Control of fear/cognition by MAP kinase signaling

研究特定神经元回路功能的一种方法是通过瞄准控制可塑性的关键调节分子，并观察这些回路内的可塑性与动物模型行为之间的关系。由于MAP激酶是海马体可塑性所必需的，并且在杏仁核中高度表达，我们假设MAP激酶是恐惧和认知行为的重要调节剂。为了研究MAP激酶依赖性突触可塑性的调节是否有助于恐惧和认知行为的控制，我们分析了p42MAP激酶和Rap1基因亚型A和b的前脑限制性敲除小鼠。Rap1已知可以调节p42MAP激酶。这个项目的目标是：

One way to investigate functions of specific neuronal circuits is by targeting key regulatory molecules which control plasticity and looking at relationships between plasticity within these circuits and behavior of an animal model. Since MAP kinase is required for plasticity in the hippocampus and it is highly expressed in the amygdala, we hypothesized that MAP kinase is an important regulator of both fear and cognitive behaviors. To investigate whether modulation of MAP kinase-dependent synaptic plasticity contributes to the control of fear and cognitive behaviors, we are analyzing mice with the forebrain-restricted knockouts of p42 MAP kinase, and Rap1 gene isoforms A and B. Rap1 is known to regulate p42MAP kinase. The goals of this project are: 1) characterization of MAP kinase role in learning and fear behaviors using mice with forebrain-restricted knockout of MAP kinase and Rap1, 2) finding specific neuronal population in the brain where MAP kinase activity alter expression of fear, 3) characterization of MAP kinase-dependent electrophysiological properties of these neurons, 4) identification of the downstream molecular substrates of MAP kinase that mediate changes in the neuronal properties. The following has been accomplished during the last fiscal year: 1) Behavioral analysis of p42 MAP kinase forebrain restricted knockout mice and double forebrain-restricted Rap1A and Rap1B knockout mice revealed impaired learning in both cued and contextual fear conditioning indicating that both Rap1 and p42 MAP kinase are required for synaptic plasticity in the amygdala. 2) Electrophysiological analysis of spike-timing dependent plasticity in the baso-lateral nucleus of the amygdala from Ra1 knockout mice revealed LTP impairment correlated with the increase probability of neurotransmitter release from the cortical input. 3) Behavioral analysis of Rap1 knockouts revealed reduced anxiety, and reduced fear of novelty. These changes may result from increased synaptic transmission between cortex and amygdala as a consequence of an increased neurotransmitter release probability in this synapse.