The frontal-basal ganglia network supports our ability to update action plans based on reward feedback. A prevailing theory posits that stress perturbs frontal cortical function, thereby impairing motivated behavior. Although this theory is supported by morphological and molecular evidence, data detailing the maladaptive changes in neural activity in vivo are lacking. One challenge is heterogeneity, because frontal cortical neurons exhibit diverse task-related activity patterns. To overcome this challenge, we developed experimental approaches to record from an ensemble of neurons as mice perform an instrumental sucrose preference task. Our preliminary results showed that layer 2/3 medial frontal cortical neurons display distinct activity patterns associated with the timing and initiation of voluntary actions. These results led us to propose two hypotheses for how chronic stress may impair the cortical circuitry for voluntary actions. One, chronic stress diminishes the activity of cells involved in action initiation. Two, frontal corticostriatal neurons send command-like signal in service of action initiation. To test these hypotheses, we propose two specific aims.
In Aim 1, we will investigate the longitudinal effects of chronic stress on frontal cortical ensemble activity. We will use a computational model to gain insights into how the neural activity modifications can alter instrumental behavior.
In Aim 2, we will record from corticostriatal neurons during the instrumental task. Using optogenetics and targeted ablation, we will test their potential causal roles in mediating purposive actions. Accomplishing these aims will provide circuit-level insights into the neural basis of voluntary behavior. Framework of chronic stress that includes the complexity of neural dynamics will allow a better understanding of depressive-like behaviors.

Public Health Relevance

Chronic stress perturbs frontal cortical function, thereby impairing our ability to plan actions. The proposed studies will determine how neural activity dynamics during voluntary behavior are impacted by chronic stress. The results will provide circuit-level insights into the etiology of depressive-like behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH112750-01
Application #
9286602
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Ferrante, Michele
Project Start
2017-02-15
Project End
2021-11-30
Budget Start
2017-02-15
Budget End
2017-11-30
Support Year
1
Fiscal Year
2017
Total Cost
$418,750
Indirect Cost
$168,750
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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