10.13125/CH/4495
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2533-1825
4495
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urn:nbn:it:unica-26453
SARAH A. STERN
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Critical Hermeneutics
memory enhancement, learning and memory, animal models
Mechanisms of Memory Enhancement
Text.Serial.Journal
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4
Articles
2020-12-17
2020-12-17
2020-12-17
2020-12-17
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1
SARAH A. STERN
2020/12/17
10.13125/CH/4495
121
2533-1825
special II
memory enhancement, learning and memory, animal models
166
urn:nbn:it:unica-26453
Mechanisms of Memory Enhancement
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Critical Hermeneutics, special 2 (2020)                       Received: 17/7/2020
Biannual International Journal of Philosophy                 Accepted: 17/7/2020
http://ojs.unica.it/index.php/ecch/index                    Published: 17/12/2020
ISSN 2533-1825 (on line); DOI 10.13125/CH/4495




              Mechanisms of Memory Enhancement


                     SARAH A. STERN, CRISTINA M. ALBERINI




Abstract
The ongoing quest for memory enhancement is one that grows neces-
sary as the global population increasingly ages. The extraordinary pro-
gress that has been made in the past few decades elucidating the un-
derlying mechanisms of how long-term memories are formed has pro-
vided insight into how memories might also be enhanced. Capitalizing
on this knowledge, it has been postulated that targeting many of the
same mechanisms, including CREB activation, AMPA/ NMDA receptor
trafficking, neuromodulation (e.g. via dopamine, adrenaline, cortisol or
acetylcholine) and metabolic processes (e.g. via glucose and insulin)
may all lead to the enhancement of memory. These and other mecha-
nisms and/or approaches have been tested via genetic or pharmaco-
logical methods in animal models, and several have been investigated
in humans as well. In addition, a number of behavioral methods, in-
cluding exercise and reconsolidation, may also serve to strengthen and
enhance memories. By capitalizing on this knowledge and continuing
to investigate these promising avenues, memory enhancement may
indeed be achieved in the future.
[Keywords: memory enhancement, learning and memory, animal
models]
Sarah A. Stern, Cristina M. Alberini, Mechanisms of Memory Enhancement



                       Those who cannot remember the past are condemned to repeat it.
                                                                   George Santayana




Memories1 are a fundamental part of our identity. As highlighted by the
quote above, memories guide our behavior at every moment by re-
minding us of our past actions and their outcomes. For those individu-
als whose capacity to form memories is disrupted, life becomes in-
creasingly difficult and isolating. The cognitive dysfunction associated
with many debilitating diseases, including Alzheimer’s disease (AD),
diabetes, Parkinson’s disease (PD), and even in aging, demands effec-
tive therapies that can lead to recovery of memory functions or
memory enhancement.
      One strategy that may lead to the identification of memory en-
hancers is to capitalize on the knowledge gained by the biological study
of long-term memory formation and storage. In the last two decades,
extraordinary progress has been made in the understanding of the cel-
lular and molecular mechanisms that are used for memory formation
in several different species and types of learning. Results from these
studies have left us with core knowledge about the role of conserved
gene expression pathways, such as those regulated by the cAMP re-
sponse element-binding-CCAAT enhancer binding protein (CREB-
C/EBP) transcription factors (Alberini 2009). In parallel, cellular and
electrophysiological investigations have led to the discovery of long-
term potentiation (LTP) and long-term depression (LTD) which provide
cellular models for testing mechanisms of plasticity associated with
memory formation (Bliss, Collingridge 1993). Disruption of these
mechanisms has pointed to useful approaches and targets for the de-
velopment of therapies that attenuate obtrusive memories, such as


1
 Reprinted from Wiley Interdiscip Rev Syst Biol Med. 5(1), Stern S. A., Alberini C.
M.,   Mechanisms    of  Memory      Enhancement,    37–53     Copyright    (2013);
doi:10.1002/wsbm.1196.



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those contributing to post-traumatic stress disorder (PTSD), phobias,
and drug addiction (Ressler, Mayberg 2007). On the other hand, the
identification of mechanisms that can amplify, enhance and/or
strengthen synaptic plasticity represents potential therapeutic tools for
enhancing adaptive memories and contrasting the onset and progres-
sion of disorders of cognitive functions.
    The focus of this Review is to provide an overview of the treat-
ments that have been reported to promote memory enhancement and,
where known, their underlying mechanisms. Particular attention will be
given to the description of the various stages of learning and memory
storage that can be targeted for enhancement as well as the different
forms of memories that can be enhanced. First, we will summarize the
basic knowledge underlying learning and memory that is relevant for
discussions pertaining to memory enhancement. We will then review
mechanisms of memory enhancement found with various substances/
approaches, focusing on which types and stages of memory are en-
hanced in both animal models and human subjects. Given the vast lit-
erature on pharmacological compounds or approaches that modulate
memory, it is not feasible to discuss every possible route to cogni-
tive/memory enhancement; however, it is our intent to summarize the
major findings obtained with pharmacological, neuromodulatory and
behavioral methods. Moreover, we do not provide a comprehensive
knowledge of memory enhancement obtained in transgenic models,
with a few exceptions that are pertinent to the topics of this review.
We thus refer to excellent and exhaustive reviews for genetic ap-
proaches to memory enhancement (Lee, Silva 2009; Cooke, Bliss
2003).




