The primary goal of this project is to determine the anatomical organization, molecular phenotype, and electrophysiological properties of locus coeruleus (LC) neurons that innervate sub-regions of the rat prefrontal and motor cortex. The prefrontal cortex (PFC) including its sub-regions the orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and anterior cingulate cortex (ACC), and the primary motor cortex (M1) are innervated by the LC and subject to the modulatory actions of its primary transmitter, norepinephrine (NE). Each of the PFC sub-regions mediates distinct aspects of executive function that are compromised in many neuropsychiatric disorders including ADHD, PTSD, and schizophrenia. Likewise, the NE system has been implicated in the control of many PFC-dependent behavioral functions including flexible and sustained attention.
The first aim of the proposed research will include retrograde tracing studies and immunohistochemical procedures to identify and characterize the subsets of NE-containing neurons within the LC that project to each PFC sub-region. In this and all subsequent aims M1 will serve as a non-cognitive brain region for comparison.
The second aim of the project will determine the molecular complement of each class of projection cells by examining their transcriptomes and their expression levels of selected genes that are critical for noradrenergic function using combinations of laser micro-dissection, RNA microarray analysis and qRT-PCR.
The third aim will profile individual LC-PFC and M1 projection cells on the basis of membrane properties, synaptic responsiveness, and sensitivity to drug activation using whole cell patch clamp techniques. These studies will provide a more complete understanding of the anatomical, molecular, and physiological attributes of the LC-cortical projection and challenge the longstanding notion that the LC is a functionally homogeneous cluster of NE-containing neurons that exert uniform modulatory effects across all LC- noradrenergic terminal fields, simultaneously. Instead, the general working hypothesis is that the LC-NE system operates by heterogeneous and asynchronous modulation of modality-specific terminal fields. This new theoretical construct has far reaching implications for our understanding of normal brain function and treatment of many neuropsychiatric disorders that involve noradrenergic and prefrontal cortical dysfunction.

Public Health Relevance

The proposed research will provide new information about the diversity of anatomical organization, molecular phenotype, and electrophysiological properties of projections from the brainstem locus coeruleus to prefrontal and motor cortices. This work challenges the conventional view that the locus coeruleus exerts a uniform modulatory effect on its efferent targets via simultaneous release of norepinephrine in terminal projection fields, and reveals how organizational features and physiological attributes of the locus coeruleus-cerebrocortical projection system promote adaptive motor behaviors and normal executive function through asynchronous influences on cognitive and movement circuitries. This new theoretical construct challenges conventional thinking about the operation of the locus coeruleus modulatory pathway and has far reaching implications for our understanding of normal brain function and treatment of many neuropsychiatric disorders that involve noradrenergic prefrontal cortical dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH101178-01A1
Application #
8693195
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Rossi, Andrew
Project Start
2014-03-01
Project End
2019-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$384,035
Indirect Cost
$134,035
Name
Drexel University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Aston-Jones, G; Waterhouse, B (2016) Locus coeruleus: From global projection system to adaptive regulation of behavior. Brain Res 1645:75-8
Chandler, Daniel J (2016) Evidence for a specialized role of the locus coeruleus noradrenergic system in cortical circuitries and behavioral operations. Brain Res 1641:197-206
Chu, Richard; Shumsky, Jed; Waterhouse, Barry D (2016) Differentiation of rodent behavioral phenotypes and methylphenidate action in sustained and flexible attention tasks. Brain Res 1641:306-19
Bhattacharya, Shevon E; Shumsky, Jed S; Waterhouse, Barry D (2015) Attention enhancing effects of methylphenidate are age-dependent. Exp Gerontol 61:1-7
Chandler, Daniel J; Gao, Wen-Jun; Waterhouse, Barry D (2014) Heterogeneous organization of the locus coeruleus projections to prefrontal and motor cortices. Proc Natl Acad Sci U S A 111:6816-21
Chandler, Daniel J; Waterhouse, Barry D; Gao, Wen-Jun (2014) New perspectives on catecholaminergic regulation of executive circuits: evidence for independent modulation of prefrontal functions by midbrain dopaminergic and noradrenergic neurons. Front Neural Circuits 8:53
Chandler, Daniel J; Lamperski, Carolyn S; Waterhouse, Barry D (2013) Identification and distribution of projections from monoaminergic and cholinergic nuclei to functionally differentiated subregions of prefrontal cortex. Brain Res 1522:38-58