and suppresses noise, which is essential for focusing on the task at hand and ignoring distracters. The goal of the proposed studies is to investigate the largely unexplored synaptic circuits that underlie these processes, using as a model system the robustly interconnected anterior cingulate cortex (ACC), the dorsolateral prefrontal cortices (DLPFC) and the auditory association cortices, which have a demonstrated role in excitatory and inhibitory control. The working hypothesis is that pathways that interlink these areas interact differentially with excitatory neurons and distinct classes of inhibitory neurons, in circuits that allow functional diversity for flexible behavior. This hypothesis is based on a conceptual model of cortical connections and their relationship to distinct neurochemical and functional classes of inhibitory neurons summarized by two principles: (1) Corticocortical connections have characteristic laminar origins and terminations that can be predicted by the structural architecture of the linked areas. (2) Connections originate and terminate in laminar microenvironments that vary significantly in the density of neurochemical and functional classes of inhibitory neurons. Experiments are designed within this conceptual framework to investigate: the synaptic specificity of pathways that link auditory association cortices with the functionally distinct ACC and DLPFC;the synaptic circuits that link the functionally distinct ACC and DLPFC with each other, as well as with their respective neighboring and functionally related areas;the projections of both ACC and DLPFC to the premotor cortex, in pathways that may underlie decision for action. Prefrontal pathways will be labeled with neural tracers, combined with double- or triple labeling for distinct neurochemical classes of inhibitory neurons, molecular markers or receptors. Brain tissue will be processed for correlated light and electron microscopic analysis, synaptic reconstruction and quantitative analyses. Information from this study will provide a foundation to understand the role of the prefrontal cortex in central executive functions, and the resulting imbalance in excitatory and inhibitory control in neurologic and psychiatric diseases affecting prefrontal-temporal pathways, including schizophrenia and autism.

Public Health Relevance

Disruption in the balance of excitation and inhibition underlies the deficits in several neurologic and psychiatric diseases. Damage to the prefrontal cortex results in loss of the ability to filter out noise in auditory processing in humans. The dorsolateral prefrontal cortex, anterior cingulate and temporal auditory cortices are affected in schizophrenia, consistent with the auditory nature of hallucinations, distractibility and debilitating deficits in cognition. In autism, prefrontal and cingulate circuits involved in response inhibition are underactive and poorly synchronized. Investigation of the excitatory and inhibitory synaptic interactions within this integrated cortical circuit will have important implications for the development of therapeutic interventions for neurologic diseases, schizophrenia and autism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS024760-26
Application #
8606252
Study Section
Cognitive Neuroscience Study Section (COG)
Program Officer
Babcock, Debra J
Project Start
1987-07-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
26
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Boston University
Department
Other Health Professions
Type
Sch Allied Health Professions
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02215
Anderson, Michael C; Bunce, Jamie G; Barbas, Helen (2016) Prefrontal-hippocampal pathways underlying inhibitory control over memory. Neurobiol Learn Mem 134 Pt A:145-61
García-Cabezas, Miguel Á; Barbas, Helen (2016) Anterior Cingulate Pathways May Affect Emotions Through Orbitofrontal Cortex. Cereb Cortex :
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
John, Yohan J; Zikopoulos, Basilis; Bullock, Daniel et al. (2016) The Emotional Gatekeeper: A Computational Model of Attentional Selection and Suppression through the Pathway from the Amygdala to the Inhibitory Thalamic Reticular Nucleus. PLoS Comput Biol 12:e1004722
Barbas, Helen; García-Cabezas, Miguel Ángel (2016) How the prefrontal executive got its stripes. Curr Opin Neurobiol 40:125-134
Zikopoulos, Basilis; John, Yohan J; García-Cabezas, Miguel Ángel et al. (2016) The intercalated nuclear complex of the primate amygdala. Neuroscience 330:267-90
Barbas, Helen; García-Cabezas, Miguel Á (2015) Motor cortex layer 4: less is more. Trends Neurosci 38:259-61
Timbie, Clare; Barbas, Helen (2015) Pathways for Emotions: Specializations in the Amygdalar, Mediodorsal Thalamic, and Posterior Orbitofrontal Network. J Neurosci 35:11976-87
Barbas, Helen (2015) General cortical and special prefrontal connections: principles from structure to function. Annu Rev Neurosci 38:269-89
Medalla, Maria; Barbas, Helen (2014) Specialized prefrontal ""auditory fields"": organization of primate prefrontal-temporal pathways. Front Neurosci 8:77

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