Alzheimer : Neurons that are responsible for new experiences interfere with memories

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Neurons that are responsible for new experiences interfere with the signals of neurons that contain memories and thereby disturb the recall of memories – at least in mice.

The research group of Martin Fuhrmann of the German Center for Neurodegenerative Diseases (DZNE) reports this phenomenon in the scientific journal Nature Neuroscience.

The results of this study potentially shed new light on memory impairment in Alzheimer‘s disease.

The hippocampus is a brain region responsible for memories and is early affected during Alzheimer’s disease. Neurons in the hippocampus respond to our experiences and build networks to store these memories.

Thereby, experiences and learned content can be recalled: we can for example remember our way home or to work. Individuals suffering from dementia have problems retrieving this kind of memories – as a specific region in the hippocampus, the so-called CA1 area, responsible for spatial memory, is strongly affected by Alzheimer pathology.

So far it was thought that neurons that “contain” a memory are impaired by the disease in a way that they fail to be reactivated and eventually lose the memory. Apparently, the process of forgetting during Alzheimer’s disease – at least in a mouse model – works in a different way: a research group at the DZNE investigated mice with similar protein deposits in their brains (so-called amyloid-beta plaques) as people with Alzheimer’s disease.

The deposits resulted in symptoms in these mice similar to those seen in Alzheimer’s disease. The researchers found that the neurons responsible for the memory were still active in the diseased mice. However, recall of the memory failed.

Signals of other neurons interfere with the memory

“The reason is novel experience encoding neurons disturbing the signals of memory-containing neurons and superimposing them with their signal,” says Dr. Martin Fuhrmann, group leader at the DZNE.

“It is like a noisy TV signal: the picture becomes diffuse and distorted; you might even see pixels or stripes. Something similar happened inside the mice’s brain: Interfering signals suppressed their memories. This disturbance is obviously a result of the pathological changes in the brain.”

When healthy mice remember a situation, like learning a new path or exploring a novel environment, the neuronal network will be reactivated that was active during encoding the initial experience.

To find out what actually happens to this neuronal network, the researchers performed an experiment: They let healthy, as well as mice with Alzheimer-like pathology explore a novel environment.

With the help of a special microscopy method – two-photon in vivo microscopy – the researchers were able to follow the activity of individual neurons in the hippocampus.

When the mice were exposed to the very same environment a few days later both groups behaved differently: the healthy mice remembered the environment; mice with Alzheimer-like pathology did not.

They explored the environment as if it was their first experience. This was accompanied by differences in brain activity. Dr. Stefanie Poll, postdoc in the lab of Martin Fuhrmann and first author of this study explained:

“In the diseased mice we not only found active neurons encoding the memory, but also a group of active neurons that contained novel environmental information. The signal of these novelty-containing neurons caused a superimposition disturbing signal of the memory encoding neurons.”

To verify this, the researchers employed a technique based on the combination of chemical molecules and genetics: “chemogenetics.”

Thereby, neurons encoding novelty were made responsive to a specific chemical molecule. “Applying this molecule, we were able to modulate the activity of these neurons. It works like a switch, the molecule presses the switch,” says Stefanie Poll.

On and off switching of novelty-containing neurons

“Like that we were able to specifically target neurons encoding novel information and switch these neurons on and off—controlling their activity,” explains Martin Fuhrmann. “In the diseased mice we switched these neurons off, in the healthy group we did the opposite.”

Thereby, it was possible to on the one hand to reduce and on the other hand to induce the disturbing noise artificially.” This was evident in the mice’s behavior: “Mice with Alzheimer-like pathology now recognized the environment again, their memory was restored.

The memory of healthy mice, however, was impaired by the artificial noise,” says Stefanie Poll.

“The results of this study indicate a previously unknown mechanism that may contribute to the memory impairment in Alzheimer’s disease,” explains Martin Fuhrmann. “Imagining future therapies, we might be able to rescue memories of individuals suffering from Alzheimer’s disease or other diseases impacting memory recall.

We might achieve this by lowering the activity of these noise-inducing neurons with future methods. Furthermore, it could be possibly helpful for individuals suffering from post-traumatic stress disorders.

Here, noise-inducing neurons could be artificially activated to interfere with the traumatic memory aiming to overwrite it. The remaining question, whether our results can be translated to humans, has to be answered by future studies.”


