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
$340,727
Indirect Cost
$132,586
Name
Boston University
Department
Other Health Professions
Type
Schools of Allied Health Profes
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
García-Cabezas, Miguel Ángel; Barbas, Helen (2014) Area 4 has layer IV in adult primates. Eur J Neurosci 39:1824-34
Timbie, Clare; Barbas, Helen (2014) Specialized pathways from the primate amygdala to posterior orbitofrontal cortex. J Neurosci 34:8106-18
Garcia-Cabezas, Miguel A; Barbas, Helen (2013) A direct anterior cingulate pathway to the primate primary olfactory cortex may control attention to olfaction. Brain Struct Funct :
Bunce, Jamie G; Zikopoulos, Basilis; Feinberg, Marcia et al. (2013) Parallel prefrontal pathways reach distinct excitatory and inhibitory systems in memory-related rhinal cortices. J Comp Neurol 521:4260-83
Barbas, Helen; Garcia-Cabezas, Miguel Angel; Zikopoulos, Basilis (2013) Frontal-thalamic circuits associated with language. Brain Lang 126:49-61
John, Yohan J; Bullock, Daniel; Zikopoulos, Basilis et al. (2013) Anatomy and computational modeling of networks underlying cognitive-emotional interaction. Front Hum Neurosci 7:101
Zikopoulos, Basilis; Barbas, Helen (2013) Altered neural connectivity in excitatory and inhibitory cortical circuits in autism. Front Hum Neurosci 7:609
Medalla, Maria; Barbas, Helen (2009) Synapses with inhibitory neurons differentiate anterior cingulate from dorsolateral prefrontal pathways associated with cognitive control. Neuron 61:609-20
Xiao, D; Zikopoulos, B; Barbas, H (2009) Laminar and modular organization of prefrontal projections to multiple thalamic nuclei. Neuroscience 161:1067-81
Hoistad, Malin; Barbas, Helen (2008) Sequence of information processing for emotions through pathways linking temporal and insular cortices with the amygdala. Neuroimage 40:1016-33

Showing the most recent 10 out of 34 publications