Effects of normal aging on prefrontal area 46 in the rhesus monkey

Abstract

This review is concerned with the effects of normal aging on the structure and function of prefrontal area 46 in the rhesus monkey (Macaca mulatta). Area 46 has complex connections with somatosensory, visual, visuomotor, motor, and limbic systems and a key role in cognition, which frequently declines with age. An important question is what alterations might account for this decline. We are nowhere near having a complete answer, but as will be shown in this review, it is now evident that there is no single underlying cause. There is no significant loss of cortical neurons and although there are a few senile plaques in rhesus monkey cortex, their frequency does not correlate with cognitive decline. However, as discussed in this review, the following do correlate with cognitive decline. Loss of white matter has been proposed to result in some disconnections between parts of the central nervous system and changes in the structure of myelin sheaths reduce conduction velocity and the timing in neuronal circuits. In addition, there are reductions in the inputs to cortical neurons, as shown by regression of dendritic trees, loss of dendritic spines and synapses, and alterations in transmitters and receptors. These factors contribute to alterations in the intrinsic and network physiological properties of cortical neurons. As more details emerge, it is to be hoped that effective interventions to retard cognitive decline can be proposed.

Figure 1

A, Lateral view of the rhesus monkey brain shows the extent of area 46 (small dotted line). Large dashed line is a diagrammatic representation of the upper and lower banks of the principal sulcus. Area 46 is divided into a rostral and a caudal sector (vertical dotted line). The thick vertical line shows the level at which the section shown in B was taken. B. Nissl stained coronal section through the frontal lobe at the level of the rostral end of the corpus callosum (cc). The principal sulcus (ps), which is on the lateral surface of the cortex, contains area 46 that extends over the upper and lower lips of the sulcus. C. Nissl stained section of area 46 in the lower bank of the principal sulcus shows the appearance of the six cellular layers and the underlying white matter (WM).

Figure 2

The principal cortical connections of area 46. A, Lateral view of the rhesus monkey brain shows projections from sensory association areas originating from: visual (red); auditory (yellow); and somatosensory (green) association cortices; Projections are also shown for a visuomotor region in the lateral bank of the intraparietal sulcus (pink). The diagram shows the origin of projections and their termination in area 46, but connections with these cortices are reciprocal. B, Interconnections of area 46 within the prefrontal cortex. C, Medial (top), lateral (center) and ventral (bottom) views of the rhesus monkey brain show projections from limbic (shades of blue) and premotor cortices (brown). Abbreviations: CC, corpus callosum; names of sulci (shown with black letters): A, arcuate; C, central; Cg, cingulate; IP, intraparietal; L, lunate; LF, lateral fissure; P, principal; Rh, rhinal; ST, superior temporal. Silhouette numbers and letters show architectonic areas: Pre-SMA, pre-supplementary motor area; SMA, supplementary motor area. TF, area TF in anterior medial temporal lobe; TH, area TH in posterior medial temporal lobe (parahippocampal cortex).

Figure 3

Electron micrographs show myelinated nerve fibers in area 46. A is from area 46 of a 10 year old monkey and shows that at this age the myelin sheaths around axons are compact. B is from area 46 of a 27 year old monkey, in which many of the myelin sheaths (D) have begun to degenerate and show dense inclusions within their lamellae. Other sheaths (asterisk) are empty because the axon has degenerated. Scale bars equal one micron.

Figure 4

Summary of key age-related changes in area 46. Shown at top is a cartoon demonstrating the significant loss of dendritic spines and myelin dystrophy that occurs in pyramidal cells in area 46 with normal aging. Below this cartoon are representative data showing loss of dendritic spines, reduced frequency of glutamatergic synaptic currents, myelin dystrophy and increased action potential firing rates.