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1. Defining Memory and Targeting Phases for Memory Enhance-
ment
1.1 Stages of Memory Formation and Storage
Since Ebbinghaus conducted his famous studies in memorizing non-
sense syllables (Ebbinghaus 1913), it has been universally recognized
that memory consists of multiple stages, including acquisition/ encod-
ing, working memory/short-term memory, long-term memory/consol-
idation, memory retrieval, and reconsolidation (see Box A for detailed
description of memory stages). Acquisition/Encoding is the initial stage
of memory formation in which the subject learns something new (ie.
acquires information). This process requires that the subject be atten-
tive, and that there be no retroactive or proactive interference that
occlude learning of the current information. Working memory refers to
the holding of information online in order to keep processing additional
information, whereas short-term memory is the ability to hold the
given information offline in mind for a given period. Short-term
memory (STM) thus refers to memories that are held in mind for a
relatively short period of time – seconds to minutes (ie. remembering
a phone-number until you can write it down) (Cowan 2008). This differs
from long-term memory, which can hold information for long periods
of time, without a predefined limit on the quantity of information held.
Long-term memories (LTM), in fact, can last for days, months, years,
even a lifetime. The process that transforms the learned information
into LTM is known as memory consolidation, the process that accom-
panies the transition from a labile memory to one that is stable and
resistant to disruption. This transition requires a number of molecular,
cellular and structural changes that occur over time, with some com-
pleting over hours or days and others extending over weeks, months
or perhaps even years; once those events are completed, the memory
is considered stable or consolidated (McGaugh 2000). If any of the
phases underlying consolidation is disrupted, memory is lost. Finally,



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retrieval is the process of recalling a memory. A challenge for studies
aiming to identify the mechanisms of memory consolidation is the dif-
ficulty in discerning whether a memory deficit lies in the consolidation
process (ie. the memory was never formed or was eliminated) or the
retrieval process (ie. the memory is stored but cannot be retrieved, or
recalled). Furthermore, it is likely that substances that enhance re-
trieval might be clinically beneficial, yet this stage of memory has re-
ceived little attention thus far. Importantly, both the number and mo-
dality of retrievals can influence memory consolidation and storage. In
the 1960’s, and later again around the year 2000, it was shown that
retrieval of a memory that has become resilient to the initial molecular
interference initiates another round of consolidation as, in fact, this
retrieved memory becomes again temporarily labile, and undergoes a
re-stabilization process in order to be maintained (Nader, Einarsson
2010). This re-stabilization is known as reconsolidation. The function
of reconsolidation is still being debated, however, one compelling hy-
pothesis is that it facilitates memory strengthening, an intriguing out-
come which will be discussed in further detail below. Why is it im-
portant to differentiate these different stages of memory in the context
of discovering memory enhancers? Cognitive dysfunction can result
from impairments in one or more of these stages, and is it thus critical
to identify stages can be selectively or better targeted for the most
efficacious cognitive therapy. For example, a substance that enhances
attention may increase the probability of the information being en-
coded successfully, and therefore may enhance the memory (Lynch,
Palmer, Gall 2011). Additionally, a prominent symptom of the devas-
tating AD seems to be the inability to consolidate long-term memories,
as a gradient of retrograde amnesia accompanies AD progression
(Simard, Reekum 1999; Carlesimo, Oscar-Berman 1992). However,
many AD patients also have attention deficits, which would in turn
cause a problem with the initial encoding (Perry, Hodges 1999). This is



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particularly true also for PD patients, where deficits in attention and
executive control are the paramount cognitive impairments (Dubois,
Pillon 1997). But even without the extremes of these devastating pa-
thologies, in healthy individuals – particularly with aging – a common
complaint is not being able to “remember” well enough, which com-
monly refers to the inability to retrieve memories (Cansino 2009),
though it is not entirely clear where the exact impairment in normal
aging lies (Light 1991). Thus, in an experimental setting, it is important
to consider which stage of memory a putative memory enhancer is
affecting. This is relatively straightforward via pharmacological means,
which can be administered at any time point, before or after training
or retrieval. Genetic or molecular approaches represent other means
to manipulate memories, and different behavioral tasks may be tested
to get a sense of which stages are affected by the manipulation, for
example working memory tasks vs. long-term memory tasks (See Box
A for descriptions of common tasks used for these purposes). Undoubt-
edly, all behavioral, pharmacological and molecular approaches repre-
sent important levels of investigation that, in combination, can provide
a better understanding of mechanisms of memory formation and en-
hancement.


