The neural circuits that keep memories distinct and resistant to confusion present a complex set of unknown mechanisms critical both to basic understanding and human well-being. Failure to discriminate between aversive and harmless stimuli due to the similarity of external cues present during trauma in humans can lead to the intrusive recollection of aversive memories. Overgeneralized fear evoked by trauma reminders is typical of anxiety disorders including posttraumatic stress disorder (PTSD), believed to be triggered by cues resembling traumatic experience despite a currently secure environment. Our long-term goal is to characterize mechanisms for fear memory accuracy versus generality and how these translate into control of neural circuits, behavior, and mental disorders. The central hypothesis of this project, based on our preliminary data and a large body of previous work, is that fear memory accuracy is attained via a medial prefrontal cortex (mPFC) dependent mechanism involving reduction of fear responses to harmless nonreinforced stimuli. Fear extinction appears to rely on prefrontal circuitry through a process by which initially generalized fear memories are selectively reduced by responses to non-reinforced (harmless) stimuli, possibly consolidating selective memories through interactions with the amygdala and/or the hippocampal system.
The first Aim of this project is to investigate the role of signaling in the medial prefrontal cortex in fear discrimination learning. Using genetic tagging of neurons activated in response to external stimuli, we will evaluate changes in neuronal activity patterns in the mPFC, amygdala and hippocampus. The investigation will include evaluation of the capability of histone deacetylase inhibitors to rescue induced deficits in discriminative fear learning. The clinical rationale for the proposed research is that understanding the control of acetyltransferase function over discriminative fear learning will present a specific mechanism and target for known drugs which, in combination with cognitive therapy, can reverse a phenotype reminiscent of PTSD.
The second Aim i nvestigates the role of prefrontal long-range contacts in fear discrimination. Manipulation of the prefrontal projection to amygdala, using circuit-specific regulation of neural activity and by targeting neural biomarkers of memory consolidation, will precede electrophysiological assessment of circuit properties and rescue experiments. Designed to gain insight into information processing, coding and gating relevant to discriminatory fear learning, these experiments also will identify molecular and neural mechanisms underlying cognitive dysfunction. If successful, the proposed mouse model will reproduce defined biomarker(s) of cognitive dysfunction that can be targeted by known pharmacological molecules to reverse the physiological and cognitive symptoms related to abnormal fear generalization and discrimination. The proposed research is directly relevant to the mission of the NIH, addressing impaired cognitive function caused by maladaptations in prefrontal cortex/amygdala circuits, likely to be associated with neural processes underlying neuropsychiatric disorders such as post-traumatic stress disorder (PTSD).
: Studies suggest that the coordination of functionally distinctive neuronal populations in neural network is critical for brain processing but the molecular and neural mechanims underlying fear generalization and discrimination remains elusive. In this project, we seek to identify genetic methods for targeting neuronal population relevant to fear memory specificity. Proposed experiments will provide insights into the molecular and neural mechanisms governing discriminative fear learning. This study provides an innovative genetic approach for the identification and integration of biomarkers and behavioral indicators of anxiety related disorders.
| Corches, Alex; Hiroto, Alex; Bailey, Tyler W et al. (2018) Differential fear conditioning generates prefrontal neural ensembles of safety signals. Behav Brain Res 360:169-184 |
| David, Clément N; Frias, Elma S; Szu, Jenny I et al. (2016) GLT-1-Dependent Disruption of CNS Glutamate Homeostasis and Neuronal Function by the Protozoan Parasite Toxoplasma gondii. PLoS Pathog 12:e1005643 |
