ABSTRACT

Amnesia – the loss of memory function – is often the earliest and most persistent symptom of dementia. It occurs as a consequence of a variety of diseases and injuries. These include neurodegenerative, neurological or immune disorders, drug abuse, stroke or head injuries. It has both troubled and fascinated humanity. Philosophers, scientists, physicians and anatomists have all pursued an understanding of how we learn and memorise, and why we forget. In the last few years, the development of memory engram labelling technology has greatly impacted how we can experimentally study memory and its disorders in animals. Here, we present a concise discussion of what we have learned about amnesia through the manipulation of engrams, and how we may use this knowledge to inform novel treatments of amnesia.

Introduction

Amnesia refers to a deficit of memory due to a specific cause. It is a disorder that arises as a consequence of more than 15 different types of diseases and injuries that affect the brain, such as neurodegenerative and neurological diseases, vascular disorders and traumatic lesions (Markowitsch and Staniloiu, 2012). It is often the earliest and most persistent symptom of dementia (Wells, 1979). Amnesia has a huge clinical significance – its effects on the daily life of patients who suffer from it can be enormous. As a result, there are many efforts towards developing successful treatments. Currently, therapeutic interventions are limited by the lack of understanding of how memory functions in both health and disease.

Memory is the ability to store information of past experiences in the brain. Knowledge learnt by animals alters their brain and modulates how the brain then regulates future behaviour. Understanding memory, and its mechanisms, is a central goal of modern neuroscience. In 1904, Richard Semon postulated that experiences provoke long-lasting changes in specific neurons that result in an enduring memory trace – an engram of the acquired information. Reactivation of these engram cells will result in the recall of that particular memory (Semon, 1904). To understand the mechanisms of engram formation, we have primarily relied on indirect methodological approaches, for example, by studying amnesia. The general approach is to interfere with a brain region, physiological process or gene that we hypothesize is important for memory, and then look for experimental amnesia in a given behavioural paradigm (McGaugh, 2000). Recently, we have begun to make progress in our understanding of both memory and amnesia through the development of memory engram technology.

Memory engram technology is based on the combination of transgenic, optogenetic, behavioural and electrophysiological approaches. Developed originally by Tonegawa and colleagues, the technology integrates optogenetics and immediate early gene (IEG) labelling to drive the expression of a transgene in cells that specifically respond to an experience (Boyden et al., 2005; Reijmers et al., 2007; Tonegawa et al., 2015a,b). In its first demonstration, a promoter of the IEG c-fos was used to drive the expression of channelrhodopsin (ChR2), a light-responsive ion channel, in hippocampal dentate gyrus neurons that were activated by a target contextual experience (Fig. 1). Temporal control is allowed by the tetracycline-controlled transactivator (tTA)-tetracycline response element (TRE) system, inducible by the removal of the antibiotic doxycycline so that it only labels the neurons that are responding to the controlled contextual experience. This approach demonstrated that direct activation of engram neurons for contextual memories associated with fear/threat is sufficient (Liu et al., 2012; Ramirez et al., 2013), as well as necessary (Denny et al., 2014; Tanaka et al., 2014; Trouche et al., 2016), to recall this specific episodic memory.

Fig. 1.

Engram labelling technology and memory retrieval in retrograde amnesia. (A) The promoter of the immediate early gene (IEG) drives expression of tTA in an activity-dependent manner. Doxycycline (DOX), which is delivered through the animal's diet, prevents tTA from binding to the TRE element of the channelrhodopsin (ChR2) transgene in hippocampal dentate gyrus (DG) neurons. (B) Shock delivery, which causes fear, in context A subsequently elicits a freezing response specifically to context A. In the absence of DOX, DG neurons that are active during the encoding of that fear memory express ChR2. Injection of the drug anisomycin after the encoding induces retrograde amnesia. (C) Amnesic animals are unable to elicit a behavioural (freezing) response using natural cues. (D) Optogenetic activation of engram neurons induces the recall of a distributed and context-specific fear response in amnesic animals.

Fig. 1.

