During normal ageing humans and other animals experience cognitive decline even in the absence of disease. This review focuses on age-related changes in the neurobiology of the hippocampus and the prefrontal cortex (PFC) and how altered synaptic connectivity and plasticity, Ca2+ homeostasis, gene expression and network firing properties contribute to the selective behavioural deficits observed in advanced age.
Historically, it was believed that the neurobiology of normal ageing was marked by massive cell loss and deterioration of dendritic arborization. However, the application of stereological principles to cell counting methods led to the conclusion that significant cell loss does not occur during normal ageing and that changes in dendritic complexity are subtle and region-specific.
Most biophysical properties of neurons remain the same during ageing. In the hippocampus and the PFC there are no differences between old and young neurons in resting membrane potential, membrane time constant, threshold to elicit an action potential, and rise time and duration of an action potential. In both regions, however, there is a significant increase in Ca2+ conductance, which probably contributes to age-related changes in plasticity (long-term potentiation (LTP) and long-term depression (LTD)).
The maintenance of long-term memory and plasticity (for example, LTP) requires gene expression; therefore, it is not surprising that aged animals also show alterations in these processes. Notably, the immediate-early gene Arc, which is known to be involved in plasticity, shows differences in expression patterns between young and old rats.
Age-associated changes in the dynamics of neuronal ensembles contribute to cognitive impairment. In particular, electrophysiological recordings from many neurons simultaneously in the hippocampus of young and old rats have revealed age differences in the dynamics of 'place cells' that correlate with spatial memory deficits.
The hippocampus and the PFC are particularly vulnerable to the impact of ageing, so it is not surprising that behaviours relying on these brain regions decline with age. In many species, there is a decline in associative learning and spatial memory, both of which require the hippocampus. In addition, aged animals show working memory and executive function deficits, which depend on the PFC.
Although considerable advances have been made in our understanding of the neurobiology of normal ageing, much remains to be learned. Given that the average lifespan is increasing worldwide, understanding the brain mechanisms that are responsible for age-related cognitive decline becomes increasingly important.
The mechanisms involved in plasticity in the nervous system are thought to support cognition, and some of these processes are affected during normal ageing. Notably, cognitive functions that rely on the medial temporal lobe and prefrontal cortex, such as learning, memory and executive function, show considerable age-related decline. It is therefore not surprising that several neural mechanisms in these brain areas also seem to be particularly vulnerable during the ageing process. In this review, we discuss major advances in our understanding of age-related changes in the medial temporal lobe and prefrontal cortex and how these changes in functional plasticity contribute to behavioural impairments in the absence of significant pathology.
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We would like to thank G. Rao for help with carboxyfluorescein images, M. R. Penner and M. K. Chawla for c-fos data, and A. P. Maurer and Z. Navratilova for critical reading of this manuscript. The authors' work was supported by a grant from the National Institute on Aging (NIA).
The authors declare no competing financial interests.
- Stereological principles
A set of rules that allows objective counting of the number of objects in a three-dimensional structure independent of the size of the objects. Among these is the dissector principle, which ensures that objects are sampled with a probability that is proportional to their number and not their size.
- Long-term potentiation
The physiological mechanism for selectively increasing synaptic weight distributions to develop the associations between neurons that are necessary for learning and memory.
- Long-term depression
A mechanism for selectively decreasing synaptic weights so that new associations can be stored in the network without reaching saturation.
- Immediate-early gene
(IEG). Any gene whose expression does not require the activation of any other responsive genes or de novo protein synthesis.
- Reverse northern strategy
A technique in which levels of tissue mRNA are assessed by monitoring the intensity of the hybridization signal of radiolabelled cDNA prepared from tissue RNA to Southern blots containing cloned cDNAs of multiple candidate genes. The hybridization signal for each gene is indicative of the tissue mRNA level.
- Morris swim task
The most widely used test of spatial learning and memory in rats. In this task, rats are placed into a tank of cloudy water. To escape from the water the rats need to find the location of a platform hidden just below the surface. The platform is always in the same location relative to the room and the distal cues.
- Pattern completion
The ability of a network to retrieve an entire stored pattern when only a fragment of the pattern is presented.
- Pattern separation
The ability of a network to make the stored representations of similar input patterns more dissimilar.
- Delayed non-matching-to-sample task
(DNMS task). A sample stimulus is presented to the subject. After a delay, the sample is presented again, along with a new stimulus. The subject is rewarded for selecting the new stimulus.
- Perirhinal cortex
High level association cortex in the medial temporal lobe that receives highly processed polymodal information from the entire cortical mantel and sends direct projections to the entorhinal cortex and hippocampus as well as back-projections to the cortex.
- Wisconsin card sorting task
(WCST). Participants are required to sort response cards of different dimensions (shape, colour and number) by a particular category, which is determined by an experimenter-defined rule. Card sorting principles must be inferred. Once the sorting rule is discovered and a determined number of correct responses are made, the experimenter changes the rule and the subject must then infer the new rule.
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