1.2. Types of Memories and Memory Systems
Memories can be classified not only in a temporal manner, but also
according to their type and function, as well as by which brain regions
underlie their formation and processing (Squire 1992). The view that
memories could be anatomically localized has been long disputed. A
landmark discovery in this area was that of Brenda Milner who studied
the memory deficits of a patient known as H.M. Due to severe epilepsy,
H.M. underwent a bilateral medial temporal lobe resection and, while
he emerged fully treated from the epilepsy, he developed profound
memory deficits that were mostly restricted to the formation of long-



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term explicit memories. Studies conducted with H.M. and other pa-
tients with selective brain damage suggested that there are numerous
memory types that can exist independently, but often interact (Corkin,
Amaral, Gonzalez, Johnson 1997) (Figure 1). Explicit – or declarative
– memories, which were disrupted in H.M., can be either semantic (re-
ferring to memories of facts or concepts ie. your date of birth) or epi-
sodic (referring to memories of events ie. your birthday party), and are
subserved primarily by the medial temporal lobe, particularly by the
hippocampus. Moreover, there are implicit types of memories, the
memories of how to do things, which critically involve motor learning,
such as skiing, playing piano, or riding a bicycle. One type of implicit
memory is the memory formed as a consequence of simple associative
learning; when the associations are emotional, (i.e. between a neutral
stimulus and a stimulus with a valance, either aversive or rewarding),
the learning relies primarily on the amygdala. When the associations
produce reflexive skeletal responses, as in the case of delay eyeblink
conditioning, the learning relies primarily on the cerebellum. A more
gradual type of implicit learning that results in the formation of motor
skills and habits relies primarily on the striatum.
    Importantly, these memory systems are not separated in nature,
acting alone and on one type of memory, but rather, they coexist and
often interact. For example, inhibitory avoidance and contextual fear
conditioning memories that are commonly used in rodent memory
studies (see Box A for description of behavioral tasks) involve multiple
brain regions and multiple types of memories. In fact, these tasks re-
quire, for example, both an emotional, implicit component, mediated
by the amygdala, and a contextual, explicit component mediated by
the hippocampus. Similarly, by shifting certain parameters such as
cueing specific arms or providing enriched contextual cues, the same
radial arm maze with food reward (see Box A for a detailed description
of task) can be used to train animals to visit specific arms by very



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different strategies, mediated by either amygdala, hippocampus, or
striatum (White, McDonald 2002). Thus, depending on task demands,
various structures may be engaged to process what seems like identi-
cal information (ie. that a number of arms contain food) in different
ways, producing different kinds of memories.
      For the purposes of developing memory enhancers, it is important
to note that in cognitive impairments associated with AD or aging-re-
lated cognitive decline, the most vulnerable memories are those same
memories that were lost in H.M. Implicit memories are very often
spared, or at the very least, impaired at the last stages of the disease.
Thus, there is an urgent need to identify therapies that target impair-
ments of hippocampal-dependent memories. However, as mentioned
above, impairments associated with PD are often linked to working
memory and executive control, and thus discovering mechanisms of
enhancement for those disorders are equally important.
      Importantly, it is critical to keep in mind that there might be sev-
eral drawbacks with the use of cognitive enhancers; for example the
effect could be non-selective enhancement, as a drug that enhances
synaptic plasticity may result in the enhancement of both adaptive and
maladaptive memories. Another drawback could be that memories are
enhanced but become rigid and inflexible, or cognitive stimulants may
lead to hyperactivation and seizure. Thus, while enhancement of in
vitro synaptic plasticity and excitability is a useful tool for establishing
physiological effects of various substances, it is always necessary to
comprehensively investigate all possible effects using in vivo treat-
ments and behavioral as well as physiological measures, as they pro-
vide the most compelling evidence of which approaches will be most
effective in clinical populations.




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2. Mechanisms of Memory Enhancement
2. 1. Gene Expression: The CREB-C/EBP Pathway
One of the first mechanisms identified as critical for long-term memory
consolidation (both explicit and implicit) is the requirement for de novo
protein and RNA synthesis (Davis, Squire 1984). Similar requirements
have been found for long-term plasticity, including long-term facilita-
tion in Aplysia californica and a phase of LTP that lasts more than one
hour, known as late-LTP (LLTP) (Alberini 2009), though not all late
forms of LTP appear to share this requirement (Villers, Godaux, Ris
2012). Many years of discussions have debated the functional effects
of protein synthesis inhibitors used in many experiments, and we refer
to this literature for questions, outcomes and debates (Alberini 2008;
Sharma, Nargang, Dickson 2012). Regardless, the findings that in ad-
dition to pharmacological approaches molecular and genetic methods
have provided evidence that transcription and translation are essential
for memory, led to the subsequent discovery of important, evolution-
arily conserved pathways required for long-term memory formation:
that regulated by the transcription factors CREB and C/EBP (Figure 2).
CREB is activated by numerous signal transduction pathways impli-
cated in memory consolidation and enhancement, from growth factor
stimulation of tyrosine kinase receptors coupled to the activation of Ras
and extracellular signal-regulated kinase (ERK); to G-Protein Coupled
Receptor (GPCR) activation coupled to activation of adenylyl cyclase,
increase in cAMP, and activation of protein kinase A (PKA); to the ac-
tivation of stress pathways and glutamate release leading to release of
intracellular calcium and relative downstream events. All of these path-
ways can lead to the activation of an activator form of CREB, CREB1.
This activation in turn can lead to the transcriptional regulation of a
number of target genes, including immediate early genes (IEG). Some
IEGs are transcription factors, which regulate the expression of effector
genes that are thought to participate in downstream synaptic changes



