We are studying molecular and cellular mechanisms of learning and memory focusing on learned fear , the most simple and evolutionally conserved type of memory in mammals. From lizards to humans, the key area of the brain responsible for memories of fear is the amygdala. The anatomy of learned fear is well understood making it amenable for molecular analysis. However, genes and biochemical pathways defining the logic of memory processing are largely unknown. We concentrate on sensory processing in the basolateral nucleus of the amygdala, thought to be the major brain area involved in fear memory processing.

To begin studying learned fear at the molecular level, we screened for amygdala-enriched genes (Shumyatsky et al. 2002). As a result, we have identified some of the genetic components and neural circuitries in the brain that play an important role in how fear is regulated.

Because the role of the amygdala is essential to behaviors related to safety, the identification and characterization of amygdala-enriched genes, as well as the molecular signaling cascades these genes are involved in, can shed light on the mechanisms specifically devoted to the role of the amygdala in health and disease. Our work on amygdala-enriched genes, including gastrin-releasing peptide (GRP; Shumyatsky et al. 2002), zinc transporter 3 (ZnT3; Kodirov et al. 2006), and stathmin (Shumyatsky et a. 2005; Martel et al. 2008), has shown that these genes, although originally isolated from the same cDNA library derived from an individual amygdala principal neuron, have distinctly different functions in fear processing. Gastrin-releasing peptide (GRP) and its receptor GRPR serve as a inhibitory constraint on amygdala synaptic plasticity and learned fear but not innate fear; ZnT3 is thought to be involved in the cortical but not auditory sensory inputs to the lateral nucleus of the amygdala; finally, stathmin controls both amygdala synaptic plasticity as well as innate and learned fear. In addition, stathmin regulates amygdala involvement in social and parenting behaviors.

Our results demonstrate a spectrum of dissociable roles that the basolateral nucleus of the amygdala plays in innate behaviors dependent on danger detection, and pinpoints stathmin as a new molecular target for designing pharmacological interventions to treat mental disorders where decision making based on risk assessment is affected, including chronic anxiety and panic disorder.

Shumyatsky G.P., Tsvetkov E., Malleret G., Hatton M., Vronskaya S., Hampton L., Battey J., Dulac C., Kandel E.R. and Bolshakov V., (2002) Identification of a signaling network in the lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear. Cell 111:905-918.

Shumyatsky G.P., Malleret G., Shin R.-M., Takizawa S., Tully K., Tsvetkov E., Zakharenko S.S., Joseph J., Vronskaya S., Yin D.-Q., Schubart U.K., Kandel E.R. and Bolshakov V.Y. (2005) stathmin, a gene enriched in the amygdala, controls both learned and innate fear. Cell 123:697-709.

Etkin A., Shumyatsky G.P., Pittenger C.J. and Kandel E.R. (2005) Genetic Analyses of Functional Connectivity in the Nervous System. In: Databasing the Brain: From Data to Knowledge (Neuroinformatics) (Ed. by S. H. Koslow and S. Subramaniam). John Wiley & Sons, pp. 221-240.

Kodirov S.A., Takizawa S., Joseph J., Kandel E.R., Shumyatsky G.P. and Bolshakov V.Y. (2006) Synaptically released zinc gates long-term potentiation in fear conditioning pathways. Proceedings of the National Academy of Sciences USA 103:15218-15223.

Balci F., Papachristos E.B., Gallistel C.R., Brunner D., Gibson J., and Shumyatsky G.P. (2008) Interval timing in genetically modified mice: a simple paradigm. Genes, Brain and Behavior 7:373-84.

Martel, G., Nishi, A., and Shumyatsky, G.P. (2008). Stathmin reveals dissociable roles of the basolateral amygdala in parental and social behaviors. Proceedings of the National Academy of Sciences USA 105:14620-14625.