Sleep, memory and aging
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Author: francesca mo
Date: 05/03/2013


Sleep, memory and aging: how Aging Affects Sleep-Dependent Memory Consolidation?

How Aging Affects Sleep-Dependent Memory Consolidation? 2012

Sleep plays a major role in memory consolidation, notably due to the specific neurochemical environment and the electrophysiological activity observed during the night.
Aging is characterized by memory impairment, changes in sleep architecture and neurochemical alterations: these elements suggest that sleep-dependent memory consolidation may be impaired in older adults.

In humans, sleep is characterized by the cyclic occurrence of two main physiological stages: the N-REM (non-rapid eye movement) sleep and the REM sleep.
The N-REM sleep is subdivided into stage 1, stage 2 and slow wave sleep (SWS, stages 3, 4) according to sleep depth: a sleep cycle lasts about 90-100 minutes, but SWS is most abundant during the first half of the night (up to 80%) whereas REM sleep prevails in the second half of the night.
Both REM sleep and SWS and their succession in sleep cycle are important for memory consolidation: SWS mainly helps declarative memory consolidation while REM sleep helps non-declarative and procedural memory consolidation.

The Hippocampal–Neocortical Dialogue: A Model of Sleep-Dependent Memory Consolidation

During wakefulness, freshly acquired information is temporarily encoded into hippocampal networks. These memories are hippocampus-dependent (declarative memories).
LTP (long term potentiation), a form of synaptic plasticity, is the leading molecular process for the initial encoding and subsequent stabilization of memory.

A molecular basis for interactions between sleep and memory, 2011

In LTP, Ca++ influx through glutamate receptors, the AMPA and NMDA receptors, can trigger the covalent modification (e.g., phosphorylation) of pre-existing proteins at active synapses resulting in short-term changes in synaptic strength. An increase in intracellular Ca++ levels can activate the calmodulin dependent protein kinase (CAMKII) and PKA. Then CAMKII and PKA can phosphorylate the NMDA and AMPA receptors subunits thereby altering the synaptic transmission.
Gene transcription and translation is required for the maintenance of LTP: while early-LTP (E-LTP) requires only the phosphorylation of pre-existing proteins, late-LTP (L-LTP) requires transcription and translation. The Ca++ influx plays an important role again: it stimulates the production of the second messenger 3′-5′-cyclic adenosine monophosphate (cAMP) by adenylyl cyclase, which activates the PKA and MAPK (MAP- kinase). Once activated, PKA and MAPK can phosphorylate and activate the transcription factor cAMP response element binding protein (CREB) in order to start new protein synthesis.
Fluctuations in the levels of excitatory and inhibitory neurotransmitters that occur during sleep can have important influences on memory consolidation by binding to G-protein coupled receptors (GPCRs): dopamine and acetylcholine can bind to both stimulatory and inhibitory GPCRs. Also, sleep deprivation can increase adenosine levels: adenosine binds to an inhibitory GPCR and lowers the cAMP levels. By this way, sleep deprivation results in reduced efficiency in acquiring new memories.

Once consolidated on a synaptic level, newly formed memories undergo a process of system consolidation. Systems consolidation refers to the slow transference of memory out of the hippocampus to the neocortex for permanent storage: this is named the hippocampo-neocortical dialogue. This process takes place mainly during sleep, especially during the SWS.
During SWS, memory traces are repeatedly reactivated: slow oscillations synchronize reactivations to drive the transfer of memory traces toward neocortical sites where they will be stored durably.

In conclusion:
- During wakefulness new information enters the hippocampal CA3 region through the entorhinal cortex, where it is stored temporarily without disturbing previously acquired memories.
- During SWS there is a flow of information from the hippocampus to the neocortex, where information is stored indefinitely.

Why is SWS important for declarative memory consolidation?

An opportunistic theory of cellular and systems consolidation, 2011

There are some hypothesis:
1. Unique-to-sleep consolidation hypothesis: according to this hypothesis, consolidation of declarative memories depends on neural mechanisms that are unique to SWS and SWS is crucial for consolidation. This hypothesis does not consider the important role for interference reduction (the reducing of sensorial inputs from the outside, due to the thalamic gate)
2. Opportunistic consolidation hypothesis: this hypothesis suggests that SWS is not the only crucial mechanism that triggers consolidation; according to this theory, memory consolidation is facilitated by a period of reduced interference, which occurs during SWS, within a limited temporal window
3. Passive interference reduction hypothesis: sleep has beneficial effects merely because it eliminates interference that would otherwise occur.