MEMORY
Our memories define our character and have a completely unique perspective than everyone else’s experiences. Creating a memory involves three stages. The first, encoding, occurs when a stimulus results in the formation of a new memory (11–13).

This new formation is often referred to as an engram, which is thought to be a physical memory trace in the brain (14). This trace is very susceptible to decay until the next stage occurs, consolidation (14).

Consolidation is the process in which a memory becomes stable and is assimilated into previously acquired knowledge (14). The final stage, retrieval, occurs when the memory is recollected (14).

Sometimes when we create a memory, it only lasts for a short period of time, when other memories last a lifetime (15, 16). Memories are temporally defined as long term or short term depending on the length of time the memory lasts. Short-term memories last less than 2 min, whereas long term memories can last 2 min to a lifetime (15, 16).

Short-term memories usually are comprised of working memory (15, 16). Working memory typically involves small amounts of information that we only need to retain for a couple seconds, for example, the prices two items when comparing costs while shopping.

Types of memory
There are multiple types of memory and subdivisions within each type. The main two types are explicit (declarative) and implicit (nondeclarative) (15). When a memory is explicit, the individual is consciously aware of the memory, whereas with implicit memory, the individual is not (15).

There are two subsets within explicit memory: episodic and semantic. Episodic, or autobiographical memories, include a what, where, and when aspect of the memory (16–18). Semantic memories are facts about the world around us (15).

An example of semantic memory may be knowing that baseball is a sport, whereas an episodic memory may be remembering the first time you went to a baseball game. Implicit memories also have two subdivisions: procedural and priming (15).

Procedural memories include motor skills and other actions we complete automatically without conscious thought (e.g., walking and writing) (15). Priming occurs when an individual is exposed to a stimulus that influences their response to a later stimulus (15). An example of priming may be seeing a flash of an image on a computer while taking a computer-based memory task.

Forgetting
Why are some memories retained yet others are lost?

There are many reasons that we forget information we have learned or events we have experienced (19–21). The act of forgetting can occur actively or passively.

Passive forgetting occurs through natural decay, or biological degradation, of neurons within a memory engram (19). Partial decay of an engram can make it challenging to activate the memory during retrieval (19).

Active forgetting can occur through several mechanisms: interference, motivated forgetting, or retrieval-induced forgetting (19). Interference, which will be detailed later in this chapter, occurs when competing information makes it difficult to retrieve the correct memory (19).

Motivated forgetting often occurs when an individual actively suppresses a memory due to some unpleasant quality (e.g., guilt, shame, and embarrassment) (19). Finally, retrieval-induced forgetting occurs when only parts of a memory are normally recalled, causing the other parts to degrade over time (19).

Memory Interference
As stated in the previous section, memory interference (MI) is a cause of forgetting. There are two types of MI, proactive and retroactive. Proactive interference (PI) occurs when previously acquired information interrupts the recall of newly learned information (old → new).

For example, calling your new boyfriend by your old boyfriend’s name. Retroactive interference (RI) occurs in the opposite direction, newly acquired information interrupts the recall of old information (old ← new).

Following the previous example, this would be calling your old boyfriend by your new boyfriend’s name. Interference can be benign to serious memory disruption depending on the situation. Interference is also linked to similarity of the content. If the competing material is similar, interference is more likely to occur.

In experiments, MI is measured using paired associate learning tasks. These tasks are typically comprised of lists of word pairs or figure pairs (e.g., “bread knife” or ♦♣) that a participant is asked to memorize as a pair.

Research participants memorize lists of the word or figure pairs and subsequently recall them (e.g., bread – _ or ♦ – _). There are multiple models of paired associate tasks, but ones commonly used include AB–CD, AB–AC, AB–ABr, and AB–DE AC–FG.

For the models, the letter pairs (e.g., AB and CD) signify one list each (e.g., AB = List 1, CD = List 2), each letter in the name (e.g., AB–CD) stands for one word (A = bread B = knife), and the combined letters (e.g., AB) represent one word-pair (breadknife). Examples of measuring MI using various models are summarized in tables 1–4.

