PROJECT SUMMARY / ABSTRACT
Though stress is necessary for the adaptive survival of a species, stress exposure can also elicit maladaptive
physiological and behavioral responses. Stress-induced maladaptive responses may lead to subsequent
development of psychiatric disorders such as post-traumatic stress disorder (PTSD) and major depressive
disorder (MDD). A core symptom observed in these disorders is increased fear expression, as defined by
heightened fear responses in the presence of stimuli associated with fear. We have previously discovered that
a single injection of (R,S)-ketamine, a rapid-acting antidepressant, attenuates learned fear following contextual
fear conditioning (CFC). We and others have reported that the ventral hippocampus (vHPC), specifically
ventral CA3 (vCA3), mediates (R,S)-ketamine’s effects on attenuating learned fear. However, how exactly
(R,S)-ketamine modulates the ensembles in vCA3 to decrease fear generalization is yet to be explored. It has
additionally been shown that ventral CA1 (vCA1) contributes to fear behavior. Thus, this research plan will lay
the groundwork to uncover the effects of (R,S)-ketamine administration on fear behavior using of in vivo
microdialysis to complement and further explain the data already collected from in vivo Ca2+ imaging in vCA3
and vCA1. Overall, my goal for this proposal is to better understand how (R,S)-ketamine alters
neurotransmitters and neuronal ensembles to buffer against heightened fear expression. My preliminary
findings outlined in Aim 1 show that (R,S)-ketamine: 1) blunts responses to shocks during fear encoding
specifically in vCA3; 2) differentially affects activity in ventral hippocampal regions CA3 and CA1; and 3)
decreases correlated activity in the ventral hippocampus during both fear encoding and retrieval. Together,
these findings lead me to my hypothesis that there are distinct changes in neurotransmitter content
immediately following (R,S)-ketamine administration that are long-lasting and that blunt the experience of a
fearful stressor. However, to test this hypothesis, I need to utilize in vivo microdialysis as outlined in Aim 2 to
measure levels of glutamate, gamma-aminobutyric acid (GABA), and serotonin (5-HT) in vCA3 or vCA1 of
male and female mice to understand how they potentially mediate (R,S)-ketamine’s effects. To date, no
longitudinal studies utilizing in vivo Ca2+ imaging or in vivo microdialysis studies have yet been performed
investigating (R,S)-ketamine effects on fear behavior. In Aim 3, I describe a postdoctoral research direction to
accomplish my goal of understanding the biological substrates of stress resilience. I have gained experience in
behavior, in vivo techniques, cellular and molecular neuroscience, and microscopy. However, I have yet to
conduct techniques that manipulate circuits, or that probe the contribution of transcriptomic changes after drug
treatment or with stress. Thus, I plan to address these gaps in my knowledge by finding a post-doctoral
position that allows me to grow in these skills. In summary, this proposal will lead to the development of a
diverse skillset in order to become a successful independent researcher in the psychiatric field.