Acetylcholine, a neurotransmitter regulating sleep and memory

Declarative memory consolidation: Mechanisms acting during human sleep, 2004

Acetylcholine is involved in the regulation of the N-REM/REM sleep cycle. Cholinergic activation in the CNS mainly stems from two regions: the mesopontine tegmentum and the nucleus basalis of Meynert. During wakefulness and REM sleep, these regions provide cholinergic input to thalamocortical neurons, which in turn activate the cortex via glutamatergic projections. Other projections from the tegmentum, also using glutamate, activate the nucleus basalis of Meynert, which in turn provides cholinergic activation throughout the cortex.
According to a model, Ach inhibits feedback loops within the hippocampus and between the hippocampus and the neocortex. Thus, high cholinergic activity during wakefulness allows acquiring new information and storing it in the hippocampus (by LTP), whereas low cholinergic activity during SWS allows the replay of newly acquired memories in the hippocampus: the release from cholinergic suppression permits outflow of information from hippocampus to the cortex.
Also, during SWS, hippocampal plasticity is low and activity along input pathways is suppressed: both these mechanisms contribute to protect recently induced LTP from interference.

Neuroendocrine contributions to memory consolidation

Neuroendocrine contributions to memory consolidation, 2004

The neuroendocrine hypothalamic-pituitary-adrenocortical system is related to both memory formation and sleep. Cortisol released from the adrenal gland enhances the acquisition of new information and interferes with retrieval of old memories during wakefulness.
During the first hours of nocturnal sleep, cortisol levels drop to a minimum due to a circadian rhythm and a direct inhibition of the activity of the pituitary-adrenocortical axis by SWS. So the lowering of cortisol levels enhances memory consolidation during SWS.
This effect seems to be mediated by glucocorticoid receptors: their activation suppresses hippocampal output from CA1 neurons.
The somatotropic axis, with its release of growth hormone, may contribute toward memory consolidation: in fact a peak in GH secretion can be registered during SWS (according to a circadian rhythm).

Age-Related Changes in Sleep

Age-Related Changes in Sleep, 2012

Older adults complain of early awakening in the morning and of difficulties to maintain continuous sleep: this is because aging affects sleep in many ways.
An increase in the number of arousals during the night leads to sleep fragmentation. Total sleep time decreases whereas time spent awake during the night increases: as a result, sleep efficiency is diminished (proportion of sleep time compared to time spent in bed).
The most striking change in sleep architecture is the dramatic decrease in time spent in SWS; this decline is accompanied by a reduction in the number and amplitude of slow oscillations.
Changes concerning REM sleep tend to become significant only after age 50.
Aging is further characterized by alterations of circadian rhythms and a reduction in melatonin secretion, having an impact on sleep-dependent memory consolidation. In fact melatonin, secreted by the pineal gland in close association to the light-dark cycle, may be helpful by inducing sleep.

Sleep-Dependent Consolidation of Memories in Older Adults

Sleep-Dependent Consolidation of Memories in Older Adults, 2012

Sleep-dependent memory consolidation is impaired with aging. Older adults usually complain of impairment concerning mainly episodic/declarative memory: as mentioned above, consolidation of declarative memory relies upon SWS, which is significantly reduced in older adults.
Furthermore, with age some cortical areas important for memory consolidation (for example the frontal cortex) undergo structural and functional alterations: the so-called physiological atrophy of the CNS. The alteration of the hippocampus is more debated: some studies report a significant volume loss of CA3. In addition, frontal white-matter tracts are also affected by age and may lead to impaired interactions between the prefrontal cortex and the hippocampus.

Age-related changes in some neuroendocrine systems may affect sleep quality and architecture and therefore memory consolidation.
Aging is accompanied by a cholinergic hypofunction, which may not have consequences on SWS-dependent consolidation of declarative memories but could have repercussions on consolidation of procedural/non-declarative memories during REM sleep, during which acetylcholine levels are high.
Finally, aging is also accompanied by changes in the hypothalamo-pituitary-adrenal axis leading to an increase in evening cortisol levels. As memory consolidation requires low levels of cortisol during the first half of the night and since the hippocampus contains a high density of glucocorticoid receptors, elevated cortisol levels may impair hippocampal functioning and impede the hippocampal-neocortical transfer of memories during SWS.

