GABAergic modulation of hippocampal population activity: Sequence learning, place field development, and the phase precession effect
GABAergic modulation of hippocampal population activity: Sequence learning, place field development, and the phase precession effect
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DOI：
10.1152/jn.1997.78.1.393
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发表时间：
1997-07-01
影响因子：
2.5
通讯作者：
Hasselmo, ME
中科院分区：
文献类型：
--
作者：
Wallenstein, GV;Hasselmo, ME
建立海马CA3区详细的生物物理模型，研究gaba能调节对位置场发育和序列信息学习记忆的影响。模拟包括1000个多室锥体细胞，每个细胞由7个固有电流和4个突触电流组成，以及200个多室中间神经元，由2个固有电流和4个突触电流组成。锥体细胞顶端树突的兴奋性节律性间隔输入和中间神经元在θ频率上的兴奋性和抑制性输入为群体活动中θ和γ频率振荡的发展提供了细胞基础。θ振荡的基本频率是由中隔的驱动节奏决定的。然而，伽马振荡频率是由γ -氨基丁酸-A （GABA）受体介导的突触电流的衰减时间和α -氨基-3-羟基-5-甲基-4-异恶唑本体酸和n -甲基- d-天冬氨酸（NMDA）受体控制的通道激活引起的中间神经元兴奋性的总体水平决定的。在θ波种群活动期间，gabab受体介导的总电导水平随着主要种群频率（θ波节律）有节奏地逐渐上升和下降。这导致周期性GABA(B)受体介导的锥体细胞循环侧支（固有纤维）兴奋性突触传递的抑制，以及锥体细胞和中间神经元的抑制性突触传递的抑制。为了测试该模型学习和回忆时间序列信息的能力，采用了补全任务。在学习过程中，向网络提供一系列非正交的空间模式。每个输入模式代表了模拟老鼠在特定导航路径上的空间“位置”。hebbian型学习表现为突触后nmda受体介导的传导增加。由于模型中锥体细胞之间的稀疏、不对称的兴奋性突触连接以及与输入模式无关的足够程度的随机“背景”放电等因素，重复的模拟运行导致位置场的逐渐出现，其中给定的细胞开始对路径上连续的位置片段做出反应。在回忆过程中，模拟大鼠被放置在先前学习过的路径上的一个随机位置，并测试是否可以在这个初始位置的基础上完成位置序列。GABA(B)受体介导的兴奋性和抑制性传递在固有纤维而非传入纤维中的周期性抑制，导致在每个θ波周期的早期，GABA(B)受体相关作用最高的时候，关于位置的感觉信息占主导地位。这种抑制随着伽马氨基丁酸(B)受体在θ波周期结束时的激活水平而下降，导致内在纤维突触传递增加，随后回忆起整个位置序列的一部分。这种情况通常会持续多个θ循环，直到整个序列被回忆起来。当GABA(B)受体介导的内在纤维兴奋性和抑制性传递的抑制不包括在模型中时，位置场的发展受到限制，因此网络表现出较差的学习和回忆性能。这在一定程度上是由于在每个θ波周期的早期，来自内在和传入纤维的信息竞争增加了。由于传入感觉信息在每个周期的早期并不占主导地位，因此大鼠的当前位置被来自内在源的持续活动所掩盖。此外，即使准确地识别了当前位置，传入源和内在源之间的竞争也会导致一次快速回忆几个位置的趋势，这往往会导致序列的不准确。因此，大鼠经常回忆起与所学到的特定路径不同的路径。GABA(B)受体介导的兴奋性突触传递在θ波周期内的调节导致单单位活动与锥体细胞群体行为（θ波节律）的峰值之间的系统关系。因为内禀纤维的突触前抑制在每个θ波周期的早期部分是最强的，所以单单元放电通常在周期的后期，随着相关细胞的位置场的接近而开始。当位置场被穿越时，这种放电通常会在θ波周期中逐渐推进到更早的阶段。因此，当大鼠在完成试验中沿着学习轨迹移动连续的位置时，位置细胞的放电逐渐从θ循环的后期阶段（未来位置被“预测”（内在信息主导））转变为周期的早期阶段（当前位置被“感知”（传入源主导））。这一结果表明，gaba能对时间序列学习的调节可以作为理解相位进动效应等导航现象的一般框架。
A detailed biophysical model of hippocampal region CA3 was constructed to study how GABAergic modulation influences place field development and the learning and recall of sequence information. Simulations included 1,000 multicompartmental pyramidal cells, each consisting of seven intrinsic and four synaptic currents, and 200 multicompartmental interneurons, consisting of two intrinsic and four synaptic currents. Excitatory rhythmic septal input to the apical dendrites of pyramidal cells and both excitatory and inhibitory input to interneurons at theta frequencies provided a cellular basis for the development of theta and gamma frequency oscillations in population activity. The fundamental frequency of theta oscillations was dictated by the driving rhythm from the septum. Gamma oscillation frequency, however, was determined by both the decay time of the gamma-aminobutyric acid-A (GABA(A))-receptor-mediated synaptic current and the overall level of excitability in interneurons due to alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid and N-methyl-D-aspartate (NMDA)-receptor-gated channel activation. During theta population activity, total GABAB-receptor-mediated conductance levels were found to gradually rise and fall in rhythmic fashion with the predominant population frequency (theta rhythm). This resulted in periodic GABA(B)-receptor-mediated suppression of excitatory synaptic transmission at recurrent collaterals (intrinsic fibers) of pyramidal cells and suppression of inhibitory synaptic transmission to both pyramidal cells and interneurons. To test the ability of the model to learn and recall temporal