Functional imaging studies in PTSD patients suggest that reduced activation of the medial prefrontal cortex (mPFC) contributes to the excessive fear response and to the impaired response to treatment seen in these patients. To understand why the mPFC is less activated in PTSD patients, we need to understand the mechanisms by which fear conditioning and extinction alter mPFC activity. Patch-clamp recordings of mPFC neurons, which populate the prelimbic (PL) and infralimbic (IL) cortices, revealed that fear conditioning and extinction in rats induces intrinsic and synaptic changes in the mPFC. First, IL neurons showed decreased excitability after fear conditioning, and enhanced excitability after extinction. The depressed IL excitability could reduce IL activation and enhance conditioned fear responses, whereas the increased IL excitability could result in the opposite effect. Consistent with this, reducing IL intrinsic excitability enhances conditioned fear responses and increasing IL excitability enhances fear response inhibition. These findings imply that the intrinsic excitabilit state of IL is one determinant of the level of fear expression. Second, neurons from PL showed synaptic changes after fear conditioning and extinction, whereas neurons from IL showed synaptic changes only after extinction. However, the identities of the inputs onto mPFC neurons exhibiting changes in synaptic efficacy after fear conditioning and extinction remain unknown. Taken together, these findings suggest that intrinsic and synaptic changes in the mPFC mediate the formation of fear conditioning and extinction memory. The goal of this proposal is to extend these results by examining the contribution of the ventral hippocampus (vHPC) in these fear conditioning- and extinction-induced intrinsic and synaptic changes in the mPFC, since extinction is context-dependent and the vHPC conveys this crucial contextual information to the mPFC via direct connections to IL and PL.
In Aim 1, the role of the vHPC in mediating intrinsic excitability changes in IL will be examined.
In Aim 2, the role of the vHPC in mediating synaptic plasticity in the mPFC after fear conditioning and extinction will be evaluated. The results of thi study could have important implications for human extinction-based exposure therapy, which is generally done in a context that is different from the context of the traumatic experience.
PTSD affects some people exposed to traumatic events, making them unable to conduct a productive normal life. Current treatments are not effective in all PTSD patients making the search for better treatments necessary. A tactic for improving PTSD treatment is to increase our understanding of the changes occurring within the neural circuits of the rodent brain during fear extinction. This study will investigate if the ventral hippocampus exerts contextual control over fear by inducing prefrontal plasticity. The results of this study could have important implications for human extinction-based exposure therapy.
| Criado-Marrero, Marangelie; Morales Silva, Roberto J; Velazquez, Bethzaly et al. (2017) Dynamic expression of FKBP5 in the medial prefrontal cortex regulates resiliency to conditioned fear. Learn Mem 24:145-152 |
| Soler-Cedeño, Omar; Cruz, Emmanuel; Criado-Marrero, Marangelie et al. (2016) Contextual fear conditioning depresses infralimbic excitability. Neurobiol Learn Mem 130:77-82 |
| Cruz, Emmanuel; Soler-Cedeño, Omar; Negrón, Geovanny et al. (2015) Infralimbic EphB2 Modulates Fear Extinction in Adolescent Rats. J Neurosci 35:12394-403 |