Table 1AB–CD example

List 1 (AB)List 2 (CD)
BABY HUNTERSPIDER CANDLE
SUPPER SHERIFFARROW THEATER
WEDDING MOVIECHERRY MONEY
APPLE DIAMONDTIGER HOTEL
MONKEY GARDENCANNON HAMMER
FOREST BATTLELADY BUTTER
In this model, AB signifies the first list and CD the second list. There are no repeating letters in the title of the model, meaning there are no repeating words within the lists. Each list consists of unique words with no overlap. Participants may be exposed to both lists (learn List 1 then List 2) and then asked to recall only one of them. To measure PI, the participants will learn List 1 (AB), List 2 (CD), then recall List 2. For RI, the participants will learn List 1 (AB), List 2 (CD), then recall List 1.

Table 4AB–DE AC–FG example

List 1 (AB, DE)Cued recall 1
A__, D__
List 2 (AC, FG)Cued recall 2
A__, F__
MMFR
A__ __
D__ __
F__ __
BABY HUNTERSPIDER _______FOREST CITYARROW ______BABY ___ ___
SUPPER SHERIFFFOREST _______ARROW THEATERFOREST ______CHERRY ___ ___
WEDDING MOVIEBABY ________BABY SALADTIGER ______ARROW ___ ___
SPIDER CANDLECHERRY ______TIGER HOTELSUPPER ______SUPPER ___ ___
MONKEY GARDENMONKEY ______MONKEY ENGINELADY _______TIGER ___ ___
FOREST BATTLESUPPER _______LADY BUTTERCANNON ____WEDDING ___ ___
CHERRY MONEYAPPLE ________CANNON HAMMERBABY _______MONKEY ___ ___
APPLE DIAMONDWEDDING ____SUPPER JACKETMONKEY _____LADY ___ ___
SPIDER ___ ___
FOREST ___ ___
APPLE ___ ___
CANNON ___ ___
This paired associate task is more complex than the other designs because it includes control word pairs within each list, allowing for the measurement of proactive and RI within the same experiment. As before, List 1 (AB–DE) has repeating “A” words as List 2 (AC–FG). In this case, DE and FG are the control word pairs and AB and AC are the interfering word pairs. To use this model for an experiment, participants learn List 1, recall it, learn List 2, recall it, then recall the Modified Modified Free Recall (MMFR) list which is comprised of all of the word pairs from List 1 and List 2 in a pseudorandomized order.

Table 2AB–AC example

List 1 (AB)List 2 (AC)
BABY HUNTERMOVIE WEDDING
SUPPER SHERIFFAPPLE CANNON
MONKEY GARDENBABY SALAD
FOREST BATTLEMONKEY ENGINE
MOVIE CHERRYFOREST CITY
APPLE TIGERSUPPER JACKET
Similar to the previous model AB–CD, this model’s first list (AB) has no repeating words, but as we can see “AC” has a repeating “A” word. This signifies that the “A” words from List 1 (AB) and List 2 (AC) will repeat, while the “B” and “C” words will not. When testing for PI, the participant will learn List 1, List 2, and then recall List 2. For RI, the participant will learn List 1, List 2, and then recall List 1.

Table 3AB–ABr example

List 1 (AB)List 2 (ABr)
BABY HUNTERSHERIFF CHERRY
SUPPER SHERIFFDIAMOND BABY
WEDDING MOVIEBATTLE SUPPER
SPIDER CANDLEFOREST HUNTER
MONKEY GARDENMONEY MOVIE
FOREST BATTLESPIDER GARDEN
CHERRY MONEYAPPLE WEDDING
APPLE DIAMONDCANDLE MONKEY
This model repeats all of the words from List 1 (AB) in the second list (ABr) except the words are rearranged into new word pairs. To reiterate, List 1 and List 2 comprised of the same words, but the way in which they are organized is different for List 2. This model can cause severe interference since the words are so similar. Participants learn List 1, List 2, then recall either List 1 or List 2 depending on the interference being measured.

Alzheimer’s disease and MI
Alzheimer’s disease causes the decay of neurons which eventually leads to memory impairment (1, 4, 5, 9). Although there are a lot of research fields focusing on how Alzheimer’s disease damages memory, there is less research focusing directly on MI effects on patients with Alzheimer’s disease.

