Neurocognitive aging: prior memories hinder new hippocampal encoding

Abstract

Normal aging is often accompanied by impairments in forming new memories, and studies of aging rodents have revealed structural and functional changes to the hippocampus that might point to the mechanisms behind such memory loss. In this article, we synthesize recent neurobiological and neurophysiological findings into a model of the information-processing circuit of the aging hippocampus. The key point of the model is that small concurrent changes during aging strengthen the auto-associative network of the CA3 subregion at the cost of processing new information coming in from the entorhinal cortex. As a result of such reorganization in aged memory-impaired individuals, information that is already stored would become the dominant pattern of the hippocampus to the detriment of the ability to encode new information.

Figure 1

A neurobiological model of the aged hippocampus. Thick arrows represent the classic trisynaptic pathway, including the CA1 outputs to the entorhinal cortex (EC) via the subiculum (Sub). See main text for further description of this pathway. Age-related deteriorations in functional connectivity dealt with in this article are denoted by red broken lines, whereas connections depicted with green arrows remain intact (or have not yet been tested). With aging, the EC provides less input to the dentate gyrus (DG) and CA3, the medial septum (MS) provides less ACh-mediated modulation, interneuron (int) activity is decreased, the ventral tegmental area (VTA) provides less dopamine-mediated (DA) modulation, and the DG and CA1 are less excitable (depicted with red broken boxes). These changes might increase the activity of CA3 recurrent collaterals (auto-associative fibers, thickest arrow).

Figure 2

Examples of young and aged CA3 place fields. (a) Experimental setup, in which rats explore a familiar cylindrical open-field environment and a novel square open-field environment, and then are re-exposed to the familiar environment. (b,c) The recording sites, the place fields, the tetrode waveforms and the firing-rate scale in spikes per second are shown for two cells recorded simultaneously in CA3 of a young rat (b) and in CA3 of an aged rat (c). Each row represents the activity of one cell over the entire experiment shown in the firing-rate maps. Note that young CA3 cells created new spatial representations and often some were active in only one environment (e.g. (b) cell 1). By contrast, the aged CA3 cells used similar place-field representations for both environments and scarcely changed their abnormally high firing rates. Adapted, with permission, from Ref. [82].

Figure 3

Model of CA1 and CA3 transformations of input. Age-related changes are denoted by red dashed lines. The CA1 subregion responds in a linear manner to changes in input. In response to two inputs, CA1 processing of both young and aged individuals generates two outputs whose difference is equal to the difference between the two inputs. The CA3 region responds in a non-linear manner to changes in input. In response to two inputs, CA3 processing of aged individuals generates two outputs whose difference is relatively smaller than that generated by CA3 processing of young individuals. Thus, the CA3 of aged individuals performs excessive pattern completion. In this model, the linear responses of aged CA1, with its greater independence from CA3 (see main text), are not affected by the CA3 deficiencies. Adapted, with permission, from Ref. [28].