Engram labelling technology and memory retrieval in retrograde amnesia. (A) The promoter of the immediate early gene (IEG) drives expression of tTA in an activity-dependent manner. Doxycycline (DOX), which is delivered through the animal's diet, prevents tTA from binding to the TRE element of the channelrhodopsin (ChR2) transgene in hippocampal dentate gyrus (DG) neurons. (B) Shock delivery, which causes fear, in context A subsequently elicits a freezing response specifically to context A. In the absence of DOX, DG neurons that are active during the encoding of that fear memory express ChR2. Injection of the drug anisomycin after the encoding induces retrograde amnesia. (C) Amnesic animals are unable to elicit a behavioural (freezing) response using natural cues. (D) Optogenetic activation of engram neurons induces the recall of a distributed and context-specific fear response in amnesic animals.

Amnesia

From the clinical point of view, amnesia is described as a multifaceted disorder with a frequently poor prognosis (Markowitsch and Staniloiu, 2012). Anterograde amnesia refers to the inability to acquire and retain new information, whereas retrograde amnesia affects the recall of past or recently learned memories. Recent memories are more vulnerable to amnesia than older ones, and this is known as Ribot's law of regression (Ribot, 1881). Amnesia appears as a consequence of diverse clinical disorders, such as Alzheimer's and Parkinson's disease (AD and PD, respectively), depression, and head trauma, among many others. Therefore, animal models for those disorders frequently develop memory deficits (Table 1).

Table 1.

Cause, effect and animal models of amnesia

Cause, effect and animal models of amnesia
Cause, effect and animal models of amnesia

Can the combination of memory engram labelling technology and disease models help us to understand the neuropathology of amnesia? In a model of drug-induced amnesia, mice administered with a protein synthesis inhibitor after a fear-inducing training session develop retrograde amnesia for that fear memory (McGaugh, 2000). Surprisingly, using the engram labelling technology, optogenetic activation of neurons in these mice elicited a context-specific fear response, indicating that the memory was still there (Fig. 1) (Ryan et al., 2015). This approach opens the possibility that the information is not completely lost in retrograde amnesia, but it is just inaccessible.

The same methodological approach was subsequently applied to models of early AD – the major neurodegenerative disease that affects memory storage (Roy et al., 2016; Perusini et al., 2017). AD is associated with the deposition of amyloid-β peptide in extracellular plaques and with the aggregation of the microtubule-associated protein tau in neurofibrillary tangles inside neurons (Braak and Braak, 1991). As a consequence of these aggregates, synapses are compromised, and there is selective neuronal death and a decrease in specific neurotransmitters (reviewed in Masters et al., 2015). The APP/PS1 mouse model recapitulates many of the hallmarks of human AD, including deficits in spatial, social and cognitive memory (Gong et al., 2004; Lalonde et al., 2005), but some strategies have successfully improved cognition in these models. Environmental enrichment was shown to be beneficial by stimulation of synaptic activity (Jankowsky et al., 2005; Lazarov et al., 2005; Fischer et al., 2007). Photonic stimulation of the visual cortex by chronic application of light in frequencies of 40 Hz improved contextual and fear memory, and significantly reduced amyloid-β plaque deposition (Iaccarino et al., 2016). Although these studies show that certain activities and interventions can ameliorate the deterioration of memory, they do not show whether the engram itself survives amnesia. In the APP/PS1 mouse model, short-term memories (minutes to hours) are intact, whereas long-term memories (a day or more) are compromised, indicating a consolidation deficit as a cause of the amnesia (Kilgore et al., 2010; Ryan et al., 2015). The fact that this kind of amnesia is retrograde (because the initial short-term memory is observed) indicates that the engram might still be present in the brain. Using the engram tagging approach in this model, animals with amnesia due to early-stage AD were able to remember a contextual memory through optogenetic stimulation of the labelled engram neurons. This proved that, firstly, the memory is maintained and, secondly, the cells responsible for encoding the original memory are not properly reactivated in early-stage AD models (Roy et al., 2016; Perusini et al., 2017). Furthermore, engram technology has provided insights into the role of memory loss in depression. Based on human studies, it has been hypothesized that depression may be due in part to a loss of access to positive memories (Dalgleish and Werner-Seidler, 2014). Engram technology has provided strong experimental evidence in favour of this idea. When positive or pleasurable memory engrams were labelled in the mouse hippocampus prior to the induction of depression, subsequent optogenetic stimulation of these engram cells ameliorated depressive behaviour, and chronic stimulation seemed to induce new plasticity in those cells that restored natural access to the engram and normal behaviour thereafter (Ramirez et al., 2015).

