2009 — 2011 |
Choi, Dennis Clarence |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
The Role of Cortical Bdnf in the Regulation of Fear Conditioning and Extinction
DESCRIPTION (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.
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2011 |
Choi, Dennis Clarence |
P51Activity Code Description: To support centers which include a multidisciplinary and multi-categorical core research program using primate animals and to maintain a large and varied primate colony which is available to affiliated, collaborative, and visiting investigators for basic and applied biomedical research and training. |
Role of Cortical Bdnf in Reg of Fear Conditioning and Extinction
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We used selective neocortical and region-specific gene deletion, we examined the role of prelimbic BDNF of transgenic mouse lines. We found our cortex-specific BDNF knockout mice have deficits in freezing behavior (expressing learned fear) following fear conditioning, whereas innate fear behavior, locomotor, sensory and spatial learning tasks remain unaffected. Additionally, these mice were then retrained 30min after administration of either a potent TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) or vehicle, using a new, different CS tone and training context. The Cre+, cortical knockout mice injected with vehicle still showed freezing deficits compared to their litter mate controls. In contrast, Cre+, cortical knockout mice injected with the TrkB agonist, 7,8-DHF, now had equivalently robust fear expression as the control mice. For even greater region specific targeting, we induced prelimbic cortical BDNF deletions by Cre-expressing lentiviral infections into the prelimbic cortex in BDNF-floxed mice. Consistent with our earlier findings, these prelimbic BDNF deletion mice have robust deficits in consolidation of cued fear, but no effects on acquisition of cued fear, expression of unlearned fear, sensorimotor function, spatial learning, and extinction. Our current studies in neocortical BDNF knockout mice may provide further evidence that short-term memory following fear conditioning appears intact, suggesting prelimbic BDNF is critical for consolidation of learned fear memories, but is not required for unlearned fear or extinction of fear.
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