When investigating patients with Alzheimer’s disease and those with mild cognitive impairments without Alzheimer’s disease, Dewer et al. found that memory retention is much higher in these patients when there is minimal interference compared to a normal MI paradigm (22).

Their findings align with previous literature demonstrating that memory dysfunction in patients with Alzheimer’s disease is associated with an increased susceptibility to MI (22). The authors hypothesize that this may be due to a decline in the ability to consolidate new memories (22).

The interference paradigm utilized in this experiment is strong at predicting which patients with mild cognitive impairments will or will not progress to Alzheimer’s disease within 2 years, with 80% sensitivity and 100% specificity (22).

In term of semantic memory, or facts about the world (e.g., baseball is a sport), patients with Alzheimer’s disease perform worse on these memory tasks, which may be due to a deficit in working memory and attention (23).

As stated previously, working memory is short-term memory that lasts for a very short period of time with a concurrent interfering stimulus. Hartman describes how, in her experiment, there was no evidence that the patients with Alzheimer’s disease utilized semantic knowledge (relatedness) of word pairs during recall (23).

When patients’ working memory is impaired, as is typical in Alzheimer’s disease, it is more difficult to retain relevant information about the relationships of words in paired associate tasks (23).

Despite this experiment’s focus on working memory, its results shed light on MI impairments since semantically relating words is a typical strategy utilized when memorizing word pairs in paired associate tasks. When detailing the symptoms of Alzheimer’s disease, we noted that difficulty remembering and following instructions is common (23).

This may also influence performance on memory tasks. Repeatedly needing external cues or verbal instructions may alter outcome scores, as mentioned elsewhere (23). Another study that focused specifically on proactive and RI compared mildly demented Alzheimer’s disease patients, patients with mild cognitive impairment without Alzheimer’s disease, and healthy elderly patients on interference tasks (24).

When controlling for overall memory impairment, mild Alzheimer’s disease patients demonstrated higher rates of PI, but equal amounts of RI when compared to the cognitively impaired patients (24). As expected, the healthy elderly participants experienced the least amount of interference (24). Vulnerability to semantic interference may reflect early signs of the onset of Alzheimer’s disease (24).

EXERCISE AND ALZHEIMER’S DISEASE
As stated previously, physical inactivity is a risk factor for developing Alzheimer’s disease and is even considered the highest population attributable risk (25). In one systematic review, the majority of experiments demonstrated that physical activity was inversely associated with risk of developing Alzheimer’s disease (26).

Exercise has also been demonstrated to improve multiple types of memory, including long-term and short-term memory (27–33). Exercise may even prevent the onset of Alzheimer’s disease by decreasing the risk of cardiovascular disease, increasing cerebral blood flow, increasing hippocampal volume, and improving neurogenesis (34).

Higher levels of physical activity are associated with a reduced risk of developing the disease (34), with long-term prospective studies demonstrating that walking regularly is associated with a twofold reduced risk in cognitive impairment (25).

During exercise, many chemicals are released in the body, including brain-derived neurotrophic factor, which is directly associated with learning and memory (35).

Research also demonstrates that regular physical activity prevents mental decline and improves thinking in populations with vascular cognitive impairment (34). It has been used clinically in the treatment of preclinical and late-stage Alzheimer’s disease, as well as a prevention strategy (34).

Recent prospective work, that compared sedentary individuals to those who were the most active, demonstrated a 38% reduction in incidence of Alzheimer’s disease (36). In animal studies, mice with Alzheimer’s disease that completed 16 weeks of treadmill exercise have been shown to elicit changes in therapeutic parameters at the cellular and molecular level, providing biological plausibility to exercise as a therapy (37).

In order to reduce the risk of developing Alzheimer’s disease, to lessen the effects for those already suffering from memory loss, individuals should participate in regular physical activity. The American national guidelines suggest at least 150 min per week of moderate to vigorous physical activity (38).

Meta-analyses have demonstrated mixed findings on which mode of exercise is best for improving specific types of memory; however, walking, cycling, and jogging are three of the most common exercises implemented, all of which have demonstrated beneficial effects (33, 39).