Treatment of amnesia

The idea that the information survives in the context of the pathology is changing the paradigm of amnesia and instigating the search for therapeutic strategies to make seemingly lost memories obtainable again, rather than simply preventing the memory loss in the first place. Such therapeutics would have wide-ranging utility, since amnesia is a common symptom of many different brain disorders (Table 1). The first objective will be to identify which kinds of retrograde (and perhaps in some cases, anterograde) amnesia are due to retrieval deficits. The subsequent step will be to find ways to restore access to those engrams in a sustainable manner. Animal studies are best placed to achieve both these initial aims before the strategies can be translated into human clinical cases. Importantly, any treatment or intervention designed to reverse amnesia, whether chronic or acute, needs to also be tested in control wild-type animals. This is crucial to account for general cognitive effects (e.g. arousal, attention, emotional response, etc.) that might affect behavioural performance independently of any improvement of memory engram function.

However, such approaches to ameliorate or reverse amnesia need to be complemented with continuing efforts to address the underlying cause of the disorder. This is especially the case for chronic forms of amnesia, as the memory will become inaccessible again if the problem is still present, such as in neurodegenerative disorders. Since amnesia is not the primary cause of these diseases, efforts put into finding therapies that palliate the memory deficits should be tied to therapies designed to stop the overall progress of the amnesia-causing disease in question.

What achievements in treating amnesia should be expected in the short and long term? Therapies based on optogenetic stimulation are very invasive, and this is a major obstacle to their translation to the clinic. The light required to optogenetically stimulate labelled neurons needs to be delivered through optic fibres, and gene therapy is required to make cells susceptible to light-mediated activation. This limitation might be overcome in the future by the development of the next-generation optogenetic implantable devices (Zhao and Hubin, 2017; Rudmann et al., 2018; Shoffstall et al., 2018) and by optimization of gene delivery (Dobson, 2006; Wang et al., 2017). Examples of non-invasive alternatives to target and activate engrams are transcranial direct-current stimulation (tDCS) and transcranial magnetic stimulation (TMS). tCDS applies weak electrical currents with electrodes that either hyperpolarize or depolarize the neurons to modify brain function. TMS achieves the same effect by generating a magnetic field inside a coiled wire that in turn generates an electrical field at the intracranial level. Although safer and much less invasive, the benefits of tDCS and TMS on cognitive function in AD are acute and not maintained in the long term (Freitas et al., 2011), probably because of their lack of specificity in targeting neurons. Most crucially, unlike researchers, physicians are not generally present at the time of memory engram formation in the patient's brain, and so are not in the privileged observational position to label human engrams in clinical cases, even if safe and appropriate technology was available. However, given the progress in the past 10 years, there is every reason to be optimistic about future possibilities of overcoming this caveat.

As memory engram technology has become available as a new tool, the memory research field has advanced in its understanding of memory storage, consolidation and retrieval processes. Combining these approaches with disease models associated with amnesia will help us better understand the pathology on a neurobiological level, and this would certainly be followed by better management and therapeutic treatment of patients affected by memory loss.

Acknowledgements

We thank Lydia Marks for proofreading.

Footnotes

Funding

This work was supported by the European Research Council (C.O.S. and T.R.), Science Foundation Ireland and Jacobs Foundation (T.R.).

