Our lab is focused on the molecular mechanisms of fear memory as well as behaviors that share with memory some of their molecular characteristics, such as social and maternal behavior. We are also interested in abnormal changes related to these behaviors, such as post-traumatic stress disorder (PTSD), psychological correlates of mild traumatic brain injury, autism spectrum disorders, and maternal depression.
One of our major efforts is the identification and characterization of amygdala-enriched genes, which started with differential screening of single cell cDNA libraries derived from single amygdala neurons. We have shown the role of some of these genes in learned fear only (the gastrin-releasing peptide gene (GRP); Shumyatsky et al., Cell, 2002) or both in innate and learned fear (the stathmin gene; Shumyatsky et al., Cell, 2005) based on their specific expression in the neural circuits transmitting conditioned (CS) or unconditioned (US) stimuli to the amygdala. This finding laid groundwork for the analysis of the amygdala-associated neural circuitry of fear, both at the anatomic region and cell-type specific levels.
In an exciting extension of our work on the neural circuits regulating fear memory, we studies other behaviors controlled by amygdala-enriched genes. We have found that stathmin in the basolateral amygdala regulates maternal and social behaviors via threat assessment. Remarkably, this threat detection regulated by stathmin and the basolateral amygdala leads to modulating maternal and social behaviors in opposite directions. (Martel et al., PNAS, 2008).
We also studied long-term effects of fear memory formation that may lead to fear memory abnormalities, such as PTSD. We investigated how the GRP receptor (GRPR) and stathmin control fear extinction. Interestingly, cued fear extinction was increased in stathmin knockout mice while it was delayed in GRPR knockout mice. We found that the balance of neural activities between the amygdala and prefrontal cortex is correlated with the extinction outcome. Surprisingly, contextual fear extinction was normal in both mouse lines (Martel et al., PLoS One, 2012).
More recently, we have started looking at learning-dependent changes in the brain. This led us to a surprising discovery: contrary to the commonly accepted belief, microtubules are not stable, but dynamic, in the adult brain. Curiously, we found that both stathmin activity (as an inhibitor of microtubule formation) and microtubule stability/instability undergo biphasic changes during the first eight hours following learning. Moreover, we found that transport of AMPA receptors (which are critical for memory formation) to the synapse was dependent on stathmin-mediated microtubule dynamics. By regulating AMPAR transport to the synapse, we were able to rescue memory deficits in stathmin mutant mice and in aged mice which show deficits in microtubule dynamics as part of normal aging (Uchida et al., Nature Communications, 2014). We also showed how stathmin is involved in neurogenesis, spinogenesis, and NMDA receptor-dependent memory (Martel et al., Journal of Neuroscience, 2016; Uchida and Shumyatsky, Neurobiol. Learn. Mem., 2015).
