Project Summary/Abstract While advances in resuscitation science have improved cardiac arrest survival, we lack therapies to improve cognitive-affective outcomes in this patient population. Our lab has previously identified cognitive dysfunction in a mouse model of global cerebral ischemia (GCI) which has been attributed to hippocampal neurodegeneration and impaired hippocampal plasticity. However, no study has attempted to identify amygdala dysfunction after GCI, despite clinical evidence of emotional dysfunction, such as anxiety and Post-Traumatic Stress Disorder (PTSD). Therefore, it is important to identify the effect that GCI has on the amygdala, the emotional center of the brain. Our lab has a well-developed, translatable mouse model of GCI, the cardiac arrest/cardiopulmonary resuscitation model (CA/CPR), that has been instrumental in assessing amygdala function after GCI. I have utilized the amygdala-dependent delay-fear conditioning (DFC) paradigm to assess associative learning and memory and have performed field excitatory post-synaptic potential (fEPSP) recordings in two circuits within the amygdala, as measures of amygdala function. I have found a sexually dimorphic and circuit specific deficit in amygdala function after GCI and am working toward identifying the mechanism of this dysfunction. I have found that there is a male specific impairment in amygdala-dependent associative learning and a concomitant deficit of long-term potentiation (LTP) in the cortical input to the basolateral amygdala. I have also found no evidence that these deficits of amygdala function can be attributed to neurodegeneration within the amygdala. I have verified that there are differential mechanisms of LTP induction between the two circuits and this difference has led to the development of my hypothesis put forth in this proposal. The difference being, LTP of the cortical input to the BLA requires functional NMDA receptors and L-type calcium channels (LTCCs), whereas the intra amygdala circuit only requires functional NMDA receptors. Thus, I hypothesize that GCI induces dysfunction of LTCC's within the BLA of male mice, thereby contributing to the deficits in amygdala-dependent behavior and LTP. To assess this hypothesis, I have isolated and recorded LTCC mediated currents from BLA pyramidal neurons. This method, while powerful, has yielded no significant difference between CA/CPR and sham animals. However, a caveat of the method is that only somatic and peri somatic LTCCs can be measured. Therefore, to fully evaluate my hypothesis, I have proposed more site-specific experiments that will evaluate the contribution of LTCC's to synaptic transmission at individual distal dendritic spines. I will use two-photon calcium imaging of individual spines in the BLA while electrically inducing LTP of the cortical input to the BLA. I will then use pharmacology to identify the LTCC component of the calcium response and compare between sham and CA/CPR animals.