References

References
Ahmad
,
A.
,
Ramakrishna
,
S.
,
Meara
,
J.
and
Doran
,
M.
(
2010
).
Autoimmune limbic encephalitis: a reversible form of rapidly progressive amnesia and seizures
.
J. R. Coll. Physicians Edinb.
40
,
123
-
125
.
Albert
,
M. S.
,
Butters
,
N.
and
Levin
,
J.
(
1979
).
Temporal gradients in the retrograde amnesia of patients with alcoholic Korsakoff's Disease
.
Arch. Neurol.
36
,
211
-
216
.
Aleman
,
A.
,
Hijman
R.
,
de Haan
,
E. H.
and
Kahn
,
R. S.
(
1999
).
Memory impairment in schizophrenia: a meta-analysis
.
Am. J. Psychiatry
156
,
1358
-
1366
.
Almeida-Suhett
,
C. P.
,
Prager
,
E. M.
,
Pidoplichko
,
V.
,
Figueiredo
,
T. H.
,
Marini
,
A. M.
,
Li
,
Z.
,
Eiden
,
L. E.
and
Braga
,
M. F. M.
(
2015
).
GABAergic interneuronal loss and reduced inhibitory synaptic transmission in the hippocampal CA1 region after mild traumatic brain injury
.
Exp. Neurol
.
273
,
11
-
23
.
Almli
,
C. R.
,
Levy
,
T. J.
,
Han
,
B. H.
,
Shah
,
A. R.
,
Gidday
,
J. M.
and
Holtzman
,
D. M.
(
2000
).
BDNF protects against spatial memory deficits following neonatal hypoxia-ischemia
.
Exp. Neurol.
166
,
99
-
114
.
Arena
,
J. E.
and
Rabinstein
,
A. A.
(
2015
).
Transient global amnesia
.
Mayo Clin. Proc.
90
,
264
-
272
.
Beatty
,
W. W.
,
Goodkin
,
D. E.
,
Monson
,
N.
,
Beatty
,
P. A.
and
Hertsgaard
,
D.
(
1988a
).
Anterograde and retrograde amnesia in patients with chronic progressive multiple sclerosis
.
Arch. Neurol.
45
,
611
-
619
.
Beatty
,
W. W.
,
Salmon
,
D. P.
,
Butters
,
N.
,
Heindel
,
W. C.
and
Granholm
,
E. L.
(
1988b
).
Retrograde amnesia in patients with Alzheimer's disease or Huntington's disease
.
Neurobiol. Aging
9
,
181
-
186
.
Beers
,
D. R.
,
Henkel
,
J. S.
,
Kesner
,
R. P.
and
Stroop
,
W. G.
(
1995
).
Spatial recognition memory deficits without notable CNS pathology in rats following herpes simplex encephalitis
.
J. Neurol. Sci.
131
,
119
-
127
.
Boyden
,
E. S.
,
Zhang
,
F.
,
Bamberg
,
E.
,
Nagel
,
G.
and
Deisseroth
,
K.
(
2005
).
Millisecond-timescale, genetically targeted optical control of neural activity
.
Nat. Neurosci.
8
,
1263
-
1268
.
Braak
,
H.
and
Braak
,
E.
(
1991
).
Neuropathological stageing of Alzheimer-related changes
.
Acta Neuropathologica
.
239
-
259
.
Burt
,
D. B.
,
Zembar
,
M. J.
and
Niederehe
,
G.
(
1995
).
Depression and memory impairment: a meta-analysis of the association, its pattern, and specificity
.
Psychol. Bull.
117
,
285
-
305
.
Butters
,
N.
and
Cermak
,
L. S.
(
1974
).
Some comments on Warrington and Baddeley's report of normal short-term memory in amnesic patients
.
Neuropsychologia
12
,
283
-
285
.
Cermak
,
L. S.
and
O'connor
,
M.
(
1983
).
The anterograde and retrograde retrieval ability of a patient with amnesia due to encephalitis
.
Neuropsychologia
21
,
213
-
234
