Differentiating the contributions of NMDA receptor-mediated synaptic plasticity in basal and lateral nuclei of the amygdala during Pavlovian fear conditioning

Fear and the development of conditional fear are critical for survival. However, mal-adaptations in the fear system lead to psychiatric disorders such as Post-Traumatic Stress Disorder and anxiety disorders, such as specific phobias. Pavlovian fear conditioning in rodents allows for the study of the neural circuitry and biological mechanisms the underlie fear learning and memory. The basolateral amygdala complex, containing the lateral (LA) and basal (BA) nuclei, are critical for cued and contextual fear learning and memory formation through mechanisms that include N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic plasticity. However, the relative contribution of NMDAR-mediated plasticity in the BA and LA is unknown because the pharmacological techniques previously used to implicate NMDAR have limited anatomical specificity. While lesion studies can be more anatomically precise, lesions affect far more than synaptic plasticity. My thesis work has been focused on the role of the NMDA receptors in learning and memory, with a principle focus on using cellular manipulations of the N-methyl-D-aspartate receptor (NMDAR) on the BA and LA nuclei of the amygdala to measure the significance of NMDAR-mediated synaptic plasticity on auditory and contextual Pavlovian fear conditioning. This was achieved through temporary inactivation, the use of an shRNA virus targeted at depleting the Grin1 gene, and the use to transgenic mice to specifically isolate and dissociate the LA and BA nuclei. The behavioral effects of the manipulations were assessed with Pavlovian auditory and contextual fear conditioning. Specifically, Chapter 2 concerns the role of selective NMDA subunit GluN2B antagonist on fear learning and retention. Chapter 3 utilizes the shRNA virus to look at NMDA-mediated plasticity in the lateral amygdala. Chapter 4 uses transgenic mice to address the role of NMDAR-mediated synaptic plasticity in both the LA and BA nuclei. Chapter 4 also addresses specific analyses that utilize the data to extract more information from viral infusion studies. Additionally, results from Chapter 4 suggest that the LA is a relay site for the convergence of the discrete CS and US to form an association, but that the information from the LA is projected to the BA and that is where NMDAR-mediated plasticity critical for auditory fear conditioning. The data that I presented in Chapter 4, support the implication that the basal amygdala is important for contextual and auditory fear learning and memory in an intact animal. Importantly, my results show that in normal functioning animals, the NMDAR-mediated synaptic plasticity in the BA, as compared to the LA, is what is critical for driving the fear response during auditory fear conditioning. In Chapter 5 these findings will be synthesized into a model that can explain the role of NMDAR- mediated plasticity in fear learning and memory. This research reformats how the fear circuitry functions to create enduring memories. Currently, most models of fear learning involve a serial circuit, emphasizing very few sites of synaptic plasticity. Since the models involve a straightforward prediction, disruption of the circuit either prior to learning or after learning should disrupt the fear response equally. My data suggests circuitry within the amygdala is adaptive. The neuro-architecture that creates fear memories should be a dynamic network, versus a serial circuit, in order to increase the chances of survival if damage occurs to the primary pathway