The neocortex plays a central role in many higher-order functions such as the interpretation of sensory information, comprehension of language and control of voluntary movements. Many of these processes are shaped by ascending cholinergic drive from neurons in the basal forebrain complex, principally nucleus basalis. Dysfunction of this pathway leads to deficits in many behaviors that involve neocortex and has been tied to clinical conditions such as depression, Parkinson's disease and Alzheimer's disease. Our long-term aim is to understand the cellular and network mechanisms by which ACh from nucleus basalis so profoundly influences cortical function. ACh acts at muscarinic and nicotinic ACh receptors (mAChRs and nAChRs), which are widely expressed in neocortex. Pyramidal neurons in neocortex express both of these receptor types, but the physiological functions of nAChRs in pyramidal neurons are unknown. In this proposal we describe the functions of nAChRs on pyramidal neurons. We directly assess how ACh, released by axons from nucleus basalis, affects pyramidal neurons in motor cortex, using a combination of techniques, including optogenetics, viral tools, genetically-modified mice, immuno-cytochemistry, cellular electrophysiology, two-photon microscopy and electron microscopy. We express channelrhodopsin-2 in cholinergic neurons in nucleus basalis and their axons in neocortex. In preliminary experiments, activation of cholinergic axons depolarized and promoted spiking of layer 5 pyramidal neurons via nAChRs, leading us to hypothesize that ACh facilitates the transfer of information through neocortical networks from ascending excitatory inputs, e.g. from thalamus, to target structures, e.g. motor circuits in the spinal cord. In this proposal we will determine whether the effects of ACh on pyramidal neurons support this hypothesis. We will investigate the mechanisms by which nAChRs affect spiking and the nAChR receptor subunits involved (specific aim 1), determine where in the activated nAChRs are located within the dendritic trees of pyramidal neurons (specific aim 2), and determine whether these postsynaptic nAChRs mediated the effects of ACh in pyramidal neurons in other layers and neocortical areas (specific aim3). Our results will reveal a new mechanism by which ACh modulates the excitability of pyramidal neurons. Our studies will also provide the first evidence, to my knowledge, that ACh has layer-specific effects. The resulting hypothesis has the potential to transform our understanding of the manner in which the cholinergic pathway from nucleus basalis changes network function in neocortex and may therefore have important implications for debilitating conditions such as Parkinson's disease and Alzheimer's disease.

Public Health Relevance

The actions of the neuromodulator acetylcholine in neocortex play central roles many higher-order functions, including arousal, attention and learning and memory, and insufficient acetylcholine in neocortex has been tied to pathophysiological conditions such as Alzheimer's disease. He we study the locations of nicotinic acetylcholine receptors on layer 5 pyramidal neurons in the neocortex and the physiological effects of synaptically-released acetylcholine on these neurons. This study will advance our understanding of the mechanism of action of this essential neuromodulator in the healthy brain, which may also lead to insights into pathological conditions such as Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS078067-04
Application #
8890895
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Stewart, Randall R
Project Start
2012-09-30
Project End
2016-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Allen Institute
Department
Type
DUNS #
137210949
City
Seattle
State
WA
Country
United States
Zip Code
98103
Larsen, Rylan S; Waters, Jack (2018) Neuromodulatory Correlates of Pupil Dilation. Front Neural Circuits 12:21
Daigle, Tanya L; Madisen, Linda; Hage, Travis A et al. (2018) A Suite of Transgenic Driver and Reporter Mouse Lines with Enhanced Brain-Cell-Type Targeting and Functionality. Cell 174:465-480.e22
Zhuang, Jun; Wang, Quanxin; Takeno, Marc et al. (2018) Registration and Alignment Between in vivo Functional and Cytoarchitectonic Maps of Mouse Visual Cortex. Bio Protoc 8:
Zhuang, Jun; Ng, Lydia; Williams, Derric et al. (2017) An extended retinotopic map of mouse cortex. Elife 6:
Steinmetz, Nicholas A; Buetfering, Christina; Lecoq, Jerome et al. (2017) Aberrant Cortical Activity in Multiple GCaMP6-Expressing Transgenic Mouse Lines. eNeuro 4:
Hawrylycz, Michael; Anastassiou, Costas; Arkhipov, Anton et al. (2016) Inferring cortical function in the mouse visual system through large-scale systems neuroscience. Proc Natl Acad Sci U S A 113:7337-44
Hedrick, Tristan; Danskin, Bethanny; Larsen, Rylan S et al. (2016) Characterization of Channelrhodopsin and Archaerhodopsin in Cholinergic Neurons of Cre-Lox Transgenic Mice. PLoS One 11:e0156596
Danskin, Bethanny; Denman, Daniel; Valley, Matthew et al. (2016) Correction: Optogenetics in Mice Performing a Visual Discrimination Task: Measurement and Suppression of Retinal Activation and the Resulting Behavioral Artifact. PLoS One 11:e0148883
Danskin, Bethanny; Denman, Daniel; Valley, Matthew et al. (2015) Optogenetics in Mice Performing a Visual Discrimination Task: Measurement and Suppression of Retinal Activation and the Resulting Behavioral Artifact. PLoS One 10:e0144760
Hedrick, Tristan; Waters, Jack (2015) Acetylcholine excites neocortical pyramidal neurons via nicotinic receptors. J Neurophysiol 113:2195-209

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