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underlying synaptic plasticity. This is, for example, the case with the
IEG/transcription factor C/EBPβ, a CREB-regulated target gene re-
quired for memory consolidation (Alberini 2009).
      Disrupting CREB1 results in memory deficits, while augmenting
CREB1 activation results in memory enhancement. The first demon-
strations that CREB plays an essential role in both the disruption and
enhancement of memory consolidation came from studies in inverte-
brates, namely Aplysia californica and Drosophila melanogaster. In Ap-
lysia, Bartsch et al. (Bartsch, Ghirardi, Skehel, Karl, Herder, Chen, Bai-
ley, Kandel 1995) reported that the disruption of ApCREB1, the Aplysia
homolog of mouse CREB1 leads to an impairment in long-term facilita-
tion (a cellular model of long-term memory in Aplysia), and that the
interference of a repressor form of CREB, ApCREB2, induces a longterm
facilitation response from training protocols that would normally only
produce shortterm facilitation. In parallel studies, Yin et al. (Yin, Del
Vecchio, Zhou, Tully 1995) using transgenic Drosophilae with a heat
shock–inducible CREB repressor soform (hs-dCREB2-b) showed that
flies with the transgene on have impaired memory. Further studies in
mice and rats extended these conclusions by showing that while the
knockout or knockdown of CREB1 results in longterm memory impair-
ment, viral overexpression of CREB1 in amygdala and hippocampus
enable LTM formation from massed training protocols of either cued-
fear conditioning or place learning, which normally produce only STM
(Josselyn, Shi, Carlezon, Neve, Nestler, Davis 2001; Brightwell, Smith,
Neve, Colombo 2007). In Aplysia, knockdown of C/EBP impairs long-
term memory, while overexpression of C/EBP leads to memory en-
hancement, similar to that produced by overexpression of CREB1, as
short-term facilitation is converted to long-term facilitation (Alberini
2012; Lee, Kim H., Kim K., Han 2001) Manipulations of C/EBP also lead
to memory disruption or enhancement in rats (Alberini 2012) or mice,
as    hippocampal     knockdown      impairs    memory,     while    forebrain



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expression of a general dominant-negative inhibitor of the C/EBP/ATF
family (EGFP/ AZIP), which presumably relieves their inhibition, results
in enhanced spatial memory (Chen, Muzzio, Malleret, Bartsch, Verbit-
sky, Pavlidis, Yonan, Vronskaya, Grody, Cepeda et al. 2003).
    From the seminal studies that directly acted on CREB1 levels,
many other findings followed and have identified memory-enhancing
effects that correlate with increases in the activation of the CREB path-
way. A natural direction of these studies has been to target activators
that are upstream of CREB, such as cAMP, PKA or mitogen-activated
protein kinase (MAPK) (Xia, Huang, Guo, Southall, Cho, Inglese, Aus-
tin, Nirenberg 2008), though it is interesting to note that in certain
cases in which neuronal excitability is altered, a decrease in cAMP sig-
nalling may actually be preferable (Wang, Gamo, Yang, Jin, Wang, Lau-
bach, Mazer, Lee, Arnsten 2011). others have theorized that lifting the
inhibition of CREB activation might be an effective route for memory
enhancement. For example, in mice, releasing the inhibition provided
by calcineurin, a Ca2+/calmodulindependent phosphatase which regu-
lates pCREB levels, also leads to memory enhancement, via CREB-de-
pendant mechanisms, of both short-term and long-term hippocampal-
dependent memories, without changing working memory (Malleret,
Haditsch, Genoux, Jones, Bliss, Vanhoose, Weitlauf, Kandel, Winder,
Mansuy 2001). In Aplysia, inhibition of calcineurin facilitates interme-
diate-term and LTM, but not STM (Sharma, Bagnall, Sutton, Carew
2003). These studies have been extremely important in gaining an un-
derstanding of how memories can be enhanced in an experimental set-
ting by manipulation of CREB levels and/or activity, and imply that the
activation of the CREB-dependent pathway might be an effective target
for promoting and enhancing hippocampal-dependant LTMs.
    There have been a number of attempts to screen for drugs that
via CREB activation could potentially be used as cognitive enhancers in
humans. These screenings led to the identification of a number of



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candidate drugs, including rolipram, which inhibits phosphodiesterate
type 4 (PDE4), an enzyme that catalyzes hydrolysis of cAMP (Xia,
Huang, Guo, Southall, Cho, Inglese, Austin, Nirenberg, 2008; Tully,
Bourtchouladze, Scott, Tallman 2003). Additionally, CREB-C/EBP tar-
get genes may be valuable candidates for memory enhancement. One
C/EBPβ-target gene upregulated after learning in the hippocampus and
required for memory consolidation is the insulin-like growth factor 2
(IGF-II or IGF-2). Administration of recombinant IGF-II immediately
after learning or memory retrieval significantly enhances memory and
prevents forgetting (Chen, Stern, Garcia-Osta, Saunier-Rebori, Pol-
lonini, Bambah-Mukku, Blitzer, Alberini 2011). The effect and action of
IGF-2 as memory enhancer will be further discussed below. In general,
it is important to recognize that, because CREB has important functions
throughout the body and diverse effects throughout the brain, an ef-
fective treatment based on manipulating CREB or its target genes may
require the development of strategies that enhance selectivity and
specificity (Barco, Pittenger, Kandel 2003).


