Prefrontal cortical (PFC) circuit dysfunction has emerged as a central pathological finding in depression and other stress-related neuropsychiatric disorders, and has been linked to characteristic deficits in regulating attention, reward processing, and executive control. All of these functions depend on working memory: a process that supports the short-term storage and manipulation of information, despite interference from competing, task-irrelevant information. Working memory is mediated in part by PFC pyramidal neurons, which exhibit sustained activity during active maintenance of a memory trace. This unusual capacity for sustained, internally generated activity is thought to emerge from the precisely coordinated activity of excitatory pyramidal cells and inhibitory interneurons, but the microcircuit-level mechanisms remain incompletely understood. Understanding how these cells interact in the service of working memory-and how they are disrupted in psychiatric and neurodevelopmental disorders-are fundamental challenges for systems neuroscience. Here, we will use optogenetic tools and two-photon (2P) calcium imaging to quantify and manipulate neural activity in awake, behaving mice and investigate how pyramidal cells interact with two interneuron subtypes to support working memory. Next, we will test the hypothesis that chronic stress disrupts these interactions, altering the balance of excitation and inhibition in PF microcircuits and impairing working memory. Finally, we will test the hypothesis that these effects are driven at the molecular level by deficits in BDNF-mediated plasticity mechanisms for maintaining synaptic homeostasis. The results of this work will advance our understanding of how prefrontal microcircuits support working memory, a core component of multiple psychiatric and neurodevelopmental disorders. They may also inform future efforts to design new interventions targeting dysfunction in specific neuronal subtypes in mood and anxiety disorders.

Public Health Relevance

Deficits in short-term working memory are a common problem in chronic stress states, depression, and other many other psychiatric disorders, and they can be highly disabling, partly because this process interacts closely with many other cognitive functions, including language, mental arithmetic, and the ability to regulate attention and emotion. The purpose of this project is to investigate how specific cell types interact within prefrontal microcircuits to support working memory, and to understand how these interactions are disrupted by chronic stress. The results will advance our understanding of the pathology underlying a core component of multiple mental illnesses, and may inform future efforts to design more effective treatments targeting dysfunction in specific cell types.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH109685-04
Application #
9660589
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Buhring, Bettina D
Project Start
2016-04-08
Project End
2021-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Neurology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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Drysdale, Andrew T; Grosenick, Logan; Downar, Jonathan et al. (2017) Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med 23:28-38