Multicomponent exercise programs have also been effective in improving cognitive function in institutionalized older adults with mild to moderate Alzheimer’s disease (40). One particular study found that incorporating a program that included supervised aerobic, muscular resistance, flexibility, and postural exercises for 45–55 min sessions twice per week for 6 months significantly improved patients’ cognitive function when compared to a control group (40). These findings suggest that incorporating a variety of physical activities may be an effective non-pharmacological meth

REFERENCES

1.Aging NIo. Alzheimer’s disease & related dementias [Internet]. Available from: https://www​.nia.nih.gov​/health/alzheimers/basics.

2.Association As. What is Alzheimer’s? [Internet]. Available from: https://www​.alz.org/alzheimers-dementia​/what-is-alzheimers#basics.

3.Association As. Younger/early onset [Internet]. Available from: https://www​.alz.org/alzheimers-dementia​/what-is-alzheimers​/younger-early-onset.

4.Clinic M. Alzheimer’s disease [Internet]. Available from: https://www​.mayoclinic​.org/diseases-conditions​/alzheimers-disease​/symptoms-causes/syc-20350447.

5.Association As. 10 early signs and symptoms of Alzheimer’s [Internet]. Available from: https://www​.alz.org/alzheimers-dementia​/10_signs.

6.Association As. Stages of Alzheimer’s [Internet]. Available from: https://www​.alz.org/alzheimers-dementia​/stages.

7.Association As. Treatments for behavior [Internet]. Available from: https://www​.alz.org/alzheimers-dementia​/treatments​/treatments-for-behavior.

8.Association As. Causes and risk factors [Internet]. Available from: https://www​.alz.org/alzheimers-dementia​/what-is-alzheimers​/causes-and-risk-factors.

9.Medicine PCfR. Alzheimer’s disease [Internet]. Available from: https://www​.pcrm.org​/health-topics/alzheimers.

10.Association As. Medications for memory [Internet]. Available from: https://www​.alz.org/alzheimers-dementia​/treatments​/medications-for-memory.

11.Puglisi JT, Park DC, Smith AD, Dudley WN. Age differences in encoding specificity. J Gerontol. 1988;43(6):P145–50. [PubMed] [CrossRef]

12.Stickgold R, Walker MP. Sleep-dependent memory consolidation and reconsolidation. Sleep Med. 2007;8(4):331–43. [PMC free article] [PubMed] [CrossRef]

13.McGaugh JL. Memory – A century of consolidation. Science. 2000;287(5451):248–51. [PubMed] [CrossRef]

14.Loprinzi PD, Edwards MK, Frith E. Potential avenues for exercise to activate episodic memory-related pathways: A narrative review. Eur J Neurosci. 2017;46(5):2067–77. [PubMed] [CrossRef]

15.Institute QB. Types of memory The University of Queensland 2018, July 23 [Internet]. Available from: https://qbi​.uq.edu.au​/brain-basics/memory/types-memory.

16.Moscovitch M, Cabeza R, Winocur G, Nadel L. Episodic memory and beyond: The hippocampus and neocortex in transformation. Annu Rev Psychol. 2016;67:105–34. [PMC free article] [PubMed] [CrossRef]

17.Scully ID, Napper LE, Hupbach A. Does reactivation trigger episodic memory change? A meta-analysis. Neurobiol Learn Mem. 2017;142(Pt A):99–107. [PubMed] [CrossRef]

18.Shields GS, Sazma MA, McCullough AM, Yonelinas AP. The effects of acute stress on episodic memory: A meta-analysis and integrative review. Psychol Bull. 2017;143(6):636–75. [PMC free article] [PubMed] [CrossRef]

19.Davis RL, Zhong Y. The biology of forgetting – A perspective. Neuron. 2017;95(3):490–503. [PMC free article] [PubMed] [CrossRef]

20.Aguirre C, Gomez-Ariza CJ, Andres P, Mazzoni G, Bajo MT. Exploring mechanisms of selective directed forgetting. Front Psychol. 2017;8:316. [PMC free article] [PubMed] [CrossRef]

21.Anderson MC, Hanslmayr S. Neural mechanisms of motivated forgetting. Trends Cogn Sci. 2014;18(6):279–92. [PMC free article] [PubMed] [CrossRef]

22.Dewar M, Pesallaccia M, Cowan N, Provinciali L, Della Sala S. Insights into spared memory capacity in amnestic MCI and Alzheimer’s disease via minimal interference. Brain Cogn. 2012;78(3):189–99. [PubMed] [CrossRef]