2.2. Synaptic Remodeling
Long-term memory formation is critically associated with synaptic re-
modeling, including the growth or pruning of synapses, as well as al-
tered synaptic efficacy (Lamprecht, LeDoux 2004). These changes oc-
cur through a number of local regulations, including mRNA translation,
protein degradation, remodeling of cytoskeleton, and receptor traffick-
ing into and out of the synapse.
      One of the first transgenic manipulations that produced memory
enhancement targeted receptor trafficking. In that study, Tang et al.
(Tang, Shimizu, Dube, Rampon, Kerchner, Zhuo, Liu, Tsien 1999)
overexpressed in the hippocampus of mice an N-Methyl-D-aspartic acid
(NMDA) subunit, NR2B, that had previously been shown to be required
for synaptic plasticity and LTM, and found that a number of memories



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– namely, novel-object recognition, cued and contextual fear condi-
tioning, fear extinction, and Morriswater maze – were all significantly
and persistently enhanced. Similarly, later studies showed that if the
NR2B subunit was overexpressed in prefrontal cortex, working memory
tasks such as the T-maze and a modified water maze were also en-
hanced (Cui, Jin, Zhang, Xu, Yang, Du, Zeng, Tsien, Yu, Cao, 2011).
Although it is difficult to parse with a genetic manipulation what stage
of the memory is being affected, pharmacological studies indicated that
manipulations of NMDA receptors (NMDARs) can enhance both working
memory and LTM-consolidation (Riedel, Platt, Micheau 2003) suggest-
ing that synaptic glutamate receptor expression and trafficking play a
significant role in enhancing memory formation and maintenance. En-
hancement via NMDARs can be obtained both with agonists and low
doses of antagonists (Danysz, Zajaczkowski, Parsons 1995), suggest-
ing that a tight regulation of NMDARs is required in order to facilitate
memory processes. The mechanisms by which an enhanced NR2B re-
ceptor concentration at the synapses leads to memory enhancement is
not yet understood. Some insights come from LTP and LTD studies,
due to the fact that many similarities exist between the requirements
for LTP induction and maintenance and LTM acquisition and consolida-
tion (Izquierdo 1994). One theory to explain the memory enhancement
effects after increasing NR2B is that they may occur in part by the
facilitation of LTP in these regions, whereas overexpression of an alter-
nate subunit, NR2A, facilitates LTD (Wang, Cui, Zeng, Kuang, Wang,
Tsien, Cao 2009), perhaps because NR2B containing NMDARs are more
calcium permeable than NR2A-containing NMDARs. In agreement with
this model, partial agonists of NR2B improve memory and enhance LTP
in aged rats that have LTP, but not LTD, deficits (Burgdorf, Zhang,
Weiss, Matthews, Disterhoft, Stanton, Moskal 2011).
    The ability for NR2B overexpression to result in memory enhance-
ment may occur through the subsequent increased ability of NMDA



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Sarah A. Stern, Cristina M. Alberini, Mechanisms of Memory Enhancement




receptors to be activated due to their increased number. Indeed, par-
tial agonists of NMDARs such as D-cycloserine and D-serine have
memory-enhancing effects. D-Cycloserine facilitates long-term fear
memory consolidation in humans (Kalisch, Holt, Petrovic, De Martino,
Klöppel, Büchel, Dolan 2009) and facilitates fear extinction in a rodent
model of PTSD, perhaps through normalization of elevated levels of
NMDAR subunit mRNA (Yamamoto, Morinobu, Fuchikami, Kurata, Ko-
zuru, Yamawaki 2008).
      Another critical receptor type that has been implicated in memory
enhancement is the 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)pro-
panoic acid (AMPA) receptor. Though, like NMDARs, AMPARs respond
to glutamate, they do not have a magnesium block and are therefore
activated with less depolarization of the cell. Indeed, AMPARs them-
selves are required for NMDAR activation, as a synapse without AM-
PARs (known as silent synapses) will not be able to obtain sufficient
depolarization to displace the magnesium block and allow calcium in-
flux (Rao, Finkbeiner 2007). In models of LTP, changes in AMPARS (ei-
ther through increases in the number of receptors, or changes in re-
ceptor effectiveness through phosphorylation) are thought to mediate
the long-lasting changes that support LTP maintenance or persistence.
For example, inactivation of the atypical protein kinase C isoform M
Zeta (PKMzeta) in the amygdala and hippocampus leads to deficits in
fear and object recognition memory in rats, which appears to be due
to a decrease in post-synaptic GluR2-containing AMPARs (Migues,
Hardt, Wu, Gamache, Sacktor, Wang, Nader 2010). Overexpression of
PKMzeta in insular cortex leads to enhancement of conditioned taste
aversion memory in rats, and the underlying mechanisms are under
investigation (Shema, Haramati, Ron, Hazvi, Chen, Sacktor, Dudai
2011). Similarly, long-term memory correlates with an increase in syn-
aptic AMPA receptors, which are known in vitro to be trafficked via the
endosomal system (Ehlers 2000). Synthetic compounds, known as



