Trends in Cognitive Sciences
ReviewThe Locus Coeruleus: Essential for Maintaining Cognitive Function and the Aging Brain
Section snippets
Relevance of the LC to Cognitive Aging
Neuromodulators transform the firing patterns of neurons, reconfiguring neuronal circuits in ways that can dramatically change their output 1, 2. In this review we focus on how age-related changes in the function of NE, one of the main neuromodulators, can help to explain cognitive change in aging. NE is best known for its roles in behavioral arousal and in the control of heart rate and blood pressure, but it also regulates attention, memory, and cognition [3]. Most NE in the brain comes from
LC Neuropathology in Aging
Most studies examining how LC neuron counts change with age suggest an age-related decline in LC neuron number by ∼20–40% (e.g., 11, 12, 13, 14, 15), with selective cell loss in the rostral LC compartment 16, 17. However, it should be noted that some of these studies made lifespan comparisons on the basis of brain samples in the N = 5 to 13 range 11, 12, 16 and did not exclude cases with pathology elsewhere in the brain. More recent studies either excluding cases with neurofibrillary tangles
Does Activating the LC–NE System Throughout Life Create Cognitive Reserve?
One fascinating cultural phenomena is the Flynn effect, in which successive generations have been getting smarter, at least as assessed by IQ tests [68]. There is no definitive answer as to why this has been occurring, but some researchers believe that environments have gradually become more stimulating, promoting learning. One possibility is that stimulating environments enhance cognition in part via their activation of the LC–NE pathway (e.g., [69]).
Certainly, evidence from animals indicates
Can Increasing NE Levels Help Cognition in Older Adults?
Given the associations between lower brain levels of NE and impaired cognition, as well as the impaired cellular protection discussed in previous sections, one plausible intervention could be to increase NE levels in the brains of older adults. In rat brain, long-term cardiovascular training increases NE levels [79], and NE synthesis increases during exercise [80]. Several days or weeks of exercise enhances learning and memory for the next few days, and this enhancement is blocked by
Long-Term Effects of β-Blockers
Given the evidence already discussed that NE release can protect against amyloid toxicity, and that many of the protective effects of NE are mediated by β-adrenergic receptor pathways, it seems that long-term use of β-adrenergic antagonists could accelerate Alzheimer's disease. This has major public health relevance because many older adults are prescribed β-blockers to help in managing cardiovascular disease [89]. However, epidemiological studies find contradictory relationships between taking
Concluding Remarks
In the current review we have outlined evidence suggesting that age-related change in the LC structure and NE function plays more of role in cognitive aging than has been previously appreciated. LC structural integrity in late life is associated with cognitive function 6, 26, as are NE levels in the brain 23, 45. Furthermore, many of the cognitive functions that have been identified as especially vulnerable in aging are strongly influenced by NE.
Understanding the role of the LC in cognitive
Glossary
- Adrenergic antagonists
- chemicals that block the action of catecholamines at adrenergic receptors.
- β-Amyloid
- a protein with 38–43 amino acids derived from amyloid precursor protein. In Alzheimer's disease it forms small aggregates called oligomers and eventually larger aggregates known as plaques. The oligomer form is believed to be the most damaging.
- Caspases
- enzymes that are crucial in apoptosis or programmed cell death.
- Catecholamines
- monoamine neurotransmitters derived from the amino acid tyrosine.
References (132)
Neuromodulation of neuronal circuits: back to the future
Neuron
(2012)Cognitive reserve in ageing and Alzheimer's disease
Neurol.
(2012)A noradrenergic theory of cognitive reserve: implications for Alzheimer's disease
Neurobiol. Aging
(2013)Noradrenergic regulation of inflammatory gene expression in brain
Neurochem. Int.
(2002)The topography of nerve cell loss from the locus caeruleus in elderly persons
Neurobiol. Aging
(1989)Cell loss in the locus coeruleus in senile dementia of Alzheimer type
J. Neurol. Sci.
(1981)Unbiased estimation of neuronal numbers in the human nucleus coeruleus during aging
Neurobiol. Aging
(1997)Absolute number and size of pigmented locus coeruleus neurons in young and aged individuals
J. Chem. Neuroanat.
(1994)Noradrenergic changes, aggressive behavior, and cognition in patients with dementia
Biol. Psychiatry
(2002)Early life linguistic ability, late life cognitive function, and neuropathology: findings from the Nun Study
Neurobiol. Aging
(2005)
Neuromelanin marks the spot: Identifying a locus coeruleus biomarker of cognitive reserve in healthy aging
Neurobiol. Aging
Histologic validation of locus coeruleus MRI contrast in post-mortem tissue
Neuroimage
The noradrenaline precursor L-DOPS reduces pathology in a mouse model of Alzheimer's disease
Neurobiol. Aging
Distinct adrenergic system changes and neuroinflammation in response to induced locus ceruleus degeneration in APP/PS1 transgenic mice
Neuroscience
Environmental novelty activates β2-adrenergic signaling to prevent the impairment of hippocampal LTP by Aβ oligomers
Neuron
Norepinephrine differentially modulates the innate inflammatory response provoked by amyloid-β peptide via action at β-adrenoceptors and activation of cAMP/PKA pathway in human THP-1 macrophages
Exp. Neurol.
