Our long-term goal is to understand how the forebrain neuromodulatory region, nucleus basalis (NB) supports cognitive functions. NB is thought to play significant roles in learning and attention, and its degeneration parallels the decline of cognitive functions in patients in a range of dementias. However, identified projection cell-types have never been recorded. Our objective is to determine what information is represented in and signaled by distinct NB long- range cortical projections and establish their causal behavioral function. To study this issue, we have developed a quantitative psychophysical auditory detection task for mice, adapted from human and primate work, enabling us to assess a number of behavioral correlates of NB neurons. In addition, we will use our recently developed optogenetic toolkit to record from all the three known NB projection cell-types: cholinergic, GABAergic and glutamatergic neurons during behavior for the first time. Our central hypothesis is that NB broadcasts distinct cognitive signals in a cell-type-specific manner. First, we operationalized different cognitive variables so that the activity of every neuron encoding a particular cognitive variable can be statistically evaluated. Specifically we will assess the moment-to-moment, trial-to-trial correlations between firing rates and different behavioral measures (e.g. accuracy or reaction time, RT). Second, in each of the three aims we will consider one of the major projection systems and evaluate when they are recruited during behavior and what cognitive variables they encode. Finally, using the temporal information gleaned from these recordings we will test the causal role of different NB projection cell- types using optogenetic gain and loss of function manipulations. Upon completion of these aims, we expect to establish the cell-type specific broadcast signals from NB and their role in defined aspects of cognition.

Public Health Relevance

This proposal aims to determine what information different nucleus basalis (NB) long-range cortical projections convey and what is their behavioral function. We propose to record identified neurons from the three major projection outputs of NB for the first time and evaluate their role in behavior. We expect that the mechanistic insights we will gain in terms of the NB neural circuits and pathways involved in cognition will provide the necessary understanding for why its deterioration is correlated with dementias such as Alzheimer's and Parkinson's. Specifically, knowledge of firing patterns of cholinergic and non-cholinergic neurons will provide critical information to enable the development of novel translational therapeutic treatments based on deep brain stimulation (DBS) techniques.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS088661-05
Application #
9718312
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Babcock, Debra J
Project Start
2015-08-15
Project End
2020-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
Hangya, Balázs; Ranade, Sachin P; Lorenc, Maja et al. (2015) Central Cholinergic Neurons Are Rapidly Recruited by Reinforcement Feedback. Cell 162:1155-68
Lin, Shih-Chieh; Brown, Ritchie E; Hussain Shuler, Marshall G et al. (2015) Optogenetic Dissection of the Basal Forebrain Neuromodulatory Control of Cortical Activation, Plasticity, and Cognition. J Neurosci 35:13896-903