Gating of hippocampal activity, plasticity, and memory by entorhinal cortex long-range inhibition.
Gating of hippocampal activity, plasticity, and memory by entorhinal cortex long-range inhibition.
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DOI：
10.1126/science.aaa5694
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发表时间：
2016-01-08
期刊：
影响因子：
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通讯作者：
Siegelbaum SA
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文献类型：
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作者：
Basu J;Zaremba JD;Cheung SK;Hitti FL;Zemelman BV;Losonczy A;Siegelbaum SA
大脑皮层-海马区是储存联想记忆的关键区域。大多数研究都集中在从内嗅皮层到海马区的兴奋性投射在记忆存储中的作用。然而，内嗅觉皮质也发送抑制性投射，其在记忆存储和皮质-海马区活动中的作用在很大程度上仍未被探索。我们发现，这些长程抑制性投射增强了背景记忆和对象记忆编码的特异性。在电路水平上，GABA能投射作为一个去抑制门，通过抑制前馈抑制而瞬时促进海马CA1区锥体神经元的兴奋。这增强了CA1神经元激发突触诱发的树突棘波的能力，并产生了一种时间上精确的异突触可塑性。因此，来自内嗅皮层的长距离抑制可能会通过评估助记信息对即时感觉输入的显著程度来提高基于海马体的长期记忆联系的精确度。来自外侧内嗅皮层的远程GABA能输入提供了一个精确定时的去抑制门，以触发树突棘波，诱导长期的异突触可塑性，并指定上下文和对象记忆联系。背景线索与行为体验的精确关联使动物能够区分突出的(有害的或有益的)环境和中性环境。在学习过程中，哪些信号机制有助于选择特定的背景信号作为长期记忆来存储？海马CA1区锥体神经元整合了来自内嗅皮层(EC)的直接多感觉兴奋性输入和来自海马CA3区上游的间接助记性兴奋性输入，这两条通路都与记忆储存有关。直接和间接输入以与皮质-海马回路的动力学相匹配的精确时间间隔成对激活，可以诱导CA1神经元通过其CA3输入(输入-时间依赖可塑性或ITDP)的激活的长期增强。然而，EC还向CA1发送长程抑制投影(LRIP)，其功能在很大程度上尚不清楚。在这里，我们探索LRIP在调节海马突触活动和记忆中的作用。最近发现内侧内嗅皮层(MEC)的GABA能神经元向海马区发送LRIP，在CA1 GABA能中间神经元上形成相对较弱和稀疏的突触。由于外侧内脑皮层(LEC)向海马区传递重要的上下文和对象相关信息，我们研究了该区域是否也向CA1发送LRIP。我们选择性地在LEC抑制神经元中表达通道视紫红质(ChR2)，并检测LRIP光刺激对突触的影响。LRIP的行为影响是通过在情境恐惧条件反射(CFC)和新对象识别(NOR)任务期间选择性地沉默CA1中的这些输入来确定的。我们还使用体内钙离子成像来评估不同的感觉和行为刺激是如何激活LEC LRIP的。最后，我们研究了LRIP如何影响大脑皮层-海马区的信息流，并对ITDP作出贡献。来自LEC的LRIP在EC输入区的大部分CA1中间神经元上产生强烈的抑制性突触后电位。虽然通过药物遗传学沉默海马体中的LRIP并没有阻止CFC或NOR记忆，但它导致小鼠对中性环境表现出不适当的恐惧反应，并降低了区分新对象和熟悉对象的能力。钙成像显示LRIP轴突和突触前终末对各种感觉刺激有反应。此外，将这些信号与食欲或厌恶刺激配对会增加LRIP的活性，这与LRIP在记忆特异性中的作用是一致的。细胞内记录显示，LRIP能有效抑制一类表达CCK+INS的中间神经元的活动。这些中间神经元通常受到CA3传入的强烈兴奋，导致对CA1锥体神经元树突的明显前馈抑制(FFI)。通过在15-20ms的时间窗口内瞬时最大限度地抑制INS，LRIPs增强了在该时间间隔内到达的CA1锥体神经元上的CA3输入。这种去抑制使EC-SC输入(相隔15-20ms)能够在时间上精确地成对激活，从而触发CA1PNS远端树突的树突尖峰，并诱导ITDP。来自EC的LRIP作为一个强大的、在时间上精确的海马内信息流的去抑制门，当皮质和海马的输入以精确的20ms间隔到达CA1 PNS时，使可塑性的诱导成为可能。我们认为，LRIP通过评估CA3传递的助记信息对直接兴奋性EC输入传达的即时感觉背景的显著程度，增加了基于海马体的长期记忆的特异性。
The cortico-hippocampal circuit is critical for storage of associational memories. Most studies have focused on the role in memory storage of the excitatory projections from entorhinal cortex to hippocampus. However, entorhinal cortex also sends inhibitory projections, whose role in memory storage and cortico-hippocampal activity remains largely unexplored. We found that these long-range inhibitory projections enhance the specificity of contextual and object memory encoding. At the circuit level, the GABAergic projections act as a disinhibitory gate that transiently promotes the excitation of hippocampal CA1 pyramidal neurons by suppressing feedforward inhibition. This enhances the ability of CA1 neurons to fire synaptically-evoked dendritic spikes and generate a temporally precise form of heterosynaptic plasticity. Long-range inhibition from entorhinal cortex may thus increase the precision of hippocampal-based longterm memory associations by assessing the salience of mnemonic information to the immediate sensory input. Long-range GABAergic input from lateral entorhinal cortex provides a precisely timed disinhibitory gate to trigger dendritic spikes, induce long-term heterosynaptic plasticity and specify contextual and object memory associations. The precise association of contextual cues with a behavioral experience enables an animal to discriminate between salient (harmful or rewarding) versus neutral environments. What