sequence information, a completion task was employed. During learning, the network was presented a sequence of nonorthogonal spatial patterns. Each input pattern represented a spatial ''location'' of a simulated rat running a specific navigational path. Hebbian-type learning was expressed as an increase in postsynaptic NMDA-receptor-mediated conductances. Because of several factors including the sparse, asymmetric excitatory synaptic connections among pyramidal cells in the model and a sufficient degree of random ''background'' firing unrelated to the input patterns, repeated simulated runs resulted in the gradual emergence of place fields where a given cell began to respond to a contiguous segment of locations on the path. During recall, the simulated rat was placed at a random location on the previously learned path and tested to see whether the sequence of locations could be completed on the basis of this initial position. Periodic GABA(B)-receptor-mediated suppression of excitatory and inhibitory transmission at intrinsic but not afferent fibers resulted in sensory information about location being dominant during early portions of each theta cycle when GABA(B)-receptor-related effects were highest. This suppression declined with levels of GABA(B) receptor activation toward the end of a theta cycle, resulting in an increase in synaptic transmission at intrinsic fibers and the subsequent recall of a segment of the entire location sequence. This scenario typically continued across theta cycles until the full sequence was recalled. When the GABA(B)-receptor-mediated suppression of excitatory and inhibitory transmission at intrinsic fibers was not included in the model, place field development was curtailed and the network consequently exhibited poor learning and recall performance. This was, in part, due to increased competition of information from intrinsic and afferent fibers during early portions of each theta cycle.Because afferent sensory information did not dominate early in each cycle, the current location of the rat was obscured by ongoing activity from intrinsic sources. Furthermore, even when the current location was accurately identified, competition between afferent and intrinsic sources resulted in a tendency for rapid recall of several locations at once, which often lead to inaccuracies in the sequence. Thus the rat often recalled a path different from the particular one that was learned. GABA(B)-receptor-mediated modulation of excitatory synaptic transmission within a theta cycle resulted in a systematic relationship between single-unit activity and peaks in pyramidal cell population behavior (theta rhythm). Because presynaptic inhibition of intrinsic fibers was strongest at early portions of each theta cycle, single-unit firing usually started late in a cycle as the place field of the associated cell was approached. This firing typically advanced to progressively earlier phases in a theta cycle as the place field was traversed. Thus, as the rat moved through successive locations along a learned trajectory during completion trials, place cell firing gradually shifted from late phases of a theta cycle, where future locations were ''predicted'' (intrinsic information dominated), to early phases of a cycle, where the current location was ''perceived'' (afferent sources dominated). This result suggests that the GABAergic modulation of temporal sequence learning may serve as a general framework for understanding navigational phenomena such as the phase precession effect.