Understanding the roles of slow and fast gamma rhythms in memory processing

描述（由申请人提供）：异常伽马节律见于阿尔茨海默病和精神分裂症，可能与这些疾病中的记忆障碍有关。因此，有必要了解伽马节律在记忆中的作用。不同的快速（~65-100赫兹）和慢速（~25-55赫兹）伽马亚型将不同的输入路径传递到海马体，海马体是大脑中对记忆至关重要的区域。快速伽马将海马体与来自内侧内嗅皮层（MEC）的当前感觉输入连接起来。慢伽马将海马CA1子区与CA3子区偶联，CA1子区是记忆恢复所必需的。尽管如此，慢速伽玛和快速伽玛在记忆处理方面的功能相关性在很大程度上仍然未知。这项工作将验证慢伽马和快伽马在海马体网络中发挥不同功能的假设，快伽马促进记忆编码，慢伽马介导记忆检索。该研究将采用多位点电生理记录局部场电位和单单位活动在自由行为的啮齿动物。特异性目标1将测试海马体“位置细胞”和MEC“网格细胞”在慢速和快速伽马时的编码位置是否不同，如果慢速和快速伽马在功能上是不同的。位置细胞和网格细胞的集合将被记录在沿着线性轨道奔跑的大鼠身上。轨道的一维性质将允许在慢周期和快周期中比较相同的轨迹。贝叶斯解码技术将应用于解码慢速和快速伽马相关轨迹的神经元集合活动。如果快速伽马参与了记忆编码，那么位置和网格细胞应该在快速伽马期间编码最近的位置。如果慢伽马与记忆检索有关，那么位置和网格细胞代码应该在慢伽马期间预测即将到来的位置。具体目标2将测试快速伽马是否会促进空间记忆任务的记忆编码。拟议的研究将确定快速伽马是否与记忆编码有关，以及记忆编码过程中快速伽马的显著下降是否与错误试验有关。此外，Aim 2将测试编码过程中对穿孔通路的快速伽马刺激是否会改善阿尔茨海默病（AD）小鼠模型的记忆。将效果与慢伽马刺激进行比较，以确定快速伽马刺激是否特别有利于记忆编码。特异性目的3将测试慢伽马是否在相同的空间记忆任务中促进记忆检索。这些研究将确定慢伽马是否与记忆提取相关，以及在正确而非错误的试验中，慢伽马是否在记忆提取过程中被选择性地增强。本研究还将测试在记忆提取过程中，慢伽马刺激Schaffer络是否能改善AD小鼠的记忆。将效果与快速伽马刺激进行比较，以确定慢伽马刺激时机是否特别适合于记忆恢复。发现慢伽马和快伽马之间的功能差异有望改变该领域对伽马节律的概念，从而为未来令人兴奋的发现奠定基础。

DESCRIPTION (provided by applicant): Aberrant gamma rhythms are seen in Alzheimer's disease and schizophrenia and may relate to memory impairments in these disorders. It is thus imperative to understand gamma rhythms role in memory. Separate fast (~65-100 Hz) and slow (~25-55 Hz) gamma subtypes differentially route inputs to hippocampus, a brain region critical for memory. Fast gamma links the hippocampus to current sensory inputs from the medial entorhinal cortex (MEC). Slow gamma couples hippocampal subfield CA1 with CA3, a subfield essential for memory retrieval. Still, the functional relevance of slow and fast gamma with regard to memory processing remains largely unknown. The proposed work will test the hypothesis that slow and fast gamma perform distinct functions in the hippocampal network, with fast gamma promoting memory encoding and slow gamma mediating memory retrieval. The studies will employ multisite electrophysiological recordings of local field potentials and single unit activityin freely behaving rodents. Specific Aim 1 will test whether hippocampal 'place cells' and MEC 'grid cells' code locations differently during slow and fast gamma, as expected if slow and fast gamma are functionally distinct. Ensembles of place cells and grid cells will be recorded in rats running on a linear track. The track's one-dimensional nature will allow identical trajectories to be compared for slow and fast gamma periods. Bayesian decoding techniques will be applied to decipher neuronal ensemble activity for slow and fast gamma-associated trajectories. If fast gamma is involved in memory encoding, then place and grid cells should encode recent locations during fast gamma. If slow gamma is involved in memory retrieval, then place and grid cell codes should predict upcoming locations during slow gamma. Specific Aim 2 will test whether fast gamma promotes memory encoding using spatial memory tasks. The proposed studies will determine whether fast gamma correlates with memory encoding and also whether significant decreases in fast gamma during memory encoding are associated with error trials. Furthermore, Aim 2 will test whether fast gamma stimulation of the perforant path during encoding will improve memory in a mouse model of Alzheimer's disease (AD). Effects will be compared to slow gamma stimulation to determine whether fast gamma timing in particular facilitates memory encoding. Specific Aim 3 will test whether slow gamma promotes memory retrieval in the same spatial memory tasks. The studies will determine whether slow gamma correlates with memory retrieval and whether slow gamma is selectively enhanced during memory retrieval in correct, but not error, trials. This Aim will also test whether slow gamma stimulation of the Schaffer collaterals during memory retrieval improves memory in AD mice. Effects will be compared to fast gamma stimulation to determine if slow gamma timing is particularly well suited for memory retrieval. Discovering functional differences between slow and fast gamma is expected to change the field's concept of gamma rhythms and thereby lay the foundation for exciting future discoveries.