signaling mechanisms during learning help select specific contextual signals to be stored as long-term memories? Hippocampal CA1 pyramidal neurons integrate direct multisensory excitatory input from entorhinal cortex (EC) with indirect, mnemonic excitatory input from the upstream hippocampal CA3 area, and both pathways have been implicated in memory storage. Paired activation of the direct and indirect inputs at a precise timing interval that matches the dynamics of the cortico-hippocampal circuit induces a long-term enhancement of the activation of CA1 neurons by their CA3 inputs (input-timing-dependent plasticity or ITDP). However, EC additionally sends long-range inhibitory projections (LRIPs) to CA1 whose function is largely unknown. Here we explore the role of the LRIPs in regulating hippocampal synaptic activity and memory. GABAergic neurons in medial entorhinal cortex (MEC) were recently found to send to hippocampus LRIPs that form relatively weak and sparse synapses on CA1 GABAergic interneurons. As lateral entorhinal cortex (LEC) conveys important contextual and object-related information to hippocampus, we examined whether this region also sends LRIPs to CA1. We expressed channelrhodopsin (ChR2) selectively in LEC inhibitory neurons and examined the synaptic effects of LRIP photostimulation.. The behavioral impact of the LRIPs was determined by selectively silencing these inputs locally in CA1 during contextual fear conditioning (CFC) and novel object recognition (NOR) tasks. We also used in vivo Ca2+ imaging to assess how different sensory and behavioral stimuli that typically comprise a contextual experience activate the LEC LRIPs. Finally, we examined how the LRIPs influence information flow through the cortico-hippocampal circuit and contribute to ITDP. LRIPs from LEC produced strong inhibitory postsynaptic potentials in a large fraction of CA1 interneurons located in the region of the EC inputs. Although pharmacogenetic silencing of LRIPs in hippocampus did not prevent CFC or NOR memory, it caused mice to show an inappropriate fear response to a neutral context and a diminished ability to distinguish a novel object from a familiar object. Calcium imaging revealed that the LRIP axons and presynaptic terminals responded to various sensory stimuli. Moreover, pairing such signals with appetitive or aversive stimuli increased LRIP activity, consistent with a role of the LRIPs in memory specificity. Intracellular recordings demonstrated that the LRIPs powerfully suppressed the activity of a sub-class of cholecystokinin-expressing interneurons (CCK+ INs). These interneurons were normally strongly excited by the CA3 inputs, resulting in pronounced feedforward inhibition (FFI) of CA1 pyramidal neuron dendrites. By transiently and maximally suppressing the INs in a 15–20 ms temporal window, the LRIPs enhanced CA3 inputs onto CA1 pyramidal neurons that arrived within that timing interval. This disinhibition enabled temporally precise, paired activation of EC-SC inputs (15–20 ms apart) to trigger dendritic spikes in the distal dendrites of CA1 PNs and induce ITDP. LRIPs from EC act as a powerful, temporally precise disinhibitory gate of intra-hippocampal information flow and enable the induction of plasticity when cortical and hippocampal inputs arrive onto CA1 PNs at a precise 20 ms interval. We propose that the LRIPs increase the specificity of hippocampal-based long-term memory by assessing the salience of mnemonic information relayed by CA3 to the immediate sensory context conveyed by direct excitatory EC inputs.