Changes in the structural complexity of the aged brain

Abstract

Structural changes of neurons in the brain during aging are complex and not well understood. Neurons have significant homeostatic control of essential brain functions, including synaptic excitability, gene expression, and metabolic regulation. Any deviations from the norm can have severe consequences as seen in aging and injury. In this review, we present some of the structural adaptations that neurons undergo throughout normal and pathological aging and discuss their effects on electrophysiological properties and cognition. During aging, it is evident that neurons undergo morphological changes such as a reduction in the complexity of dendrite arborization and dendritic length. Spine numbers are also decreased, and because spines are the major sites for excitatory synapses, changes in their numbers could reflect a change in synaptic densities. This idea has been supported by studies that demonstrate a decrease in the overall frequency of spontaneous glutamate receptor-mediated excitatory responses, as well as a decrease in the levels of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and N-methyl-d-aspartate receptor expression. Other properties such as gamma-aminobutyric acid A receptor-mediated inhibitory responses and action potential firing rates are both significantly increased with age. These findings suggest that age-related neuronal dysfunction, which must underlie observed decline in cognitive function, probably involves a host of other subtle changes within the cortex that could include alterations in receptors, loss of dendrites, and spines and myelin dystrophy, as well as the alterations in synaptic transmission. Together these multiple alterations in the brain may constitute the substrate for age-related loss of cognitive function.

Fig. 1. Spine densities on neocortical pyramidal neurons from young and aged rhesus monkeys

Panels A and B show confocal laser scanning images of apical dendritic segments in a young (A) and aged (B) rhesus monkey (scale bar = 8 µm). Note the increased spine density in the young monkey compared to the old monkey. Panels C and D show examples of a retrogradely traced neuron, filled with Lucifer Yellow, and reconstructed in 3-dimensions using NeuroZoom and NeuroGL software applications. The neuron in (C) is from a young animal and the neuron in (D) is from an aged animal. The arrow points to the dendritic segments analyzed in A and B. (Adapted from Duan et al., 2003).

Fig. 2. Decreased frequency of excitatory and increased frequency of inhibitory PSCs in layers 2/3 pyramidal cells from aged monkeys

(A) Representative traces of spontaneous excitatory PSCs obtained from cells from young (left) and aged (right) monkeys. (B) Representative traces of spontaneous inhibitory PSCs obtained from cells from young (left) and aged (right) monkeys. (C) Bar graphs showing the mean spontaneous EPSC frequency and amplitude values for young vs aged pyramidal cells. (D) Bar graphs showing the mean spontaneous EPSC frequency and amplitude values for young vs aged pyramidal cells. A and B Scale bar: 50 pA, 200 ms.

Fig. 3. Scaling regions (gray shaded bands) for a typical young (top panel) and an aged (bottom panel) layer 2/3 pyramidal cell projecting from STC to area 46

Scaling exponents have been fitted as the slopes of log-log plots of accumulated mass (d_M, A,F), cross-sectional area (d_A, B,G) branch numbers (d_N, C,H), and average area of branch intersections (d_T, D,I), with distance from the soma. E,J: Two-dimensional (2D) projection of 3D reconstructed young and aged neurons, in which the basal trees are drawn in anatomical space, whereas the apical trees are drawn in dendrogram space (see Rothnie et al., 2006 for methodological details). Proximal (I), medial (II) scaling regions, and a distal (III) nonscaling or die-off region, are indicated on the dendrogram representation of apical trees.