A crucial step in outlining the role of genetic influences on memory is to understand the functional neuroanatomy of the memory system. Neural systems supporting declarative memory involve a set of interconnected neural networks linking neocortex, parahippocampal regions (including both perirhinal cortex and more posterior parahippocampal cortex), and the hippocampus (see ). Lesions to this region result in global amnesia characterized by an inability to form new memories and a temporally graded loss of previously acquired memories. The predominant contemporary view of the functioning of this system highlights the role of more ventral regions of neocortex, and closely-connected perirhinal cortical regions that they project to, in the immediate representation of stimulus features and maintenance of those representations over brief delays (Eichenbaum, 2000
; Ranganath, 2010
; Wang and Morris, 2010
). More dorsal regions of neocortex, and closely-connected parahippocampal cortex, participate in the representation and maintenance of stimulus context. Both of these constituents of the greater parahippocampal region cooperate to help representation persist, buffering them against interference, and providing a venue for an initial phase of feature binding across information modalities and brief time intervals. The hippocampus in turn provides an additional degree of association-building, linking representations across longer spans of time, binding items into the context of a particular learning episode (Ranganath, 2010
), and allowing generalization (and inference) between related learning episodes (Eichenbaum, 2000
). Critically, once these assemblies of neocortical representations and their relationships are encoded, reactivation of any part of the assembly triggers activation of the entire, bound set of representations, allowing for retrieval of complex memories based on only partial cues (Wheeler and Buckner, 2004
). The role of the neocortex is not restricted to sensory regions subserving stimulus feature representation, however. Heteromodal regions such as prefrontal and parietal cortices also contribute to the conscious, effortful organization of information to be encoded, as well as to conscious recollection of learned information (while suppressing irrelevant information) and judgments based on the retrieved information (Ranganath, 2010
Figure 2 Information from multiple cortical association areas converge on areas that surround the hippocampus, namely, entorhinal, perirhinal and parahippocampal regions. These regions are interconnected and project to the hippocampus itself. Efferents from the (more ...)
Positioned at the highest level of this associative hierarchy, the hippocampus displays a heterogeneous organization that facilitates its role in declarative memory functioning. Information generally flows from perirhinal and parahippocampal cortices, as noted above, to entorhinal cortex, which projects axons into the dentate gyrus, entering the hippocampus proper (see ). The dentate, in turn, projects excitatory links to area CA3, which excites area CA1. CA1 then sends inputs to deeper, out-going lamina of the entorhinal cortex, via the subiculum (Amaral and Lavenex, 2006
). Both intrinsic and extrinsic inhibitory connections innervate all levels of this system. Wang and colleagues (Wang and Morris, 2010
) have proposed that the projections into CA1 provide information establishing spatial context for stimuli to be remembered, while separate inputs into CA3, and then into CA1, are critical for indexing the stimuli themselves. Building of associations within CA1 is therefore fundamental for binding together objects and context information into the complex representation of a learning episode (Wang and Morris, 2010
Schematic illustration of the main structures within and surrounding the hippocampus, as seen from a coronal slice through its anterior part.
In light of this highly associative nature of the process by which declarative memories are constructed and reconstructed, the creation, stabilization/consolidation, modulation, and reactivation of these associations is critical. Each of these phases, and each component of the circuitry they rely on, represents a point of vulnerability. Disruption of any of these components could result in a memory deficit, and a fine-tuned cognitive dissection of the deficit is needed to determine precisely which aspects of the process are impaired. As discussed in relation to memory deficits associated with neuropsychiatric disease, below, genetic influences on any one of these processes could all result in a final common pathway of poor performance on a memory task, albeit through distinct mechanisms.