.
Dalgleish
,
T.
and
Werner-Seidler
,
A.
(
2014
).
Disruptions in autobiographical memory processing in depression and the emergence of memory therapeutics
.
Trends Cogn. Sci.
18
,
596
-
604
.
Davis
,
H. P.
and
Squire
,
L. R.
(
1984
).
Protein synthesis and memory: a review
.
Psychol. Bull.
96
,
518
-
559
.
De Renzi
,
E.
and
Lucchelli
,
F.
(
1993
).
Dense retrograde amnesia, intact learning capability and abnormal forgetting rate: a consolidation deficit?
Cortex. Masson Italia Periodici S.r.l.
,
29
,
449
-
466
.
Denny
,
C. A.
,
Kheirbek
,
M. A.
,
Alba
,
E. L.
,
Tanaka
,
K. F.
,
Brachman
,
R. A.
,
Laughman
,
K. B.
,
Tomm
,
N. K.
,
Turi
,
G. F.
,
Losonczy
,
A.
and
Hen
,
R.
(
2014
).
Hippocampal memory traces are differentially modulated by experience, time, and adult neurogenesis
.
Neuron
83
,
189
-
201
.
Dobson
,
J.
(
2006
).
Gene therapy progress and prospects: magnetic nanoparticle-based gene delivery
.
Gene Ther.
13
,
283
-
287
.
Engmann
,
O.
,
Hortobágyi
,
T.
,
Pidsley
,
R.
,
Troakes
,
C.
,
Bernstein
,
H. G.
,
Kreutz
,
M. R.
,
Mill
,
J.
,
Nikolic
,
M.
and
Giese
,
K. P.
(
2011
).
Schizophrenia is associated with dysregulation of a Cdk5 activator that regulates synaptic protein expression and cognition
.
Brain
134
,
2408
-
2421
.
Fischer
,
A.
,
Sananbenesi
,
F.
,
Wang
,
X.
,
Dobbin
,
M.
and
Tsai
,
L.-H.
(
2007
).
Recovery of learning and memory is associated with chromatin remodelling
.
Nature
447
,
178
-
182
.
Freitas
,
C.
,
Mondragón-Llorca
,
H.
and
Pascual-Leone
,
A.
(
2011
).
Noninvasive brain stimulation in Alzheimer's disease: systematic review and perspectives for the future
.
Exp. Gerontol.
46
,
611
-
627
.
Goldberg
,
E.
,
Antin
,
S.
,
Bilder
,
R.
,
Gerstman
,
L.
,
Hughes
,
J.
and
Mattis
,
S.
(
1981
).
Retrograde amnesia: possible role of mesencephalic reticular activation in long-term memory
.
Science
213
,
1392
-
1394
.
Gong
,
B.
,
Vitolo
,
O. V.
,
Trinchese
,
F.
,
Liu
,
S.
,
Shelanski
,
M.
and
Arancio
,
O.
(
2004
).
Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment
.
J. Clin. Investig.
114
,
1624
-
1634
.
Iaccarino
,
H. F.
,
Singer
,
A. C.
,
Martorell
,
A. J.
,
Rudenko
,
A.
,
Gao
,
F.
,
Gillingham
,
T. Z.
,
Mathys
,
H.
,
Seo
,
J.
,
Kritskiy
,
O.
,
Abdurrob
,
F.
, et al. 
(
2016
).
Gamma frequency entrainment attenuates amyloid load and modifies microglia
.
Nature
540
,
230
-
235
.
Jankowsky
,
J. L.
,
Melnikova
,
T.
,
Fadale
,
D.J.
,
Xu
,
G.M.
,
Slunt
,
H.H.
,
Gonzales
,
V.
,
Younkin
,
L.H.
,
Younkin
,
S.G.
,
Borchelt
,
D.R.
and
Savonenko
,
A.V.
(
2005
).
Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer's disease
.
J. Neurosci.
25
,
5217
-
5224
.
Kapur
,
N.
(
1993
).
Transient epileptic amnesia--a clinical update and a reformulation
.
J. Neurol. Neurosurg. Psychiatry
56
,
1184
