Looking beyond the hippocampus: old and new neurological targets for understanding memory disorders

Although anterograde amnesia can occur after damage in various brain sites, hippocampal dysfunction is usually seen as the ultimate cause of the failure to learn new episodic information. This assumption is supported by anatomical evidence showing direct hippocampal connections with all other sites implicated in causing anterograde amnesia. Likewise, behavioural and clinical evidence would seem to strengthen the established notion of an episodic memory system emanating from the hippocampus. There is, however, growing evidence that key, interconnected sites may also regulate the hippocampus, reflecting a more balanced, integrated network that enables learning. Recent behavioural evidence strongly suggests that medial diencephalic structures have some mnemonic functions independent of the hippocampus, which can then act upon the hippocampus. Anatomical findings now reveal that nucleus reuniens and the retrosplenial cortex provide parallel, disynaptic routes for prefrontal control of hippocampal activity. There is also growing clinical evidence that retrosplenial cortex dysfunctions contribute to both anterograde amnesia and the earliest stages of Alzheimer's disease, revealing the potential significance of this area for clinical studies. This array of findings underlines the importance of redressing the balance and the value of looking beyond the hippocampus when seeking to explain failures in learning new episodic information.