ASSOCIATIVE LTP OF AREA CA3 IN THE HIPPOCAMPUS IN VIVO

产品说明：（改编自申请人摘要）：本项目的总体目标是评估阿片样物质和NMDA受体在海马CA 3区主要传入系统中诱导联合长时程增强（LTP）的作用。CA 3区接受的传入显示两种形式的LTP诱导：NMDA受体和阿片受体依赖。阿片受体依赖性LTP在内侧穿支通路和CA 3区的连合投射中观察到。我们的初步研究表明，苔藓纤维投射到CA 3区显示联想LTP，但联想苔藓纤维LTP的诱导需要重复的突触活动，这是阿片受体激活所必需的。然而，联合苔藓纤维LTP也被NMDA受体拮抗剂阻断。同样地，当阿片受体受体依赖性LTP的诱导是由阿片受体传入的共激活引起时，在内侧穿通通路-CA 3突触的诱导被阿片受体拮抗剂阻断。我们的主要假设是，阿片和NMDA受体有助于利用这些不同的诱导过程突触之间的关联LTP诱导。具体目标1中的研究将确定阿片和/或NMDA受体拮抗剂是否改变外侧穿通路径-CA 3突触和NMDA受体依赖性内侧穿通路径-CA 3突触的阿片受体依赖性LTP之间的关联LTP诱导，使用每个投射作为弱刺激（相关）或强刺激（条件反射）路径。具体目标2中的研究将确定阿片样物质能传入中的关联LTP是否由于频率依赖性阿片肽释放而具有频率依赖性，以及显示阿片样物质受体依赖性LTP的传入中的关联LTP是否对非阿片样物质能突触处的LTP诱导产生频率依赖性约束。这将通过使用单脉冲关联范例来确定，其中在类阿片受体选择性拮抗剂存在下，一个通路的低频刺激与另一个通路的高频刺激配对。具体目标3中的研究将确定CA 3传入之间的关联相互作用的最佳时间参数是否对应于CA 3传入的正常激活顺序，以及阿片肽是否有助于这种效应。这些数据将有影响的条件下，其中关联信息存储可能会正常发生之间的传入系统的CA 3区。由于每种途径显示不同的要求关联LTP诱导，内源性阿片肽可能会赋予时间和频率依赖性的限制LTP的关联诱导。这表明，传入活动和阿片肽释放的顺序可以调节几乎所有的关联信息存储发生在海马CA 3区的投射。

DESCRIPTION: (Adapted From The Applicant's Abstract): The overall goal of this project is to evaluate the contribution of opioid and NMDA receptors in the induction of associative long term potentiation (LTP) in the major afferent systems of the CA3 region of the hippocampus. The CA3 region receives afferents displaying two forms of LTP induction: NMDA receptor and opioid receptor- dependent. Opioid receptor-dependent LTP is observed in medial perforant path and commissural projections to area CA3. Out initial studies show that mossy fiber projections to area CA3 display associative LTP, but associative mossy fiber LTP induction requires repetitive synaptic activity, which is necessary for the activation of opioid receptors. However, associative mossy fiber LTP also is blocked by NMDA receptor antagonists. Likewise, the induction of NMDA receptor-dependent LTP at medial perforant path-CA3 synapses is blocked by opioid receptor antagonists when it is induced by coactivation of opioidergic afferents. Our primary hypothesis is that both opioid and NMDA receptors contribute to associative LTP induction between synapses utilizing these different induction processes. The studies in specific aim 1 will determine if opioid and/or NMDA receptor antagonists alter associative LTP induction between the opioid receptor-dependent LTP at lateral perforant path-CA3 synapses and NMDA receptor-dependent medial perforant path-CA3 synapses using each projection as either the weakly stimulated (associated) or the strongly stimulated (conditioning) pathway. The studies in specific aim 2 will determine if associative LTP in opioidergic afferents is frequency-dependent by virtue of frequency-dependent opioid peptide release, and if associative LTP in afferents displaying opioid receptor-dependent LTP confer frequency-dependent constraints on LTP induction at non- opioidergic synapses. This will be determined by using a single- pulse associative paradigm, in which low frequency stimulation of one pathway is paired with high-frequency stimulation of another pathway in the presence of oioid receptor selective antagonists. The studies in specific aim 3 will determine if the optimal temporal parameters of associative interaction among CA3 afferents corresponds to the normal sequence of activation by CA3 afferents, and if opioid peptides contribute to this effect. These data will have implication regarding conditions in which associative information storage may normally occur among the afferent systems of the CA3 region. Because each pathway displays distinct requirements for associative LTP inductions, endogenous opioid peptides may confer both temporal and frequency-dependent constraints on the associative induction of LTP. This would suggest that the order of afferent activity and opioid peptide release may regulate virtually all associative information storage occurring among projections to the CA3 region of the hippocampus.