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Ampakines, which allow glutamate to have a prolonged effect on AM-
PARs, have been found to strengthen memory retention on a number
of tasks and in a number of different species (Lynch 2006). These com-
pounds have the advantage of passing the blood-brain barrier and of
being selective for the central nervous system (CNS).
    A number of compounds known to enhance memory are also
known to increase NMDAR/ AMPAR levels (Slutsky, Abumaria, Wu,
Huang, Zhang, Li, Zhao X, Govindarajan, Zhao M-G, Zhuo, et al. 2010;
Hu, Real, Takamiya, Kang, Ledoux, Huganir, Malinow 2007; Krugers,
Hoogenraad, Groc 2010). However, there is still little known about
which subunits are increased at different stages of memory. One mech-
anism of action could be that NMDARs activate CREB and set in motion
the gene expression changes discussed above. These changes would
then lead to morphological modifications at the synapse, including
growth of new spines and increased AMPAR insertion (Figure 3). It is
possible that these synaptic changes may represent the endpoint of
many memory enhancers. Hence targeting receptor expression may be
a general approach to achieve memory enhancement.
    One regulatory protein that seems to be linked to receptor traf-
ficking regulation and is induced by learning and required for memory
consolidation is the immediate early gene Arc. A number of studies
have linked in particular Arc to NMDA/AMPA receptor trafficking (Rao,
Finkbeiner 2007) and memory enhancement (Chen, Stern, Garcia-
Osta, Saunier-Rebori, Pollonini, Bambah-Mukku, Blitzer, Alberini 2011;
McReynolds, Donowho, Abdi, McGaugh, Roozendaal, McIntyre 2010).
In vitro studies have shown a role for Arc in removal of Glur1 from
synapses, and recent works shows that Arc may in fact be tagged to
inactive synapses to depress them during memory formation (Okuno,
Akashi, Ishii, Yagishita-Kyo, Suzuki, Nonaka, Kawashima, Fujii, Take-
moto-Kimura, Abe et al. 2012). Synaptic remodeling leading to
memory enhancement does not only refer to changes in synaptic



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Sarah A. Stern, Cristina M. Alberini, Mechanisms of Memory Enhancement




receptors. More global, morphological changes of the synaptic archi-
tecture have also been shown to correlate with memory enhancement.
Rho-GTP-ases, which lead to remodeling of the actin cytoskeleton, en-
hance memory when rendered constitutively active by Cytotoxic ne-
crotizing factor 1 (CNF1), a protein toxin from Escherichia coli (Diana,
Valentini, Travaglione, Falzano, Pieri, Zona, Meschini, Fabbri, Fiorentini
2007). Similarly, cell adhesion molecules such as neural cell adhesion
molecule (NCAM), which are involved in the remodeling of neural cir-
cuits, have been successfully targeted for memory enhancement in ro-
dents, via a mimetic peptide that interacts with the fibroblast growth
factor receptor (FGFR) (Cambon, Hansen, Venero, Herrero, Skibo, Be-
rezin, Bock, Sandi 2004). There are also suggestions that changes in
spine shape and size may correlate with memory formation, as LTP is
associated with increases in stable, mushroom-shaped spines (Bourne,
Harris 2007), but direct causative knowledge about how changes in
spine morphology relate to memory in general, and specifically to
memory enhancement, are still lacking.


2.3. Neuromodulation
Neuromodulators, which alter cellular and synaptic properties via wide-
spread projections (Kupfermann 1979) have a well-known role in
memory function and many modulation pathways have been targeted
for memory enhancement (Floresco 2011).
      One neuromodulator with a well-known effect on cognition is do-
pamine. Dopamine action is particularly evident in patients who suffer
from PD, which involves a loss of dopaminergic neurons and conse-
quently severe motor deficits. The loss of dopamine is also accompa-
nied by a noticeable cognitive impairment in many patients, who are
diagnosed with dementia as the disease progresses (Mckeith, Burn
2000). However, even in PD patients without dementia, many cognitive
domains     appear     to   be    impaired     during     neuropsychological



