(provided by candidate): Understanding the cellular mechanisms mediating the acquisition and extinction of fear Is of critical Importance for a variety of fear-related psychiatric disorders, such as Posttraumatic Stress Disorder (PTSD). It Is well established that Pavlovian fear conditioning is a powerful model to study the neural mechanisms Involved In fear learning. Additionally, when fear conditioned animals are repeatedly exposed to the conditioned fear-eliciting stimuli In the absence of the unconditioned aversive stimuli, the fear responses gradually decline. This reduction In conditioned fear Is referred to as fear extinction and results from a new form of Inhibitory learning, rather than an erasure of the original fear memory. Considerable evidence suggests the medial prefrontal cortex (mPFC) Is a major modulator of fear conditioning and extinction by directly Influencing the amygdala. However, neural mechanisms and interactions between the mPFC and the amygdala In the control of fear expression and extinction are still unclear. One potential candidate may be brain derived neurotrophic factor (BDNF), a neurotrophin that Is well known to be Involved In neuronal plasticity and has been shown to be involved In learning, Including fear conditioning. BDNF is highly expressed In the medial prefrontal cortex and TrkB (BDNF receptor) exists in the amygdala. Therefore, BDNF In the medial prefrontal cortex acting on TrkB receptors in the amygdala Is a prime candidate for mediating the neural plasticity underlying expression or extinction of learned fear.
Specific Aim 1) will test the hypothesis that a) BDNF-dependent plasticity In the prellmbic cortex is necessary for modulating the expression of previously learned fear, and b) BDNF-dependent plasticity in the infralimbic cortex Is necessary for modulating the extinction of fear.
Specific Aim 2) will test the hypothesis that BDNF-expressIng neurons 1) in the prellmbic cortex neurons specifically target the basolateral nucleus of the amygdala and 2) in the Infralimbic cortex specifically target the lateral nucleus of the amygdala to differentially regulate expression or extinction of fear respectively. Public Health Relevance: PTSD is a serious debilitating disorder that affects many war veterans with uncontrollable flashbacks of traumatic and fearful events. This research will aim to provide further knowledge on how fear is controlled by the brain In order to provide insight on assessing risk factors and treatments of mental disorders.
| Choi, D C; Gourley, S L; Ressler, K J (2012) Prelimbic BDNF and TrkB signaling regulates consolidation of both appetitive and aversive emotional learning. Transl Psychiatry 2:e205 |
| Bowers, Mallory E; Choi, Dennis C; Ressler, Kerry J (2012) Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y. Physiol Behav 107:699-710 |
| Andero, R; Ressler, K J (2012) Fear extinction and BDNF: translating animal models of PTSD to the clinic. Genes Brain Behav 11:503-12 |
| Choi, Dennis C; Maguschak, Kimberly A; Ye, Keqiang et al. (2010) Prelimbic cortical BDNF is required for memory of learned fear but not extinction or innate fear. Proc Natl Acad Sci U S A 107:2675-80 |
