Hypocretin/orexin neurons contribute to hippocampus-dependent social memory and synaptic plasticity in mice.
Hypocretin/orexin neurons contribute to hippocampus-dependent social memory and synaptic plasticity in mice.
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DOI：
10.1523/jneurosci.3200-12.2013
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发表时间：
2013-03-20
期刊：
影响因子：
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通讯作者：
Xie XS
中科院分区：
文献类型：
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作者：
Yang L;Zou B;Xiong X;Pascual C;Xie J;Malik A;Xie J;Sakurai T;Xie XS
下丘脑外侧的下丘脑分泌素/食欲素（Hcrt）神经元投射到整个大脑，包括海马体，Hcrt受体在海马体广泛表达。Hcrt神经元激活这些目标来协调全局唤醒状态、觉醒-睡眠结构、能量稳态、压力适应和奖励行为。Hcrt最近被认为与认知功能和社会互动有关。在这里，我们使用神经行为评估和电生理方法测试了Hcrt神经元对社会互动，特别是社会记忆至关重要的假设。采用经验证的“双围式家庭测试”装置和程序测试社交性、社会新颖性偏好和识别记忆。进行了常规的直接接触社会测试来证实研究结果。我们发现，成年orexin/ataxin-3转基因小鼠（AT，其中Hcrt神经元在3个月大时退化）对野生型（WT）幼崽表现出正常的社交能力和社交新颖性。然而，AT小鼠在长期社会记忆方面表现出缺陷。经鼻给药外源性Hcrt-1在一定程度上恢复了AT小鼠的社会记忆。与WT海马切片相比，AT小鼠海马切片显示CA1区的基础突触神经传递正常，但其配对脉冲促进度（PPF）和长期增强（LTP）的幅度均有所下降。AT海马区磷酸化的环amp反应元件结合蛋白（pCREB）水平较低，pCREB是一种活性依赖的转录因子，对突触可塑性和长期记忆储存很重要。我们的研究表明，Hcrt神经元在社会识别记忆的巩固中发挥重要作用，至少部分是通过增强海马突触可塑性和CREB磷酸化。
Hypocretin/orexin (Hcrt) neurons in the lateral hypothalamus project throughout the brain, including to the hippocampus, where Hcrt receptors are widely expressed. Hcrt neurons activate these targets to orchestrate global arousal state, wake-sleep architecture, energy homeostasis, stress adaptation, and reward behaviors. Hcrt has recently been implicated in cognitive functions and social interaction. Here, we tested the hypothesis that Hcrt neurons are critical to social interaction, particularly social memory, using neurobehavioral assessment and electrophysiological approaches. The validated “two-enclosure homecage test” devices and procedure were used to test sociability, preference for social novelty (social novelty), and recognition memory. A conventional direct contact social test was conducted to corroborate the findings. We found that adult orexin/ataxin-3 transgenic mice (AT, in which Hcrt neurons degenerate by 3 months of age) displayed normal sociability and social novelty with respect to wildtype (WT) littermates. However, AT mice displayed deficits in long-term social memory. Nasal administration of exogenous Hcrt-1 restored social memory to an extent in AT mice. Hippocampal slices taken from AT mice exhibited decreases in degree of paired-pulse facilitation (PPF) and magnitude of long-term potentiation (LTP), despite displaying normal basal synaptic neurotransmission in the CA1 area compared to WT hippocampal slices. AT hippocampi had lower levels of phosphorylated cyclic AMP-response element binding protein (pCREB), an activity-dependent transcription factor important for synaptic plasticity and long-term memory storage. Our studies demonstrate that Hcrt neurons play an important role in the consolidation of social recognition memory, at least in part through enhancements of hippocampal synaptic plasticity and CREB phosphorylation.