The Locus Coeruleus: Essential for Maintaining Cognitive Function and the Aging Brain

Abstract

Research on cognitive aging has focused on how decline in various cortical and hippocampal regions influence cognition. However, brainstem regions play essential modulatory roles, and new evidence suggests that, among these, the integrity of the locus coeruleus (LC)-norepinephrine (NE) system plays a key role in determining late-life cognitive abilities. The LC is especially vulnerable to toxins and infection and is often the first place Alzheimer's-related pathology appears, with most people showing at least some tau pathology by their mid-20s. On the other hand, NE released from the LC during arousing, mentally challenging, or novel situations helps to protect neurons from damage, which may help to explain how education and engaging careers prevent cognitive decline in later years.

Figure 1

Images of the locus coeruleus (LC). A) The LC is shown in red. B) Axial slices corresponding to the lines indicated on the whole brain sagittal image, with red arrows pointing to the LC visible as white spots where higher levels of neuromelanin led to greater contrast. C) Computer reconstruction of post-mortem distribution of LC neurons in an adult aged 64, with slices cut 45° above the horizontal plane. As cells descend caudally, they are displaced laterally by the fourth ventricle. D) A reconstruction from a sagittally sectioned brain aged 60. The dorsal part of the LC starts at the level of the inferior colliculus (IC) and extends to about the level of the superior medullary velum. Figures 1A and B reprinted from [124], C and D modified from [11].

Figure I

Horizontal section through the locus coeruleus showing that two or more capillaries tend to be wrapped around each cell. The small arrows indicate cells of the nucleus of the mesencephalic root of the Vth that have a lower capillary supply and a different appearance than the locus coeruleus cells. Figure reprinted from [101].

Figure II

Glutamate and norepinephrine interact to further amplify excitation where there are high levels of glutamatergic activity in sensory and limbic regions. This type of hotspot occurs when (A) glutamate released at a synapse spills over and activates NMDA receptors on NE neuron varicosities while (B) concomitant depolarization of the LC neuron stimulates local NE release.

Figure II

Glutamate and norepinephrine interact to further amplify excitation where there are high levels of glutamatergic activity in sensory and limbic regions. This type of hotspot occurs when (A) glutamate released at a synapse spills over and activates NMDA receptors on NE neuron varicosities while (B) concomitant depolarization of the LC neuron stimulates local NE release.