Post-traumatic stress disorder (PTSD) is a stress- and trauma- induced condition that affects millions of Americans, with women facing PTSD diagnoses at almost twice the rate of men. PTSD is characterized by persistent anxiety, a dysregulated autonomic nervous system, avoidance behaviors, and is often co-morbid with major depressive disorder and substance abuse. Diminished engagement of the medial prefrontal cortex concomitant with a hyperactive basolateral amygdala (BLA) strongly contribute to the dysregulated emotional responses associated with PTSD. During extinction learning, the medial prefrontal cortex is thought to suppress BLA activity, thereby decreasing defensive responding to non-threatening cues, a process that is disrupted in PTSD. There is much evidence to support the idea that direct prefrontal input affects plasticity in the BLA, and shifts the excitatory-inhibitory balance in the amygdala towards inhibition. However, the mechanisms of this circuit-level interaction are not well understood. Notably, the medial prefrontal cortex is not a monolithic structure, and its contiguous subregions, in rodents designated as the prelimbic (PL) and infralimbic (IL), are associated with increased and decreased defensive responding, respectively. Although some ideas have been proposed, thus far no differences have been found in direct PL vs. IL interactions with the BLA that can account for their functional dichotomy. This gap in knowledge prevents the development of more targeted therapeutic treatments for PTSD. One possibility is that the PL and IL may have differential effects upon amygdala function via indirect pathways. Previous work shows that the PL and IL are differentially connected with the basal forebrain, a critical region for modulating fear and extinction learning in the amygdala. The basal forebrain provides strong cholinergic, glutamatergic, and GABAergic inputs to the amygdala, the cortical mantle, and the hippocampus, making it an intriguing centralized location for prefrontal modulation of extinction learning in downstream structures. The goal of the proposed experiments is to uncover the structure and function of PL and IL -basal forebrain -amygdala communication during extinction. To this end, in Specific Aim I will use viral tracing and immunohistochemistry to uncover the detailed circuitry of PL and IL connectivity with amygdala-projecting cells in the ventral pallidum/substantia innominata, and horizontal limb of the diagonal band of the basal forebrain. Then, in Specific Aims 2 and 3, I will use optogenetics to manipulate IL and PL inputs to the basal forebrain, and multi-site in-vivo recordings to record the neurophysiology across the IL/PL-basal forebrain-BLA circuit during fear conditioning, extinction training and recall. Additional immunohistochemical analyses of neural activity will indicate which cell types the PL and IL drive in the basal forebrain during extinction. All experiments will be performed in both sexes to assess whether this circuit contributes to increased rates of PTSD diagnosis in women. This approach is specifically designed to improve our understanding of the circuitry underlying extinction learning, and is geared toward finding novel therapeutic approaches for improving treatment outcomes in PTSD.

Public Health Relevance

Trauma- and stress-induced psychiatric disorders affect millions of Americans, and are characterized by an underactive prefrontal cortex and a hyperactive amygdala - the fear center of the brain - resulting in maladaptive learning and generalized anxiety. An active prefrontal cortex is essential for regulating emotion and decreasing amygdala activity, but the circuits that mediate these effects downstream of the prefrontal cortex remain poorly understood. This project will uncover how prefrontal connectivity with the basal forebrain, a hub for modulating learning and memory in the amygdala, impacts extinction learning and amygdala physiology, paving the way for targeted therapeutic intervention in psychiatric dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH118441-02
Application #
9961665
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Vicentic, Aleksandra
Project Start
2019-06-20
Project End
2024-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Hunter College
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
620127915
City
New York
State
NY
Country
United States
Zip Code
10065