-
1190
.
Kapur
,
N.
(
1999
).
Syndromes of retrograde amnesia: a conceptual and empirical synthesis
.
Psychol. Bull.
125
,
800
-
825
.
Kapur
,
N.
,
Mclellan
,
D. L.
and
Burrows
,
E. H.
(
1992
).
Focal retrograde amnesia following bilateral temporal lobe pathology. A neuropsychological and magnetic resonance study
.
Brain: J.l Neurol.
115
,
73
-
85
.
Kesner
,
R. P.
,
Dixon
,
D. A.
,
Pickett
,
D.
and
Berman
,
R. F.
(
1975
).
Experimental animal model of transient global amnesia: role of the hippocampus
.
Neuropsychologia
13
,
465
-
480
.
Kilgore
,
M.
,
Miller
,
C. A.
,
Fass
,
D. M.
,
Hennig
,
K. M.
,
Haggarty
,
S. J.
,
Sweatt
,
J. D.
and
Rumbaugh
,
G.
(
2010
).
Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease
.
Neuropsychopharmacology
35
,
870
-
880
.
Kim
,
D. Y.
,
Hao
,
J.
,
Liu
,
R.
,
Turner
,
G.
,
Shi
,
F.-D.
and
Rho
,
J. M.
(
2012
).
Inflammation-mediated memory dysfunction and effects of a ketogenic diet in a murine model of multiple sclerosis
.
PLoS ONE
7
,
e35476
.
Kinoshita
,
K.
,
Muroi
,
Y.
,
Unno
,
T.
and
Ishii
,
T.
(
2017
).
Rolipram improves facilitation of contextual fear extinction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease
.
J. Pharmacol. Sci.
,
134
,
55
-
58
.
Kopelman
,
M. D.
(
1992
).
Storage, forgetting, and retrieval in the anterograde and retrograde amnesia of the Alzheimer's type. Memory functioning in dementia, pp. 45-71
.
Kuroda
,
T.
,
Futamura
,
A.
,
Sugimoto
,
A.
,
Midorikawa
,
A.
,
Honma
,
M.
and
Kawamura
,
M.
(
2015
).
Autobiographical age awareness disturbance syndrome in autoimmune limbic encephalitis: two case reports
.
BMC Neurol.
15
,
238
.
Lalonde
,
R.
,
Kim
,
H. D.
,
Maxwell
,
J. A.
and
Fukuchi
,
K.
(
2005
).
Exploratory activity and spatial learning in 12-month-old APP695SWE/co+PS1/ΔE9 mice with amyloid plaques
.
Neurosci. Lett.
390
,
87
-
92
.
Lazarov
,
O.
,
Robinson
,
J.
,
Tang
,
Y.-P.
,
Hairston
,
I. S.
,
Korade-Mirnics
,
Z.
,
Lee
,
V. M.-Y.
,
Hersh
,
L. B.
,
Sapolsky
,
R. M.
,
Mirnics
,
K.
and
Sisodia
,
S. S.
(
2005
).
Environmental enrichment reduces Aβ levels and amyloid deposition in transgenic mice
.
Cell
,
120
,
701
-
713
.
Lister
,
R. G.
(
1985
).
The amnesic action of benzodiazepines in man
.
Neurosci. Biobehav. Rev.
9
,
87
-
94
.
Liu
,
X.
,
Ramirez
,
S.
,
Pang
,
P. T.
,
Puryear
,
C. B.
,
Govindarajan
,
A.
,
Deisseroth
,
K.
and
Tonegawa
,
S.
(
2012
).
Optogenetic stimulation of a hippocampal engram activates fear memory recall
.
Nature
484
,
381
-
385
.
Markowitsch
,
H. J.
and
Staniloiu
,
A.
(
2012
).
Amnesic disorders
.
Lancet
380
,
1429
-
1440
.
Masters
,
C. L.
,
Bateman
,
R.
,
Blennow
,
K.
,
Rowe
,
C. C.
,
Sperling
,
R. A.
and
Cummings
,
J. L.
(
2015
).
Alzheimer's disease
.
Nat. Rev. Dis. Primers.
1
,
1
-
18
.
Mcgaugh
,
J. L.
(
2000
