Histamine Enhances Theta-Coupled Spiking and Gamma Oscillations in the Medial Entorhinal Cortex Consistent With Successful Spatial Recognition

Encoding of spatial information in the superficial layers of the medial entorhinal cortex (sMEC) involves theta-modulated spiking and gamma oscillations, as well as spatially tuned grid cells and border cells. Little is known about the role of the arousal-promoting histaminergic system in the modification of information encoded in the sMEC in vivo, and how such histamine-regulated information correlates with behavioral functions. Here, we show that histamine upregulates the neural excitability of a significant proportion of neurons (16.32%, 39.18%, and 52.94% at 30 mu M, 300 mu M, and 3 mM, respectively) and increases local theta (4-12 Hz) and gamma power (low: 25-48 Hz; high: 60-120 Hz) in the sMEC, through activation of histamine receptor types 1 and 3. During spatial exploration, the strength of theta-modulated firing of putative principal neurons and high gamma oscillations is enhanced about 2-fold by histamine. The histamine-mediated increase of theta phase-locking of spikes and high gamma power is consistent with successful spatial recognition. These results, for the first time, reveal possible mechanisms involving the arousal-promoting histaminergic system in the modulation of spatial cognition.

内侧内嗅皮层（sMEC）浅层的空间信息编码涉及θ调制的放电和γ振荡，以及具有空间调谐特性的网格细胞和边界细胞。关于促觉醒的组胺能系统在体内sMEC所编码信息的修饰中所起的作用，以及这种受组胺调节的信息如何与行为功能相关，人们知之甚少。在此，我们发现组胺通过激活1型和3型组胺受体，上调了相当比例神经元的神经兴奋性（在30μM、300μM和3mM时分别为16.32%、39.18%和52.94%），并增加了sMEC中的局部θ（4 - 12Hz）和γ功率（低频：25 - 48Hz；高频：60 - 120Hz）。在空间探索过程中，组胺使假定的主神经元的θ调制放电强度和高γ振荡增强了约2倍。组胺介导的放电的θ相位锁定和高γ功率的增加与成功的空间识别是一致的。这些结果首次揭示了促觉醒的组胺能系统在空间认知调节中可能涉及的机制。