Post Traumatic Stress Disorder (PTSD) and Acute Stress Disorder are anxiety disorders that produce impairment of contextual fear memory. For example, individuals suffering from PTSD report stress-induced deficits in retention of contextual fear, such as the inability to recall important aspects of the traumatic event. The signaling mechanisms underlying stress-induced memory deficits are still unclear. The central hypothesis of this proposal is that acute stress induces rapid and sustained activation of hippocampal c-Jun-N-terminal kinase (JNK) signaling pathways. This activation of hippocampal JNK pathways is one mechanism mediating stress-induced deficits of contextual conditioned memory. We also hypothesize that contextual fear conditioning alone activates hippocampal JNKs. JNK activation represents a novel mechanism for regulating consolidation of the contextual fear memory trace. The objective of the application is to gain understanding of the cellular and molecular bases of stress regulation of contextual fear memory formation such that effective therapies can be developed. We will examine the role of hippocampal JNKs in regulating contextual fear formation under both acute stress and baseline conditions. We will employ a combination of molecular, electrophysiological, and behavioral assays, and correlate alterations seen at the behavioral levels with those at the synaptic level. Additional experiments using constitutive and conditional JNK transgenic mice will delineate the contribution of specific JNK isoforms in mediating fear memory. The proposal offers an innovative step forward in our understanding of learning and memory by investigating the possible roles of hippocampal JNKs in these processes. First, the proposal provides a model for how exposure to acute stress could over-activate JNK signaling and produce memory deficits. Second, the proposal evaluates changes in hippocampal JNK signaling during contextual fear conditioning under baseline conditions, and will provide an integrated understanding of how stress and learning may activate partially overlapping signaling pathways involving common protein kinases. Finally, these studies will provide insight into the molecular and electrophysiological mechanisms responsible for memory dysfunction observed in various anxiety disorders, including PTSD.

Public Health Relevance

The goal of this research project is to investigate the role of the cJun NH2-terminal kinase (JNK) isoforms in contextual fear formation. In particular, it suggests that hippocampal JNK2 and JNK3 isoforms are critically involved in stress-induced deficit of contextual fear, while hippocampal JNK1 mainly regulates baseline learning in this behavioral task. The project will provide insight into the molecular mechanisms responsible for memory dysfunction observed in various anxiety disorders, including Post-traumatic Stress Disorder.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Neurobiology of Learning and Memory Study Section (LAM)
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Desmond, Nancy L
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University of Hawaii
Anatomy/Cell Biology
Schools of Medicine
United States
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Murthy, Saravana R K; Sherrin, Tessi; Jansen, Chad et al. (2015) Small-conductance Ca2+-activated potassium type 2 channels regulate the formation of contextual fear memory. PLoS One 10:e0127264