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MAILMAN RESEARCH CENTER

Press Release

Researchers Identify the Brain's On-Off Switch for Fear

Cellular Neurobiology Laboratory

The Cellular Neurobiology Laboratory is interested in understanding the cellular and molecular mechanisms of neurotransmitter release, as well as the modulation of release through various receptor-activated signal transduction pathways in the amygdala and hippocampus. We utilize a combination of electrophysiological, cell biological, and molecular genetic techniques to investigate the molecular mechanism of synaptic transmission at central synapses. Such basic mechanisms are likely to play an important role in long-term synaptic plasticity in the mammalian brain.

More recently we have begun to explore the synaptic mechanisms of learned fear using fear conditioning training paradigm. Now we are trying to relate the long-term synaptic modifications in the amygdala synapses induced by behavioral training to memory of this conditioning experience (see the articles in Harvard Gazette (1 and 2), Focus, Harvard Crimson and Harvard Medicine).

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Representative publications

Janz R, Sudhof TC, Hammer RE, Unni V, Siegelbaum SA and Bolshakov VY (1999) Essential roles in synaptic plasticity for synaptogyrin I and synaptophysin I. Neuron 24, 687-700.

Bolshakov VY, Carboni L, Cobb M, Siegelbaum SA and Belardetti F (2000) Dual MAP kinase pathways mediate opposing forms of long-term plasticity at CA3-CA1 synapses. Nature Neuroscience 3, 1107-1113.

Tsvetkov E, Carlezon WA, Benes F, Kandel E and Bolshakov VY (2002) Fear conditioning occludes LTP-induced presynaptic enhancement of synaptic transmission in the cortical pathway to the lateral amygdala. Neuron 34, 289-300.

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

Hinds HL, Goussakov I, Nakazawa K, Tonegawa S, Bolshakov VY (2003) Essential function of a-CaMKII in neurotransmitter release at a glutamatergic central synapse. Proceedings of the National Academy of Sciences USA 100, 4275-4280.

Feinmark SJ, Begum R, Tsvetkov E, Goussakov I, Funk CD, Siegelbaum SA and Bolshakov VY (2003) 12-Lipoxygenase metabolites of arachidonic acid mediate metabotropic glutamate receptor-dependent LTD at hippocampal CA3-CA1 synapses. Journal of Neuroscience 23; 11427-11435.

Tsvetkov E, Shin R and Bolshakov VY (2004) Glutamate uptake determines pathway specificity of long-term potentiation in the neural circuitry of fear conditioning. Neuron 41; 139-151.

Shumyatsky GP, Malleret G, Shin RM, Tully K, Takizawa S, Tsvetkov E, Zakharenko SS, Joseph J, Vronskaya, Yin DQ, Schubart UK, Kandel ER, Bolshakov VY (2005) Stathmin, a gene enriched in the amygdala, controls both learned and innate fear. Cell 123, 697-709.

Kodirov SA, Takizawa S, Joseph J, Kandel ER, Shumyatsky GP, Bolshakov VY (2006) Synaptically released zinc gates long-term-potentiation in fear conditioning pathways. Proceedings of the National Academy of Sciences USA 103, 15218-15223.

Shin RM, Tsvetkov E, Bolshakov VY (2006) Spatiotemporal asymmetry of associative synaptic plasticity in fear conditioning pathways. Neuron 52, 883-896.

Bolshakov VY. (2007) SCOPing out proteases in long-term memory. Cell 128, 1029-1030.

Tully K, Li Y, Tsvetkov E, Bolshakov VY. (2007). Norepinephrine enables the induction of associative LTP at thalamo-amygdala synapses. Proceedings of the National Academy of Sciences USA 104, 14146-14150.

Tully K, Li Y, Bolshakov VY. (2007). Keeping in check painful synapses in central amygdala. Neuron 56, 757-759.

Pan BX, Vautier F., Ito W., Bolshakov VY, Morozov A. (2008). Enhanced cortico-amygdala efficacy and suppressed fear in absence of Rap1. Journal of Neuroscience 28, 2089-2098.

Bolshakov VY. (2009). Nipping fear in the bud: Inhibitory control in the amygdala. Neuron 61, 817-819.

Riccio A, Li Y, Moon J, Kim KS, Smith KS, Rudolph U, Gapon S, Yao GL, Tsvetkov E, Rodig SJ, Van't Veer A, Meloni EG, Carlezon WA, Bolshakov VY, Clapham DE. (2009). Essential role for TRPC5 in amygdala function and fear-related behavior. Cell 137, 761-772.

Shin RM, Tully K, Li Y, Cho JH, Higuchi M, Suhara T, Bolshakov VY. (2010). Hierarchical order of coexisting pre- and postsynaptic forms of long-term potentiation at synapses in amygdala. Proceedings of the National Academy of Sciences USA 107, 19073-19078.

Cho JH, Bayazitov IT, Meloni EG, Myers KM, Carlezon WA, Zakharenko SS, Bolshakov VY. (2012). Coactivation of thalamic and cortical pathways induces input timing-dependent plasticity in amygdala. Nature Neuroscience 15, 113-122. 

Cho JH, Zushida K, Shumyatsky GP, Carlezon WA Jr, Meloni EG, Bolshakov VY. (2012). Pituitary adenylate cyclase-activating polypeptide induces postsynaptically expressed potentiation in the intra-amygdala circuit. Journal of Neuroscience 32,14165-14177.

Li Y, Sacchi S, Pollegioni L, Basu AC, Coyle JT, Bolshakov VY. (2013). Identity of endogenous NMDAR glycine site agonist in amygdala is determined by synaptic activity level. Nature Communications 4:1760.

Li Y, Meloni EG, Carlezon WA Jr, Milad MR, Pitman RK, Nader K, Bolshakov VY. (2013). Learning and reconsolidation implicate different synaptic mechanisms. Proceedings of the National Academy of Sciences USA 110, 4798-4803.

Cho JH, Deisseroth K, Bolshakov VY. (2013). Synaptic encoding of fear extinction in mPFC-amygdala circuits. Neuron 80, 1491-1507.

Articles:

The Harvard Mahoney Neuroscience Institute Letter: On the Brain "Stopping PTSD in its tracks" (pdf)

Newsweek: "The Mechanics of Trauma"

Washington Post: "Study Probes Roots of Fearful Memories"

01.2014