The broad objective of this research program is to understand how basal forebrain (BF) cholinergic (BFC) and non-cholinergic neurons are organized to modulate specific cortical regions. Despite its involvement in cortical activation, attention, and memory, the functional details of the BF are not well understood due to the anatomical complexity of the region. Patients with Alzheimer's disease and related dementias have a significant decrease of acetylcholine in the cortex and show pathological changes in cholinergic neurons in the BF. Thus, a complete understanding of its functional organization is warranted. The central hypothesis of this application is that cholinergic neurons constitute local ensembles in the BF ('cell clusters') that via local collaterals and/or common inputs with their projections to cortical areas provide the neural basis of a distributed functional network to selectively modulate cognitive processes. We will test this hypothesis in 4 interrelated Specific Aims using traditional and monosynaptic viral tracing, computational analysis of large-scale networks, in vitro patch-clamp recording of BF neurons, and high-resolution monitoring of cortical network activity in freely-moving rats with optogenetic stimulation of defined BF cholinergic neurons.
In Aim 1 we will build up a relatively complete database with 200 ?m resolution of mapped BF cholinergic and non-cholinergic neurons using conventional retrograde tracing techniques. Cholinergic clusters will be defined in the resulting 'database' and in the cluster volume significant association of projection cell populations will be determined.
In Aim 2 we will validate of the functional significance of the specific organization of the BFC system in wake-behaving rats. With newly developed multi-array silicon probes implanted into two specific cortical areas and light-assisted perturbation of various cholinergic cell groups in ChAT-Cre rats, in which cholinergic cells were transfected to express channelrhodopsin (ChR2), we will determine the emerging cholinergic ensembles in the BF and their effect on the functional connectivity of various large-scale cortical networks during various brain states.
In Aim 3 we will define the input to cholinergic neurons in various subdivisions of the BF using commercially available Cre-dependent AAV helper viruses (AAV-EF1a-FLEX- TVAmCherry and AAV-CA-FLEX-RG) and a replication deficient rabies vector (RV: EnvA G-deleted Rabies- eGFP).
In Aim 4 we will determine, using in vitro patch clamp recording and retrograde tracing in ChAT-cre X ChAT-eGFP crossbred mice, how does the system of early (EF) and late firing (LF) cholinergic neurons and local cholinergic axon arborizations fit into the global organization of the BFC system. The in vivo large-scale, high-density recording design that is built on a realistic forebran model will lead to substantially improved animal models for addressing function in behavioral studies. Concomitantly, it will facilitate the understanding of the aberrant processing in basalo-cortical networks and may help the development of new treatment strategies to ameliorate the cognitive symptoms in Alzheimer's and related disorders.

Public Health Relevance

Cholinergic cells, which are widely distributed in the basal forebrain (BF), provide the majority of acetylcholine found in the cerebral cortex. This highly complex brain region has been implicated in a range of behaviors, including cortical activation, attention, motivation and memory, but the functional details are not well understood. Patients with Alzheimer's disease and in related dementias have a significant decrease of acetylcholine in the cortex and show pathological changes in cholinergic BF neurons. Part of the difficulty in understanding the role of the BF, as well as the processing characteristics of these disorders lies in the anatomical complexity of the region. The overall goal of this application is to improve our knowledge of the functional organization of the BF. The results will lead to more realistic animal models for addressing function in behavioral studies. Concomitantly, it will facilitate the understanding of the aberrant processing in basalo-cortical networks and may help the development of new treatment strategies to ameliorate the cognitive symptoms in these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023945-26
Application #
9413373
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Corriveau, Roderick A
Project Start
1986-08-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
26
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Rutgers University
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
130029205
City
Newark
State
NJ
Country
United States
Zip Code
07102
Gielow, Matthew R; Zaborszky, Laszlo (2017) The Input-Output Relationship of the Cholinergic Basal Forebrain. Cell Rep 18:1817-1830
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
Bardóczi, Zsuzsanna; Pál, Balázs; K?szeghy, Áron et al. (2017) Glycinergic Input to the Mouse Basal Forebrain Cholinergic Neurons. J Neurosci 37:9534-9549
Cantero, Jose L; Zaborszky, Laszlo; Atienza, Mercedes (2016) Volume Loss of the Nucleus Basalis of Meynert is Associated with Atrophy of Innervated Regions in Mild Cognitive Impairment. Cereb Cortex :
Lammers, Florian; Mobascher, Arian; Musso, Francesco et al. (2016) Effects of Ncl. Basalis Meynert volume on the Trail-Making-Test are restricted to the left hemisphere. Brain Behav 6:e00421
Ovsepian, Saak V; O'Leary, Valerie B; Zaborszky, Laszlo (2016) Cholinergic Mechanisms in the Cerebral Cortex: Beyond Synaptic Transmission. Neuroscientist 22:238-51
Kondo, Hideki; Zaborszky, Laszlo (2016) Topographic organization of the basal forebrain projections to the perirhinal, postrhinal, and entorhinal cortex in rats. J Comp Neurol 524:2503-15
Kline, Ryan L; Zhang, Sheng; Farr, Olivia M et al. (2016) The Effects of Methylphenidate on Resting-State Functional Connectivity of the Basal Nucleus of Meynert, Locus Coeruleus, and Ventral Tegmental Area in Healthy Adults. Front Hum Neurosci 10:149
Chaves-Coira, Irene; Barros-Zulaica, Natali; Rodrigo-Angulo, Margarita et al. (2016) Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice. Front Neural Circuits 10:28
Unal, Cagri T; Pare, Denis; Zaborszky, Laszlo (2015) Impact of basal forebrain cholinergic inputs on basolateral amygdala neurons. J Neurosci 35:853-63

Showing the most recent 10 out of 59 publications