23.Hartman M. The use of semantic knowledge in Alzheimer’s disease: Evidence for impairments of attention. Neuropsychologia. 1991;29(3):213–28. [PubMed] [CrossRef]

24.Loewenstein DA, Acevedo A, Luis C, Crum T, Barker WW, Duara R. Semantic interference deficits and the detection of mild Alzheimer’s disease and mild cognitive impairment without dementia. J Int Neuropsychol Soc. 2004;10(1):91–100. [PubMed] [CrossRef]

25.Loprinzi PD, Frith E, Ponce P. Memorcise and Alzheimer’s disease. Phys Sports Med. 2018;46(2):145–54. [PubMed] [CrossRef]

26.Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of Alzheimer’s disease: An analysis of population-based data. Lancet Neurol. 2014;13(8):788–94. [PubMed] [CrossRef]

27.Angevaren M, Aufdemkampe G, Verhaar HJ, Aleman A, Vanhees L. Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment. Cochrane Database Syst Rev. 2008;(3):CD005381. [PubMed] [CrossRef]

28.Chang YK, Labban JD, Gapin JI, Etnier JL. The effects of acute exercise on cognitive performance: A meta-analysis. Brain Res. 2012;1453:87–101. [PubMed] [CrossRef]

29.Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: A meta-analytic study. Psychol Sci. 2003;14(2):125–30. [PubMed] [CrossRef]

30.Cotman CW, Berchtold NC. Exercise: A behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002;25(6):295–301. [PubMed] [CrossRef]

31.McMorris T, Hale BJ. Differential effects of differing intensities of acute exercise on speed and accuracy of cognition: A meta-analytical investigation. Brain Cogn. 2012;80(3):338–51. [PubMed] [CrossRef]

32.McMorris T, Sproule J, Turner A, Hale BJ. Acute, intermediate intensity exercise, and speed and accuracy in working memory tasks: A meta-analytical comparison of effects. Physiol Behav. 2011;102(3–4):421–8. [PubMed] [CrossRef]

33.Roig M, Nordbrandt S, Geertsen SS, Nielsen JB. The effects of cardiovascular exercise on human memory: A review with meta-analysis. Neurosci Biobehav Rev. 2013;37(8):1645–66. [PubMed] [CrossRef]

34.Cass SP. Alzheimer’s disease and exercise: A literature review. Curr Sports Med Rep. 2017;16(1):19–22. [PubMed] [CrossRef]

35.Loprinzi PD, Frith E. A brief primer on the mediational role of BDNF in the exercise-memory link. Clin Physiol Funct Imaging. 2019;39(1):9–14. [PubMed] [CrossRef]

36.Guure CB, Ibrahim NA, Adam MB, Said SM. Impact of physical activity on cognitive decline, dementia, and its subtypes: Meta-analysis of prospective studies. Biomed Res Int. 2017;2017:9016924. [PMC free article] [PubMed] [CrossRef]

37.Um HS, Kang EB, Leem YH, Cho IH, Yang CH, Chae KR, et al. Exercise training acts as a therapeutic strategy for reduction of the pathogenic phenotypes for Alzheimer’s disease in an NSE/APPsw-transgenic model. Int J Mol Med. 2008;22(4):529–39. [PubMed]

38.Piercy KL, Troiano RP, Ballard RM, Carlson SA, Fulton JE, Galuska DA, et al. The physical activity guidelines for Americans. JAMA. 2018;320(19):2020–8. [PubMed] [CrossRef]

39.Loprinzi PD, Blough J, Crawford L, Ryu S, Zou L, Li H. The temporal effects of acute exercise on episodic memory function: Systematic review with meta-analysis. Brain Sci. 2019;9(4):pii: E87. [PMC free article] [PubMed] [CrossRef]

40.Sampaio A, Marques EA, Mota J, Carvalho J. Effects of a multicomponent exercise program in institutionalized elders with Alzheimer’s disease. Dementia (London). 2019;18(2):417–31. [PubMed] [CrossRef]


More information: Stefanie Poll et al, Memory trace interference impairs recall in a mouse model of Alzheimer’s disease, Nature Neuroscience (2020). DOI: 10.1038/s41593-020-0652-4

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