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examination. In contrast with many other diseases of cognitive impair-
ment, PD is specifically accompanied by deficits in tasks associated
with prefrontal cortex, including executive function and planning, ra-
ther than with memory consolidation impairments (Dubois, Pillon
1997). Dopamine is thus widely thought to be extremely important for
working memory tasks relying on the prefrontal cortex (PFC), and low
levels of dopamine receptor D1 (DRD1 or D1) antagonists enhance
working memory as revealed by an increase in neuronal activity during
a delay period of a delayed-non-match-to-sample task, whereas high
levels of antagonists and agonists both impair that activity (Williams,
Goldman-Rakic 1995). Hence, there is an inverted-U curve effect of
dopamine on working memory. However, the effects of dopamine on
working memory may be restricted to improvement of conditions com-
promised in dopamine function, as the same treatments in young ani-
mals do not show memory enhancement that is seen in aged animals
(Castner, Goldman-Rakic 2004). The effects of dopamine alterations
on LTM have been given less attention. An early study showed that
dopamine itself given i.c.v. to mice after training enhanced step-
through IA at 24h (Haycock, Van Buskirk, Ryan, McGaugh 1977), and
recently, the D1 agonist SKF38393 given i.p. post-training was shown
to enhance 24h and 72h memory of novel object recognition in rats (de
Lima, Presti-Torres, Dornelles, Scalco, Roesler, Garcia, Schröder
2011). Many of the behavioral results are complemented by electro-
physiological data showing that AMPA and NMDA currents are en-
hanced by the injection of a D1/D5 agonist in the hippocampus (Yang
2000).
    It has long been known that emotional events are better remem-
bered than non-emotional events. Therefore, other neuromodulators
that are particularly important for memory are the stress hormones
corticosteroids and adrenaline, which are released during arousing ex-
periences. Corticosteroids can activate two receptors – glucocorticoid



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Sarah A. Stern, Cristina M. Alberini, Mechanisms of Memory Enhancement




(GR) and mineralocorticoid (MR). While MRs have a very high affinity
for corticoids and are therefore tonically activated, GRs have a much
lower affinity and are therefore preferentially activated in conditions of
high stress. Manipulations of both receptors have effects of memory,
but the behavioural effects of GR have been better characterized (Kru-
gers, Hoogenraad, Groc 2010). Thus, when cortisol (in humans) or cor-
ticosterone (in rodents) is released in concert with a stressful experi-
ence, memory is better recalled at later times (McGaugh, Roozendaal
2002). The enhancing effect of cortisol administration can be obtained
via behavioral methods of inducing stress as well, a this is thought to
be a key mechanism regulating intrusive memories that occur with
post-traumatic stress disorder (PTSD) (Yehuda 2002). However, it is
also known that very intense or prolonged stress may cause memory
impairments, as may be the case with intense physical exertion such
as occurs with marathon runners (Eich, Metcalfe 2009). Experimen-
tally, this effect is known as the inverted-U effect of stress on perfor-
mance, and is seen in animal models as well. Moderate to high stress
produce a robust memory in rodents, whereas extremely high stress
results in low memory retention. Many studies conclude, however, that
glucocorticoids can only enhance memories that inherently involve
emotional arousal. Animals tested in a novel context for object recog-
nition show memory enhancement via corticosterone administration,
whereas animals that underwent habituation to the context prior to
training did not show enhancement with corticosterone (Roozendaal,
Okuda, Van der Zee, McGaugh 2006). Likewise, administration of nor-
adrenaline after training enhances memory retention (Gold, Ruskirk
1976) which likely occurs through the activation of beta-adrenergic re-
ceptors, subsequent activation of adenylyl cyclase, PKA and Ca2+/cal-
modulin-dependent protein kinases II (CAMKII). Thus, specific agonists
of β-adrenergic receptors enhance memory, similarly to what occurs
via increased arousal during encoding. Noradrenaline is produced



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primarily in the locus coeruleus and adrenal medulla and many enhanc-
ing effects of other modulators, such as glucocorticoids, are critically
regulated by the activity of noradrenaline in the amygdala, as sug-
gested by classical studies of Roozendaal et al. showing that a β-adre-
nergic receptor antagonist infused into the amygdala blocks memory
enhancement produced by glucocorticoids infused into the hippocam-
pus (Roozendaal, Nguyen, Power, Mcgaugh 1999).
    In line with all these findings, a number of stimulant drugs that
work on inhibiting monoamine reuptake, including amphetamines,
methylpehidate (Ritalin®) and modafinil (Provigil®), have been found
to improve cognitive function in patients with attention-deficithyperac-
tive-disorder (ADHD), and there have been reports of improved func-
tion in healthy subjects as well. Recently, methylphenidate was tested
on human subjects who learned a list of words; immediate recall did
not differ, but delayed recall, 1 day to 1 week later, showed improve-
ment at two doses (Linssen, Vuurman, Sambeth, Riedel 2011).
    Though prior studies did not find the same effect, the authors note
that this may be due to shorter word lists that were used which may
have produced a ceiling effect. Regardless, methylphenidate is well
known to have pronounced effects on spatial working memory and sus-
tained attention (Advokat 2010). The same is generally thought to be
true of modafinil, which is traditionally prescribed for narcolepsy. Some
studies indicate that positive effect on cognition may be due to in-
creased arousal and attention rather than enhancement of LTM or con-
solidation processes (Lynch, Palmer, Gall 2011). Thus, modafinil may
be effective in treating specific aspects of cognitive dysfunctions that
target attention rather than memory.
    Acetylcholine is perhaps one of the most well-studied neuromod-
ulators in the context of hippocampal-dependant memory, and the ac-
etylcholine theory of memory enhancement has been studied for many
years. Acetylcholine is required for memory formation, as observed by



