Abstract: Working memory, as a core component of higher-order cognitive functions, its neural basis involves the dynamic coordination mechanisms among distributed neural networks. Although the functions of the prefrontal cortex (PFC) and hippocampus in working memory have been intensively investigated, the neural mechanisms underlying cross-brain region information integration, especially the role of key sub-cortical structures in this process, still await systematic elucidation. This review aims to address a crucial scientific question: As a key hub between the PFC and hippocampus, how does the medial septal nucleus (MS) regulate working memory through the theta-gamma phase-amplitude coupling mechanism and thus mediate the information transmission process in the PFC-hippocampal-MS three-node circuit? Based on this, we propose and elaborate on an innovative “three-node coordination model”. This model systematically integrates the MS into the classical PFC-hippocampus working memory framework for the first time and identifies theta-gamma phase-amplitude coupling as the core electrophysiological mechanism for achieving cross-brain region coordination.
By integrating evidence from neuroanatomical and functional studies, this research has established that the MS is not merely a simple information relay station but an active regulatory hub within the working memory circuit. In terms of neural connectivity architecture, the MS has direct synaptic connections with both the PFC and hippocampus. This unique neural connectivity enables the MS with an irreplaceable role in coordinating the activities of the PFC and hippocampus. At the functional mechanism level, GABAergic neurons in the MS exhibit distinct theta-frequency burst firing characteristics and are considered the pacemaker source of the hippocampal theta rhythm. Applying “theta rhythm stimulation” to the MS using optogenetic techniques can effectively enhance the power of hippocampal theta oscillations and significantly improve the behavioral performance of spatial working memory. These causal findings comprehensively demonstrate the indispensability of the MS in working memory information processing.
Theta-gamma phase-amplitude coupling serves as the fundamental neural coding mechanism for information integration in the three-node circuit. Specifically, theta oscillations provide a global temporal reference framework for cross-brain region information transmission, while gamma oscillations act as local information representation units nested within specific theta phases. There is a complex bidirectional theta-gamma phase-amplitude regulatory process between the PFC and hippocampal circuits. During the information encoding stage of working memory, the hippocampus transmits environmental information to the PFC. During the working memory decision-making stage, the PFC exerts top-down executive control over the hippocampus. Both of these processes are mediated by theta-gamma coupling. The MS profoundly influences the strength and spatio-temporal characteristics of hippocampal theta-gamma coupling by regulating the hippocampal theta rhythm. Meanwhile, the feedback loop of somatostatin-positive interneurons in the hippocampus enables dynamic fine-tuning to prevent excessive network synchronization. This multi-level regulatory mechanism solidifies the central position of the MS in neural information integration. Moreover, abnormal theta-gamma coupling in the PFC-hippocampal-MS circuit is closely associated with cognitive deficits in various neuropsychiatric disorders.
In summary, this study has established the critical regulatory role of the MS during the maintenance phase of working memory, clarified its mechanism of controlling the hippocampal theta rhythm via the GABAergic pathway; revealed the neural pathway through which the MS, as a theta oscillation regulatory hub, influences local hippocampal activity and thereby regulates overall working memory efficiency; and constructed a “PFC-hippocampal-MS three-node circuit model”, which for the first time systematically incorporates the MS into the working memory theoretical framework. Future research should combine multimodal neuroimaging, cell-specific regulation, and computational modeling approaches to delve deeper into the functional connectivity between the PFC and MS and the dynamic characteristics of theta-gamma coupling, providing a theoretical foundation for promoting intervention strategies for cognitive impairments based on neural oscillations.

Key words: working memory, θ-γ, phase amplitude coupling, cross-frequency coupling, prefrontal cortex, hippocampus, medial Septal neural