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

Abstract

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.

Keywords: amnesia; dementia; mamillary bodies; memory; retrosplenial cortex; thalamus.

Figure 1.

Interconnections between sites implicated in anterograde amnesia. (a) Depiction of the connections (solid lines) that comprise the Papez circuit [25], upon which the Delay and Brion memory circuit [5] was placed, with additional connections from the ‘extended hippocampal system’ [26] shown by dashed lines. (b) A more extensive (though still incomplete) depiction of the direct connections between cores sites implicated in episodic memory. ATN, anterior thalamic nuclei; BF, basal forebrain (including septum and diagonal band); CING, cingulate cortex (including retrosplenial cortex); HPC/SUB, hippocampal formation (including subiculum); LD, laterodorsal thalamic nucleus; MB, mamillary bodies; PARAH, parahippocampal region; PFC, prefrontal cortex; RE, nucleus reuniens of the thalamus; RSC, retrosplenial cortex; TNG, tegmental nucleus of Gudden.