Locus coeruleus, norepinephrine and Aβ peptides in Alzheimer's disease
Neurobiol. Stress
Biochemical changes in dementia disorders of Alzheimer type (AD/SDAT)
Neurobiol. Aging
Monoaminergic innervation of the frontal and temporal lobes in Alzheimer's disease
Brain Res.
A post-mortem study of noradrenergic, serotonergic and GABAergic neurons in Alzheimer's disease
J. Neurol. Sci.
Metabolomic changes in autopsy-confirmed Alzheimer's disease
Alzheimers Dement.
Cerebrospinal fluid norepinephrine and cognition in subjects across the adult age span
Neurobiol. Aging
Flow rate of cerebrospinal fluid (CSF) – a concept common to normal blood-CSF barrier function and to dysfunction in neurological diseases
J. Neurol. Sci.
The alpha-2A-adrenoceptor agonist, guanfacine, increases regional cerebral blood flow in dorsolateral prefrontal cortex of monkeys performing a spatial working memory task
Neuropsychopharmacology
Network reset: a simplified overarching theory of locus coeruleus noradrenaline function
Trends Neurosci.
Norepinephrine-mediated emotional arousal facilitates subsequent pattern separation
Neurobiol. Learn. Mem.
An enriched environment increases noradrenaline concentration in the mouse brain
Brain Res.
The behavioral effects of enriched housing are not altered by serotonin depletion but enrichment alters hippocampal neurochemistry
Neurobiol. Learn. Mem.
Adrenergic pharmacology and cognition: Focus on the prefrontal cortex
Pharmacol. Ther.
Central β-adrenergic receptors play an important role in the enhancing effect of voluntary exercise on learning and memory in rat
Behav. Brain Res.
Atomoxetine augmentation of cholinesterase inhibitor therapy in patients with Alzheimer disease: 6-month, randomized, double-blind, placebo-controlled, parallel-trial study
Am. J. Geriatr. Psychiatry
Chronic treatment with the α2-adrenoceptor antagonist fluparoxan prevents age-related deficits in spatial working memory in APP× PS1 transgenic mice without altering β-amyloid plaque load or astrocytosis
Neuropharmacology
The human locus coeruleus in neurology and psychiatry: Parkinson's, Lewy body, Hallervorden–Spatz, Alzheimer's and Korsakoff's disease, (pre) senile dementia, schizophrenia, affective disorders, psychosis
Prog. Neurobiol.
Uptake of environmental toxicants by the locus ceruleus: A potential trigger for neurodegenerative, demyelinating and psychiatric disorders
Med. Hypotheses
Beyond the wiring diagram: signalling through complex neuromodulator networks
Phil. Trans. R. Soc. B Biol. Sci.
The locus coeruleus and noradrenergic modulation of cognition
Nat. Rev. Neurosci.
Neuroanatomy and Pathology of Sporadic Alzheimer's Disease
Locus (coeruleus) minoris resistentiae in pathogenesis of Alzheimer's disease
Curr. Alzheimer Res.
Neural reserve, neuronal density in the locus ceruleus, and cognitive decline
Neurology
Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine
Proc. Natl. Acad. Sci. U.S.A.
The human locus coeruleus: computer reconstruction of cellular distribution
J. Neurosci.
Locus ceruleus morphometry in aging and schizophrenia
Acta Psychiatr. Scand.
Quantitative study of the pigmented neurons in the nuclei locus coeruleus and subcoeruleus in man as related to aging
J. Neuropathol. Exp. Neurol.
Quantitation of catecholamine neurons in the locus coeruleus in human brains of normal young and older adults and in depression
J. Comp. Neurol.
Locus-coeruleus cell loss in the aging human brain: A nonrandom process
J. Comp. Neurol.
Preservation of midbrain catecholaminergic neurons in very old human subjects
Brain
Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years
J. Neuropathol. Exp. Neurol.
Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature
J. Neuropathol. Exp. Neurol.
Amyloid-β may be released from non-junctional varicosities of axons generated from abnormal tau-containing brainstem nuclei in sporadic Alzheimer's disease: a hypothesis
Acta Neuropathol.
Detection of changes in the locus coeruleus in patients with mild cognitive impairment and Alzheimer's disease: High-resolution fast spin-echo T1-weighted imaging
Geriatr. Gerontol. Int.
Cited by (283)
Impact of high-fat diet on cognitive behavior and central and systemic inflammation with aging and sex differences in mice
2024, Brain, Behavior, and ImmunityLower fractional dimension in Alzheimer's disease correlates with reduced locus coeruleus signal intensity
2024, Magnetic Resonance Imaging