A key question in the study of sensory memory formation concerns how and where the long-term engram of a behaviorally relevant stimulus is created and stored, given the dynamic and distributed nature of the underlying neuronal processes. In the case of auditory learning and memory, behavioral and electrophysiological evidence point to a key role played by the auditory cortex, but the molecular mechanisms operating there to enable memory formation and maintenance are unknown. In particular, how are networks of neurons encoding a stimulus-behavior association able to initiate and retain changes in their synaptic connectivity despite turnover in the underlying molecular machinery? We propose to use an auditory fear conditioning paradigm to dis- cover whether the conformational state of DNA in auditory cortical neurons is altered to permit or repress the expression of plasticity-related genes, and whether this is triggered by known experience-dependent plasticity processes to establish persistent auditory memories. Our long-term goal is to reveal the molecular mechanisms that are recruited by specific cell types in the auditory cortex to form stable memories. The objective here is to demonstrate that the BDNF-TrkB cascade, which is critical in regulating adult experience-dependent synaptic plasticity in a large number of brain areas, modifies the epigenetic status of synaptic plasticity-related genes in auditory cortical neurons during fear conditioning, a robust model of auditory learning. Our central hypothesis is that during the consolidation and storage of fear associations to auditory cues, the BDNF-TrkB pathway is upregulated in the auditory cortex leading to the epigenetic regulation of the target plasticity genes. This chain of events results in the stabilization of synapses that encode fear memories. We will test this hypothesis with two specific aims. First, we will determine whether specific genes implicated in the machinery that mediates synaptic plasticity are epigenetically modified in neurons in the auditory cortex after auditory fear conditioning. Second, we will determine whether BDNF-TrkB signaling in the auditory cortex during auditory fear conditioning is necessary for both changes in the epigenetic status/expression of those genes and fear learning. Our proposal's significance lays in the fact that by demonstrating epigenetic modifications in a core sensory cortical area during learning, it initiates a new line a research that merges modern concepts from molecular studies of learning and memory with investigations of sensory cortical contributions to auditory memories. By using a novel methodology to target epigenetic studies to specific cell types, chosen here for proof-of- principle purposes to be neurons rather than glial cells, we are laying the foundation for future studies that will dissociate the contributions of different interneuronal and pyramidal cell types n the molecular maintenance of memories. Finally, gaining these abilities to further decipher the molecular and neural mechanisms of sensory learning and memory will then enable the development of new pharmacological targets to treat disorders involving sensory memory dysfunction, such as post-traumatic stress disorder (PTSD).
The proposed research is relevant to public health because discovering that there are epigenetic modifications of synaptic plasticity genes in the auditory cortex will provide a conceptually new way to think about intervening in sensory memory disorders, both at the molecular and circuit levels. Thus, the project is relevant to the part of NIH's mission that pertains to seeking fundamental knowledge about the nature of mental disorders, and the application of that knowledge to enhance health.
| Banerjee, Sunayana B; Gutzeit, Vanessa A; Baman, Justin et al. (2017) Perineuronal Nets in the Adult Sensory Cortex Are Necessary for Fear Learning. Neuron 95:169-179.e3 |
| Keifer Jr, O P; Hurt, R C; Gutman, D A et al. (2015) Voxel-based morphometry predicts shifts in dendritic spine density and morphology with auditory fear conditioning. Nat Commun 6:7582 |
| Keifer Jr, Orion P; Hurt, Robert C; Ressler, Kerry J et al. (2015) The Physiology of Fear: Reconceptualizing the Role of the Central Amygdala in Fear Learning. Physiology (Bethesda) 30:389-401 |
| Dias, Brian G; Maddox, Stephanie; Klengel, Torsten et al. (2015) Epigenetic mechanisms underlying learning and the inheritance of learned behaviors. Trends Neurosci 38:96-107 |
