The long-term goals of this project are to understand the neural systems that mediate the context-dependence of memory, particularly memory for traumatic events. To address these questions, we use auditory fear conditioning in rats to study the acquisition and extinction of aversive memory. Extensive evidence indicates that learned fear generalizes broadly across contexts (both in space and time), whereas memories of extinction are tightly bound to the time and place of extinction. Work in previous years of the project has identified a critical role for the hippocampus in the context-dependence of fear extinction to an auditory conditioned stimulus (CS). Further, hippocampal modulation of neuronal activity in the amygdala appears to be involved in gating the expression of fear memories after they have undergone extinction. This proposal seeks to characterize the neural circuits and cellular mechanisms by which the hippocampus gates the expression of fear and safety memories encoded in the amygdala. We hypothesize that the hippocampus modulates amygdala circuits involved in fear expression via the ventromedial prefrontal cortex. We will test this hypothesis by using a combination of electrophysiological recordings and permanent or reversible brain lesions. The first specific aim of the project will investigate the contribution of the medial prefrontal cortex to the context-specificity of extinction using both permanent and reversible lesions. The second specific aim will determine the essential connections between the hippocampus, prefrontal cortex, and amygdala that are required for the context- dependence of neural and behavioral responses to an extinguished auditory CS. The third specific aim will characterize the context-dependence of cellular firing in the hippocampus, prefrontal cortex, and amygdala during the retrieval of extinction memories. Parallel recordings in all three areas will seek to uncover correlated neuronal activity in the circuit, and the latency at which context-dependent neuronal responses to auditory conditioned stimuli emerge in each area. This work has broad significance for understanding flexible memory representations in the brain and potential clinical interventions to increase the generality and permanence of fear inhibition after extinction-like therapies (e.g., exposure therapy).

Public Health Relevance

The long-term goals of this project are to understand the neural systems that mediate the context-dependence of memory, particularly memory for traumatic events. We have proposed that the context-dependent expression of fear memories involves an interaction of the hippocampus and amygdala. An attractive hypothesis is that this interaction involves a hippocampo-prefrontal cortical projection, which in turn modulates neuronal activity in the amygdala. The goal of the present proposal is to test this model using a combination of techniques, including high-density single-unit recordings, sophisticated behavioral designs, and temporary brain lesions. This work will not only yield critical information concerning the essential neural substrates underlying fear and extinction memory, but will also yield insight into the mechanisms underlying the context-dependence of memory, which is a key feature of many memory systems. Moreover, this work will have far-reaching implications for the design of therapeutic interventions for disorders of fear and anxiety in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH065961-11
Application #
8391758
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Vicentic, Aleksandra
Project Start
2002-09-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
11
Fiscal Year
2013
Total Cost
$332,249
Indirect Cost
$106,551
Name
Texas A&M University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
078592789
City
College Station
State
TX
Country
United States
Zip Code
77845
Ramanathan, Karthik R; Jin, Jingji; Giustino, Thomas F et al. (2018) Prefrontal projections to the thalamic nucleus reuniens mediate fear extinction. Nat Commun 9:4527
Ramanathan, Karthik R; Ressler, Reed L; Jin, Jingji et al. (2018) Nucleus Reuniens Is Required for Encoding and Retrieving Precise, Hippocampal-Dependent Contextual Fear Memories in Rats. J Neurosci 38:9925-9933
Goode, Travis D; Maren, Stephen (2018) Common neurocircuitry mediating drug and fear relapse in preclinical models. Psychopharmacology (Berl) :
Marek, Roger; Jin, Jingji; Goode, Travis D et al. (2018) Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear. Nat Neurosci 21:384-392
Moscarello, Justin M; Maren, Stephen (2018) Flexibility in the face of fear: Hippocampal-prefrontal regulation of fear and avoidance. Curr Opin Behav Sci 19:44-49
Ressler, Reed L; Maren, Stephen (2018) Synaptic encoding of fear memories in the amygdala. Curr Opin Neurobiol 54:54-59
Giustino, Thomas F; Maren, Stephen (2018) Noradrenergic Modulation of Fear Conditioning and Extinction. Front Behav Neurosci 12:43
Giustino, Thomas F; Seemann, Jocelyn R; Acca, Gillian M et al. (2017) ?-Adrenoceptor Blockade in the Basolateral Amygdala, But Not the Medial Prefrontal Cortex, Rescues the Immediate Extinction Deficit. Neuropsychopharmacology 42:2537-2544
Goode, Travis D; Holloway-Erickson, Crystal M; Maren, Stephen (2017) Extinction after fear memory reactivation fails to eliminate renewal in rats. Neurobiol Learn Mem 142:41-47
Acca, Gillian M; Mathew, Abel S; Jin, Jingji et al. (2017) Allopregnanolone induces state-dependent fear via the bed nucleus of the stria terminalis. Horm Behav 89:137-144

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