In both humans and experimental animals, emotional memory, such as that following learned fear, critically depends on the amygdala complex. Pavlovian fear conditioning results in the formation of a strong association between a neutral conditioned stimulus and an aversive unconditioned stimulus that can trigger stereotypic fear responses. The information from both stimuli converge in the lateral amygdala where association between neutral and aversive stimuli is formed and, possibly, stored. The objective of this proposal is to establish causal relationships between the function of the glutamatergic synapses of the amygdala circuitry and fear conditioning, a model of emotional learning in animals. To accomplish this goal, we propose an electrophysiological study, combined with an objective, state-of-the-art statistical approach, to address several crucial but poorly understood aspects of the synaptic mechanisms of learned fear.
In Aim 1, we will characterize synaptic changes underlying fear conditioning in the projections from the auditory thalamus and from the auditory cortex to the lateral amygdala. We have preliminary data indicating that synaptic changes underlying learned fear, as quantitatively measured with the fear-potentiated startle paradigm, can be directly determined in the slice preparation.
In Aim 2, we will characterize the mechanisms of LTP that are recruited behaviorally in learned fear. Our preliminary studies indicate that learned fear occludes electrically induced LTP in the cortico-amygdala pathway. Here, we propose to study in detail the effects of LTP on synaptic transmission in the auditory inputs to the LA and compare them with the effects of fear-conditioning.
In Aim 3, we will explore the effects of fear conditioning on the basic properties of synaptic transmission and plasticity at the synapses between neurons within the lateral nucleus of the amygdala using dual whole-cell patch clamp recordings. These experiments will enable us to use the amygdala slice preparation as a model system for the study of the mechanisms of synaptic plasticity underlying learning and memory acquisition. A better understanding of the mechanisms of conditioned fear will permit the rational development of better therapeutics treatments for anxiety and other disorders involving the same neural circuitry.
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| Shumyatsky, Gleb P; Malleret, Gael; Shin, Ryong-Moon et al. (2005) stathmin, a gene enriched in the amygdala, controls both learned and innate fear. Cell 123:697-709 |
| Gisabella, Barbara; Bolshakov, Vadim Y; Benes, Francine M (2005) Regulation of synaptic plasticity in a schizophrenia model. Proc Natl Acad Sci U S A 102:13301-6 |
| Dityatev, Alexander E; Bolshakov, Vadim Y (2005) Amygdala, long-term potentiation, and fear conditioning. Neuroscientist 11:75-88 |
| Tsvetkov, Evgeny; Shin, Ryong Moon; Bolshakov, Vadim Y (2004) Glutamate uptake determines pathway specificity of long-term potentiation in the neural circuitry of fear conditioning. Neuron 41:139-51 |
| Hinds, Heather L; Goussakov, Ivan; Nakazawa, Kazu et al. (2003) Essential function of alpha-calcium/calmodulin-dependent protein kinase II in neurotransmitter release at a glutamatergic central synapse. Proc Natl Acad Sci U S A 100:4275-80 |
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