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Sarah A. Stern, Cristina M. Alberini, Mechanisms of Memory Enhancement




lesion studies as well as pharmacological inhibition of acetycholine nic-
otinic and muscarinic receptors. Focusing on memory enhancement, a
number of agonists of these receptors have been targeted with varying
results (Deiana, Platt, Riedel 2011). Moreover, observations in labora-
tory mice that inhibiting acetylcholine uptake could enhance memory
led to drugs designed to inhibit the enzyme responsible for degrading
acetylcholine, acetycholinesterase. These drugs, namely donepezil
(Aricept®) are now the only available treatment for mild- to moderate-
AD. Meta-analyses of the clinical trials studies indicate that although
there are benefits of these drugs, the magnitude of their benefit is lim-
ited because they offer symptom relief without modifying the disease
(Birks 2009). Moreover, the beneficial effects are possibly restricted to
attention processes rather than enhancing consolidation mechanisms,
and may in fact impair memory consolidation by maintaining consist-
ently high levels of cholinergic activity (Deiana, Platt, Riedel 2011;
Prickaerts, Sik, van der Staay, de Vente, Blokland, 2005).


2.4. Endogenous Substances
The effects on memory enhancement discussed above are mainly the
results of pharmacological manipulations with synthetic compounds,
especially for those used in clinical studies, as is the case with Am-
pakines, D-Cylcoserine, and Donepezil. However, a number of endog-
enous substances, primarily those that are key players in metabolic
processes (ie. glucose and insulin), have been known to have a direct
memory enhancing effect for quite some time. Early studies showing
that recently fed subjects performed better than those who had not
eaten for some time piqued a long-lasting interest in whether glucose
administration can enhance memory functions (Lapp 1981). Subse-
quently, a wealth of studies examined glucose-mediated memory en-
hancement, in both animal models as well as humans due to the rela-
tive ease and safety of glucose administration.



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    Though there have been contrasting findings (Azari 1991; Foster,
Lidder, Sünram 1998), the majority report that in healthy, young adult
rodents and humans memory is enhanced by glucose given pre- or
post- training, indicating that glucose may be able to facilitate both
encoding and memory consolidation, thought in healthy individuals this
may be true only when task demands are high(Smith, Riby, Eekelen,
Foster 2011). Importantly, in humans, the vast majority of studies use
participants that have fasted for at least 2 hours to overnight before
training, indicating that many of the effects seen might actually be in-
dicating that glucose deprivation is deleterious, rather than enhance-
ment by glucose itself. The enhancing effects of glucose was mainly
found on declarative, hippocampal-dependant memories tested at rel-
atively early time points (up to 24h) after training (Gold, Vogt, Hall
1986). The effects of glucose administration on cognitively-impaired
individuals vary, revealing that individuals with very mild problems
may have a longer-lasting enhancement by glucose, but those who
have already a progressed disease do not show a sustained memory
enhancement (Gold, Vogt, Hall 1986).
    The mechanisms by which glucose enhances memories are not yet
entirely understood. A number of studies indicate that the effect may
be due to insulin, whose receptors are highly enriched in the hippo-
campus. In itself, insulin has been shown to enhance hippocampalde-
pendent memories in both rats and humans. However, in rats, insulin-
mediated memory enhancement has not been tested past 24h (McNay,
Ong, McCrimmon, Cresswell, Bogan, Sherwin 2010) and may not per-
sist up to 1 week after inhibitory avoidance training (Stern and Alberini,
unpublished data). Recent studies suggest that insulin may provide
memory enhancement also in humans (Benedict, Hallschmid, Hatke,
Schultes, Fehm, Born, Kern 2004) and several indicate that the en-
hancing effects of glucose may be due entirely to glucose-stimulated
increases in insulin levels (Craft, Asthana, Newcomer, Wilkinson,



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Sarah A. Stern, Cristina M. Alberini, Mechanisms of Memory Enhancement




Matos, Baker, Cherrier, Lofgreen, Latendresse, Petrova, et al. 1999).
In AD patients, hyperinsulinemia improves performance independent
of glucose levels, but hyperglycemia, while maintaining insulin levels
at baseline, does not provide the same benefit. Intranasal insulin ad-
ministration has begun to be tested in patients with mild cognitive im-
pairment and mild-to-moderate AD. In a double-blind study of patients
given insulin over 4 months, improvement was seen in a number of
measures tested at months 2 and 4 of treatment, as well as two months
after treatment was discontinued. The most significant improvement
was seen on delayed score recall test (measured with a delay of 20
minutes), but improvements were also seen in a general tests of cog-
nitive ability and partnership scores, a measure of assessment for care-
takers of AD patients (Craft, Baker, Montine, Minoshima, Watson, Clax-
ton, Arbuckle, Callaghan, Tsai, Plymate, et al. 2012). These results are
very promising, and it would be important if follow-up studies examine
memory over longer delays.
      In rats, in contrast to glucose and insulin which showed transient
effects, a single administration of IGF-II was recently found in our lab
to enhance hippocampal-dependant memory for at least three weeks
when administered post-training (Chen, Stern, Garcia-Osta, Saunier-
Rebori, Pollonini, Bambah-Mukku, Blitzer, