Our work is aimed at understanding the neural systems underlying complex psychological phenomena like perception, learning, memory, and emotion. The majority of our research projects use basic associative learning paradigms to analyze how the brain encodes and stores new information. We are interested in how the process of memory formation works from molecular biology and genomics through human cognitive neuroscience. The emphasis tends to be on fundamental mechanisms rather than on diseases, pathology, or clinical issues.
Mechanisms of Memory Updating
Memories for associations learned during Pavlovian fear conditioning are rapidly acquired, robust and long lasting and provide an ideal model for studying long-term fear memory formation and storage. When memories are recalled, they undergo a retrieval process in which the memory becomes temporarily labile and new protein synthesis is necessary for the transfer of the memory back into long-term storage, a process called reconsolidation. The reconsolidation process is dependent on protein degradation, de novo protein synthesis, and AMPA receptor trafficking in the amygdala when new information is presented during the retrieval session. The association learned during fear conditioning can be updated during a retrieval session, allowing for strengthening or weakening of the original memory. We are the interested in the neural systems and synaptic mechanisms required for fear memory updating. To do this, we are exploring two avenues of research to elucidate the mechanisms underlying fear memory updating during brief retrieval sessions:
- Fear memory generalization: We are interested in fear response changes to safety or neutral cues as a result of retraining or a brief retrieval session. We are using pharmacological and optogenetic techniques to understand the neural circuitry underlying transitions in fear responding from low to high generalization, in addition to changes in AMPA receptor trafficking, specifically AMPA receptor subunits GluR1 and GluR2, necessary to support the fear memory. Preliminary results show anisomycin (ANI), a protein synthesis inhibitor, infusions reduce freezing to CS+ and CS- cues during low or high generalization of fear, as well as AMPA receptor subunit surface expression at amygdala synapses following memory updating.
- Contextual fear memory re-evaluation: We have established a fear memory updating procedure dependent on retrieval mechanisms. This specifically allows us to look at increases in fear responding as well as the molecular mechanisms regulating protein degradation, which is necessary for the incorporation of new information into the original memory trace. We are currently using confocal microscopy in combination with pharmacology to determine how GluR2 AMPA receptor subunit surface expression and protein degradation regulate cellular activity and destabilization following contextual fear memory updating. Specifically, our data shows that an infusion of βlac, a proteasome inhibitor, or GluR23Y, an inhibitor of GluR2 endocytosis, are necessary for the behavioral expression of the contextual update, and regulate cellular activity and ubiqutin tagging in different ways to prevent memory updating.
Age-Related Memory Impairment
Humans and rats exhibit deficits in episodic/explicit memories during normal aging. Recent research from our lab implicates ubiquitin proteasome system (UPS)-mediated protein degradation as a key factor in the synaptic plasticity supporting memory formation and retrieval. In rats, normal aging leads to decreased basal proteolytic activity in several brain structures known to support acquisition and retrieval of trace fear conditioning (TFC) memory. Using adult (3 months), middle-aged (15 months), and aged (22 months) F344 rats, we are currently investigating whether plasticity-related protein degradation is decreased in aged rats following TFC memory retrieval. By quantifying proteasome activation, measuring levels of polyubiquitinated proteins, and performing 20S proteasome assays we can detect age-related changes in the post-synaptic profile of synapses in various brain structures following successful (or unsuccessful) memory retrieval. These experiments will guide future attempts to upregulate proteasome activity during senescence in an attempt to rescue age-related cognitive decline.
Optogenetic Dissection of Memory Retrieval
Decades of research suggest that fear memories are stored across a distributed neural network. Activity of the lateral amygdala(LA), prelimbic cortex (PL), central nucleus of the amygdala (CeA), and midbrain periaqueductal gray (PAG) are required for successful memory retrieval and subsequent fear expression. However, it remains unclear how these structures functionally interact to trigger fear responses during memory retrieval and maintain fear responding following retrieval. Our current work focuses on optogenetically inhibiting neural activity using virally-expressed ArchT in the amygdala, prefrontal cortex, and midbrain to determine how these structures contribute to memory retrieval and subsequent fear expression. Our data suggest that fear expression is triggered in the LA during retrieval and then maintained by persistent activity across the PL-CeA-PAG circuit.