The goal of this research is to determine the cognitive functions of cortical acetylcholine (ACh). Cortical ACh is hypothesized to mediate attentional processes, specifically sustained attention. The proposed experiments will assess the attentional functions of cortical ACh by measuring cortical ACh release and single unit activity in rats while they perform a task designed and validated for the measurement of sustained attention. Our preliminary experiments demonstrated that increased demands on sustained attention, caused by the presentation of distractors and indicated by specific impairments in performance, are associated with increases in ACh release in the medial prefrontal cortex. Additionally, attention-associated increases in neuronal activity were observed and blocked by the removal of cholinergic inputs to the recording area (produced by an infusion of the cholinotoxin 192 IgG-saporin into the recording field). The proposed research will determine the role of cortical ACh in sustained attention by : 1) developing a series of distractors which serve to systematically vary the demands on attention; 2) demonstrating that the attentional performance under taxing conditions depends critically on the integrity of the cortical cholinergic afferent system; 3) demonstrating that increased demands on attention are associated with increases in medial prefrontal ACh release and predictable shifts in single unit activity; 4) demonstrating that the attention-associated increases in neuronal activity are blocked by loss of cholinergic inputs to the recording area; and 5) demonstrating that infusions of a benzodiazepine receptor agonist and an inverse agonist block and augment, respectively, the attentional performance-associated increases in cortical ACh efflux and neuronal activity. Collectively, the presynaptic (i.e., ACh release) and postsynaptic (single unit activity) measures of attention-associated changes in cortical ACh will yield a specific hypothesis about the role of cortical ACh in attention. The determination of the specific cognitive functions of cortical ACh will lead to a better understanding of the disastrous cognitive consequences of deviations in the integrity of cortical cholinergic afferents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037026-04
Application #
6393879
Study Section
Special Emphasis Panel (ZRG2-BPO (01))
Program Officer
Edwards, Emmeline
Project Start
1998-09-20
Project End
2003-03-31
Budget Start
2001-08-01
Budget End
2003-03-31
Support Year
4
Fiscal Year
2001
Total Cost
$260,934
Indirect Cost
Name
Ohio State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Parikh, Vinay; St Peters, Megan; Blakely, Randy D et al. (2013) The presynaptic choline transporter imposes limits on sustained cortical acetylcholine release and attention. J Neurosci 33:2326-37
Sarter, Martin; Martinez, Vicente; Kozak, Rouba (2009) A neurocognitive animal model dissociating between acute illness and remission periods of schizophrenia. Psychopharmacology (Berl) 202:237-58
Broussard, John I; Karelina, Kate; Sarter, Martin et al. (2009) Cholinergic optimization of cue-evoked parietal activity during challenged attentional performance. Eur J Neurosci 29:1711-22
Parikh, Vinay; Sarter, Martin (2008) Cholinergic mediation of attention: contributions of phasic and tonic increases in prefrontal cholinergic activity. Ann N Y Acad Sci 1129:225-35
Sarter, Martin (2008) The substantia innominata remains incognita: pressing research themes on basal forebrain neuroanatomy. Brain Struct Funct 213:11-5
Kozak, Rouba; Martinez, Vicente; Young, Damon et al. (2007) Toward a neuro-cognitive animal model of the cognitive symptoms of schizophrenia: disruption of cortical cholinergic neurotransmission following repeated amphetamine exposure in attentional task-performing, but not non-performing, rats. Neuropsychopharmacology 32:2074-86
Parikh, Vinay; Kozak, Rouba; Martinez, Vicente et al. (2007) Prefrontal acetylcholine release controls cue detection on multiple timescales. Neuron 56:141-54
Briand, Lisa A; Gritton, Howard; Howe, William M et al. (2007) Modulators in concert for cognition: modulator interactions in the prefrontal cortex. Prog Neurobiol 83:69-91
Brooks, Julie M; Sarter, Martin; Bruno, John P (2007) D2-like receptors in nucleus accumbens negatively modulate acetylcholine release in prefrontal cortex. Neuropharmacology 53:455-63
Sarter, Martin; Bruno, John P; Parikh, Vinay (2007) Abnormal neurotransmitter release underlying behavioral and cognitive disorders: toward concepts of dynamic and function-specific dysregulation. Neuropsychopharmacology 32:1452-61

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