).
Memory--a century of consolidation
.
Science (New York, N.Y.)
287
,
248
-
251
.
Michel
,
P.
,
Beaud
,
V.
,
Eskandari
,
A.
,
Maeder
,
P.
,
Demonet
,
J. F.
and
Eskioglou
,
E.
(
2017
).
Ischemic amnesia
.
Stroke
48
,
2270
-
2273
.
Misanin
,
J. R.
,
Miller
,
R. R.
and
Lewis
,
D. J.
(
1968
).
Retrograde amnesia produced by electroconvulsive shock after reactivation of a consolidated memory trace
.
Science
160
,
554
-
555
.
Pang
,
T. Y. C.
,
Stam
,
N. C.
,
Nithianantharajah
,
J.
,
Howard
,
M. L.
and
Hannan
,
A. J.
(
2006
).
Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in huntington's disease transgenic mice
.
Neuroscience
141
,
569
-
584
.
Perusini
,
J. N.
,
Cajigas
,
S. A.
,
Cohensedgh
,
O.
,
Lim
,
S. C.
,
Pavlova
,
I. P.
,
Donaldson
,
Z. R.
and
Denny
,
C. A.
(
2017
).
Optogenetic stimulation of dentate gyrus engrams restores memory in Alzheimer's disease mice
.
Hippocampus
27
,
1110
-
1122
.
Ramirez
,
S.
,
Liu
,
X.
,
Lin
,
P.-A.
,
Suh
,
J.
,
Pignatelli
,
M.
,
Redondo
,
R. L.
,
Ryan
,
T. J.
and
Tonegawa
,
S.
(
2013
).
Creating a false memory in the hippocampus
.
Science
341
,
387
-
391
.
Ramirez
,
S.
,
Liu
,
X.
,
Macdonald
,
C. J.
,
Moffa
,
A.
,
Zhou
,
J.
,
Redondo
,
R. L.
and
Tonegawa
,
S.
(
2015
).
Activating positive memory engrams suppresses depression-like behaviour
.
Nature
522
,
335
-
339
.
Rau
,
V.
,
Decola
,
J. P.
and
Fanselow
,
M. S.
(
2005
).
Stress-induced enhancement of fear learning: An animal model of posttraumatic stress disorder
.
Neurosci. Biobehav. Rev.
1207
-
1223
.
Reijmers
,
L. G.
,
Perkins
,
B. L.
,
Matsuo
,
N.
and
Mayford
,
M.
(
2007
).
Localization of a stable neural correlate of associative memory
.
Science
317
,
1230
-
1233
.
Ribot
,
T. A.
(
1881
).
Diseases of memory-an essay in the positive psychology, the international scientific series, Vol. XLI. Diseases of memory: An Essay in the Positive Psychology, The International Scientific Series, Volume XLI, p. 236
.
Roy
,
D. S.
,
Arons
,
A.
,
Mitchell
,
T. I.
,
Pignatelli
,
M.
,
Ryan
,
T. Ã. ¡ J.
and
Tonegawa
,
S.
(
2016
).
Memory retrieval by activating engram cells in mouse models of early Alzheimer's disease
.
Nature
531
,
508
-
512
.
Rudmann
,
L.
,
Alt
,
M. T.
,
Ashouri Vajari
,
D.
and
Stieglitz
,
T.
(
2018
).
Integrated optoelectronic microprobes
.
Curr. Opin. Neurobiol.
50
,
72
-
82
.
Ryan
,
T. J.
,
Roy
,
D. S.
,
Pignatelli
,
M.
,
Arons
,
A.
and
Tonegawa
,
S.
(
2015
).
Engram cells retain memory under retrograde amnesia
.
Science
348
,
1007
-
1013
.
Sackeim
,
H. A.
,
Prudic
,
J.
,
Devanand
,
D. P.
,
Nobler
,
M. S.
,
Lisanby
,
S. H.
,
Peyser
,
S.
,
Fitzsimons
,
L.
,
Moody
,
B. J.
and
Clark
,
J.
(
2000
).
A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities
.
Arch. Gen. Psychiatry
57
,
425
.
Savage
,
L. M.
,
