The goal of the proposed research is to understand how the basal foebrain (BF) is organized to modulate distributed neuronal processes within sensory, motor and higher order cognitive systems in the cerebral cortex. Pharmacological studies have shown that dopaminergic and glutamatergic stimulation have a profound effect on cortical acetylcholine release, suggesting a critical role for these afferents in mediating increased cholinergic tone in behavioral states of attention, arousal and reward mechanisms. The proposed experiments will test various hypotheses about the ways in which corticipetal cholinergic and associated non-cholinergic neurons in specific basal forebrain circuits are influenced by dopaminergic and glutamatergic afferents. The following specific hypothesis will be tested: 1) Prefrontal glutamatergic axons terminate on different type of GABAergic neurons in the basal forebrain. 2) Different types of BF GABAergic neurons, identified by the presence of different calcium binding proteins (i.e., parvalbumin, calbindin D28, calretinin), contract BF cholinergic projection neurons. The number of and topography of synapses on the cholinergic neurons will vary according to the location and/or the type of GABAergic neuron. 3) Glutamate and dopamine influence the cholinergic output neurons through different pre- and postsynaptic mechanisms. To accomplish these goals e will undertake on a combined anatomical and electrophysiological study. The following major lines of research will be pursued: 1) Identification of the sources and site of termination of dopaminergic and glutamatergic terminals on basal forebrain neurons. 2) Electrophysiological characterization of thee effect of the stimulation of the substantia nigra or putative glutamatergic sources on identified BF neurons, recorded extracellularly in vivo. 3) Reconstruction of biocytin labeled BF GABAergic neurons to identify their synapses with cholinergic neurons. 4) Cellular characterization of dopaminergic and glutamatergic receptors. These studies will be aided by using in vivo juxtacellular recording, anterograde tracing of afferent pathways and double immunolabeling methods in various combinations at both the light and electron microscopic level, supplemented by computerized 3-D reconstruction of identified neurons and their synapses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023945-10
Application #
2883631
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Murphy, Diane
Project Start
1986-08-01
Project End
2002-02-28
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
10
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Rutgers University
Department
Type
Organized Research Units
DUNS #
130029205
City
Newark
State
NJ
Country
United States
Zip Code
07102
Ovsepian, Saak V; O'Leary, Valerie B; Zaborszky, Laszlo et al. (2018) Amyloid Plaques of Alzheimer's Disease as Hotspots of Glutamatergic Activity. Neuroscientist :1073858418791128
Lammers, Florian; Borchers, Friedrich; Feinkohl, Insa et al. (2018) Basal forebrain cholinergic system volume is associated with general cognitive ability in the elderly. Neuropsychologia 119:145-156
Yuan, Rui; Biswal, Bharat B; Zaborszky, Laszlo (2018) Functional Subdivisions of Magnocellular Cell Groups in Human Basal Forebrain: Test-Retest Resting-State Study at Ultra-high Field, and Meta-analysis. Cereb Cortex :
Záborszky, Laszlo; Gombkoto, Peter; Varsanyi, Peter et al. (2018) Specific Basal Forebrain-Cortical Cholinergic Circuits Coordinate Cognitive Operations. J Neurosci 38:9446-9458
Gielow, Matthew R; Zaborszky, Laszlo (2017) The Input-Output Relationship of the Cholinergic Basal Forebrain. Cell Rep 18:1817-1830
Cantero, Jose L; Zaborszky, Laszlo; Atienza, Mercedes (2017) Volume Loss of the Nucleus Basalis of Meynert is Associated with Atrophy of Innervated Regions in Mild Cognitive Impairment. Cereb Cortex 27:3881-3889
Bardóczi, Zsuzsanna; Pál, Balázs; K?szeghy, Áron et al. (2017) Glycinergic Input to the Mouse Basal Forebrain Cholinergic Neurons. J Neurosci 37:9534-9549
Chavez, Candice; Zaborszky, Laszlo (2017) Basal Forebrain Cholinergic-Auditory Cortical Network: Primary Versus Nonprimary Auditory Cortical Areas. Cereb Cortex 27:2335-2347
Zhang, Sheng; Hu, Sien; Fucito, Lisa M et al. (2017) Resting-State Functional Connectivity of the Basal Nucleus of Meynert in Cigarette Smokers: Dependence Level and Gender Differences. Nicotine Tob Res 19:452-459
Ovsepian, Saak V; O'Leary, Valerie B; Zaborszky, Laszlo (2016) Cholinergic Mechanisms in the Cerebral Cortex: Beyond Synaptic Transmission. Neuroscientist 22:238-51

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