Research
Our lab is interested in investigating protein synthesis dynamics in innate and learned emotional behaviors. Our long-term goal is to uncover the molecular and cellular contributions to the nervous system function that underlie complex behavioral repertoire in animals.
Prefrontal circuits and protein synthesis regulation during memory consolidation
Among the brain areas crucial for memory consolidation, medial prefrontal cortex (mPFC) is crucial for guiding adaptive behavior, and serves as a storage locus for persistent memories. Distinct changes in neural activity are detected in the mPFC during the encoding of aversive LTM, when mPFC starts mapping between contexts, events, and adaptive responses, relying on the hippocampus and amygdala to support rapid learning. Over time, mPFC is posited to store both inputs and outputs as well as the map between them, and becomes increasingly relevant for mnemonic function. While mPFC appears to be more important for remote memory recall, there is evidence supporting a role of mPFC in recent LTM, i.e., within a week, under conditions when sensory information guides decision-making and behavioral output, such as in the case of signaled active avoidance (SigAA) and differential Pavlovian threat conditioning (PTC). We hypothesize that protein synthesis is dynamically regulated in the mPFC during memory consolidation. We are investigating the role of translation programs in the prefrontal pathways during long-term consolidation of threat memories in normal and pathological brain states.
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Development of strategies to modulate nascent protein synthesis
New protein synthesis is known to be required for the consolidation of memories, yet existing methods of blocking translation lack spatiotemporal precision and cell-type specificity, preventing investigation of cell-specific contributions of protein synthesis. We have developed a combined knock-in mouse and chemogenetic approach for cell-type-specific drug-inducible protein synthesis inhibition (ciPSI) that enables rapid and reversible phosphorylation of eukaryotic initiation factor 2α, leading to inhibition of general translation by 50% in vivo. We have used cell-type-specific drug-inducible protein synthesis inhibition to show that targeted protein synthesis inhibition pan-neuronally and in excitatory neurons in the lateral amygdala (LA) impaired long-term memory. This could be recovered with artificial chemogenetic activation of LA neurons, although at the cost of stimulus generalization. Conversely, genetically reducing phosphorylation of eukaryotic initiation factor 2α in excitatory neurons in the LA enhanced memory strength but reduced memory fidelity and behavioral flexibility. Our findings provide evidence for a cell-specific translation program during consolidation of threat memories.
In addition, we have applied intersectional chemogenetic strategies to inhibitory neurons in the centrolateral amygdala of mice to block cell-type-specific translation programs that are sensitive to depletion of eukaryotic initiation factor 4E (eIF4E) and phosphorylation of eukaryotic initiation factor 2α (p-eIF2α). We showed that de novo translation in somatostatin-expressing inhibitory neurons in the centrolateral amygdala is necessary for the long-term storage of conditioned-threat responses, whereas de novo translation in protein kinase Cδ-expressing inhibitory neurons in the centrolateral amygdala is necessary for the inhibition of a conditioned response to a safety cue. Our results provide insight into the role of de novo protein synthesis in distinct inhibitory neuron populations in the centrolateral amygdala during the consolidation of long-term memories.
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Understanding pathophysiology of emotional dysregulation in Tuberous Sclerosis Complex (TSC)
Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in Tsc1 or Tsc2, the genes that encode the protein components of TSC complex along with recently identified TBC1D7. TSC is the leading monogenic cause of autism spectrum disorder, and is associated with several neuropsychiatric disorders, collectively referred to as TSC associated neuropsychiatric disorders (TAND). These symptoms have an age-related expression, and ensue at different points in lifespan of an individual with TSC. The neurological and neuropsychiatric features of TSC lead to the greatest burden of disease and remain highly under-identified and under-treated. After autism spectrum disorder, mood disorders including anxiety and depression are next most common neuropsychiatric manifestations in individuals with TSC. Using multipronged approach of combining molecular analysis with in vivo physiology and complex behavior analysis in transgenic mouse models, we study emotional dysregulation prevalent in TSC.