Hall
,
J. M.
and
Resende
,
L. S.
(
2012
).
Translational rodent models of korsakoff syndrome reveal the critical neuroanatomical substrates of memory dysfunction and recovery
.
Neuropsychol. Rev.
22
,
195
-
209
.
Schuckit
,
M. A.
(
2009
).
Alcohol-use disorders
.
Lancet
373
,
492
-
501
.
Semon
,
R.
(
1904
).
Die mneme [The mneme]. Edited by W. Engelmann. Leipzig
.
Shoffstall
,
A. J.
,
Srinivasan
,
S.
,
Willis
,
M.
,
Stiller
,
A. M.
,
Ecker
,
M.
,
Voit
,
W. E.
,
Pancrazio
,
J. J.
and
Capadona
,
J. R.
(
2018
).
A mosquito inspired strategy to implant microprobes into the brain
.
Sci. Rep.
8
,
122
.
Staniloiu
,
A.
,
Markowitsch
,
H. J.
and
Kordon
,
A.
(
2018
).
Psychological causes of autobiographical amnesia: a study of 28 cases
.
Neuropsychologia
110
,
134
-
147
.
Sullivan
,
E. V.
and
Fama
,
R.
(
2012
).
Wernicke's encephalopathy and Korsakoff's syndrome revisited
.
Neuropsychol. Rev.
22
,
69
-
71
.
Tanaka
,
K. Z.
,
Pevzner
,
A.
,
Hamidi
,
A. B.
,
Nakazawa
,
Y.
,
Graham
,
J.
,
Wiltgen
,
B. J.
(
2014
).
Cortical representations are reinstated by the hippocampus during memory retrieval
.
Neuron
84
,
347
-
354
.
Tonegawa
,
S.
,
Liu
,
X.
,
Ramirez
,
S.
and
Redondo
,
R.
(
2015a
).
Memory engram cells have come of age
.
Neuron
87
,
918
-
931
.
Tonegawa
,
S.
,
Pignatelli
,
M.
,
Roy
,
D. S.
and
Ryan
,
T. J.
(
2015b
).
Memory engram storage and retrieval
.
Curr. Opin. Neurobiol.
35
,
101
-
109
.
Trouche
,
S.
,
Perestenko
,
P. V.
,
Van De Ven
,
G. M.
,
Bratley
,
C. T.
,
Mcnamara
,
C. G.
,
Campo-Urriza
,
N.
,
Black
,
S. L.
,
Reijmers
,
L. G.
and
Dupret
,
D.
(
2016
).
Recoding a cocaine-place memory engram to a neutral engram in the hippocampus
.
Nat. Neurosci.
19
,
564
-
567
.
Van Der Kolk
,
B. A.
(
1994
).
The body keeps the score: memory and the evolving psychobiology of posttraumatic stress
.
Harv. Rev. Psychiatry
.
1
,
253
-
265
.
Viana
,
M. B.
,
Tomaz
,
C.
and
Graeff
,
F. G.
(
1994
).
The elevated T-maze: A new animal model of anxiety and memory
.
Pharmacology
49
,
549
-
554
.
Wang
,
S.
,
Kugelman
,
T.
,
Buch
,
A.
,
Herman
,
M.
,
Han
,
Y.
,
Karakatsani
,
M.E.
,
Hussaini
,
S.A.
,
Duff
,
K.
and
Konofagou
,
E.E.
(
2017
).
Non-invasive, focused ultrasound-facilitated gene delivery for optogenetics
.
Sci. Rep.
7
,
39955
.
Warrington
,
E. K.
and
Mccarthy
,
R. A.
(
1988
).
The fractionation of retrograde amnesia
.
Brain Cogn.
7
,
184
-
200
.
Wells
,
C. E.
(
1979
).
Diagnosis of dementia
.
Psychosomatics
20
,
517
-
522
.
Zhao
,
H.
and
Hubin
, (
2017
).
Recent progress of development of optogenetic implantable neural probes
.
Int. J. Mol. Sci.
18
,
1751
.
Zola-Morgan
,
S.
(
1996
).
Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus
.
Neurocase
2
,
259aw
-
25298
.
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