The prefrontal cortex (PFC) plays a critical role in multiple cognitive processes. Dysfunction in the PFC has been implicated in a wide range of disorders including Alzheimer's disease, post-traumatic stress disorder, schizophrenia, and attention deficit hyperactivity disorder. Recent research has begun to focus on understanding how the PFC operates within functionally defined networks of brain structures. In particular, the PFC and medial temporal lobe areas such as the hippocampus may work together during the formation and retrieval of memory. This project will use trace fear conditioning (TFC) in laboratory rats as a model to understand the relative contributions of the PFC and hippocampus to the formation of new long-term memories. TFC differs from standard fear conditioning in that a small temporal gap, or """"""""trace interval"""""""", is inserted between an auditory signal and an aversive outcome such as foot shock. Numerous studies have shown that normal learning in trace conditioning requires both the PFC and hippocampus, but the specific contributions of each structure as well as the principles by which they interact are currently not known. We will quantify the activity of intracellular signaling pathways known to be important for neural plasticity and learning within the PFC, hippocampus and amygdala in response to TFC training and determine how neural activity in one structure within this network affects responses in those connected to it. We will also determine the degree to which de novo protein synthesis within each brain area is required for the consolidation of a new TFC memory. This work represents the first systematic investigation of the molecular events required for memory formation in this network and one of very few studies to address the functional interactions between the PFC and hippocampus.

Public Health Relevance

The prefrontal cortex (PFC) plays a critical role in multiple cognitive processes, and dysfunction in the PFC has been implicated in a wide range of disorders including Alzheimer's disease, post-traumatic stress disorder, schizophrenia, and attention deficit hyperactivity disorder. This study will provide important new data about how the PFC interacts with medial temporal lobe structures and about how molecular events in PFC neurons contribute to normal cognition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Small Research Grants (R03)
Project #
5R03MH090426-02
Application #
8035493
Study Section
Special Emphasis Panel (ZRG1-IFCN-H (02))
Program Officer
Vicentic, Aleksandra
Project Start
2010-03-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2011
Total Cost
$71,823
Indirect Cost
Name
University of Wisconsin Milwaukee
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
627906399
City
Milwaukee
State
WI
Country
United States
Zip Code
53201
Kwapis, Janine L; Helmstetter, Fred J (2014) Does PKM(zeta) maintain memory? Brain Res Bull 105:36-45
Gilmartin, Marieke R; Balderston, Nicholas L; Helmstetter, Fred J (2014) Prefrontal cortical regulation of fear learning. Trends Neurosci 37:455-64
Kwapis, Janine L; Jarome, Timothy J; Lee, Jonathan L et al. (2014) Extinguishing trace fear engages the retrosplenial cortex rather than the amygdala. Neurobiol Learn Mem 113:41-54
Gilmartin, Marieke R; Kwapis, Janine L; Helmstetter, Fred J (2013) NR2A- and NR2B-containing NMDA receptors in the prelimbic medial prefrontal cortex differentially mediate trace, delay, and contextual fear conditioning. Learn Mem 20:290-4
Jarome, Timothy J; Helmstetter, Fred J (2013) The ubiquitin-proteasome system as a critical regulator of synaptic plasticity and long-term memory formation. Neurobiol Learn Mem 105:107-16
Kwapis, Janine L; Jarome, Timothy J; Gilmartin, Marieke R et al. (2012) Intra-amygdala infusion of the protein kinase Mzeta inhibitor ZIP disrupts foreground context fear memory. Neurobiol Learn Mem 98:148-53
Gilmartin, Marieke R; Kwapis, Janine L; Helmstetter, Fred J (2012) Trace and contextual fear conditioning are impaired following unilateral microinjection of muscimol in the ventral hippocampus or amygdala, but not the medial prefrontal cortex. Neurobiol Learn Mem 97:452-64
Kwapis, Janine L; Jarome, Timothy J; Schiff, Janet C et al. (2011) Memory consolidation in both trace and delay fear conditioning is disrupted by intra-amygdala infusion of the protein synthesis inhibitor anisomycin. Learn Mem 18:728-32
Gilmartin, Marieke R; Helmstetter, Fred J (2010) Trace and contextual fear conditioning require neural activity and NMDA receptor-dependent transmission in the medial prefrontal cortex. Learn Mem 17:289-96