In conclusion, in older adults, several factors closely interlinked are associated with impairment of memory consolidation during sleep. They are:
- Decrease in SWS density
- Decrease in amplitude and number of slow oscillation
- Hypofunctioning and atrophy of frontal areas
- Reduction of cholinergic tone
- Raising in evening cortisol levels.

Ach syntesis and some correlations with memory impairment


Acetylcholine syntesis requires:
- the precursor choline
- acetyl-coA
- the enzyme ChAT (choline acetyltransferase).


To make choline, we need methionine and the derivative S-adenosylmethionine (SAM): in fact SAM is an important metyl-donor and is involved in a lot of methylation reactions.
One of them is important to synthesize phosphatidylcholine by transferring a methyl group from SAM to phosphatidylethanolamine.
Where does methionine come from? Methionine is an aminoacid which can be introduced with the diet; also, an important source of methionine comes from the enzymatic-reaction catalized by methionine synthase.
In this reaction, we need the cofactor methyl-cobalamine: it transfers a methyl group from 5-methyl-THF to homocysteine to make methionine and THF.
In people with deficiency of cobalamine (vitamin B12) or folate, the reaction can't take place; as a consequence we have neither methionine nor phosphatidylcholine and choline syntesis.
In this type of patients we should expect a memory impairment due to choline low levels and the inability to synthesize Ach.

Vitamin B12 and folate depletion in cognition: A review, 2004

In this work, the role of folate and cobalamine in cognitive decline and dementia is stressed: actually, further studies are needed to demonstrate an association between cobalamine and folate deficiency and memory impairment.
In these patients, a reduction in methionine-synthase reaction leads to homocysteine accumulation: homocysteine seems to play an active role in this degenerative process. In fact, homocysteic acid is a mixed excitatory agonist at NMDA receptors. These receptors are important in memory long-term-potentiation system: abnormal activation of NMDA receptors results in a rise of intracellular calcium, consequent release of cellular proteases and eventual cell death.

Choline: one molecule, many functions in brain development and integrity

The role of dietary choline in optimal brain development, 2008

Numerous research observations point to the importance of choline for the developing fetus and neonate. Dietary intake of choline by the pregnant mother and later by the infant affects brain development and results in permanent changes in brain function.
Choline deficiency during these crucial periods results in persisting memory and cognitive deficits.
During pregnancy, there is a high rate of transfer of choline across the placenta and, after birth, the baby gets choline from breast milk; this is necessary in order to maintain an adequate level of choline in fetal blood.
Choline is needed for:
- migration, proliferation and differentiation of neuronal precursor cells
- normal neural tube closure: adequate dietary choline and folate intake can prevent neural tube defects (NTDs)
- hippocampal development: exposure to choline in utero and subsequent changes in hippocampal structure might result in enhanced long-term-potentiation and visuospatial memory throughout the lifespan; choline deprivation results in apoptosis in fetal hippocampus, insensitivity lo long-term potentiation in adulthood and diminished visuospazial memory
- effects on memory function: exposure to choline in this critical period results in higher memory capacity in adulthood
- neuroprotective effects in fetal alcohol syndrome: postnatal choline treatment might reduce the cognitive deficits associated with prenatal alcohol.

It was initially hypothesized that choline might act through its trasformation into Ach in the CNS; afterwards, some studies demonstrated that choline might act by altering gene expression.

For its many functions, the administration of choline might offer a chance of treatment for people with memory impairment.

Verbal and visual memory improve after choline supplementation in long-term total parenteral nutrition: a pilot study, 2001

In this study, people who required long-term total parenteral nutrition (TPN) were given choline supplementation; there was evidence of an improvement in verbal and visual memory.

Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly, 2005

In this study, CDP-choline (a form of the essential nutrient choline) was administered to elderly people in order to treat cerebrovascular disorders; when the study ended, there was also some evidence of a positive effect on memory and behaviour. Citicoline (CDP-choline) shows promise of clinical efficacy in elderly patients with cognitive deficits, inefficient memory, and early-stage Alzheimer's disease.

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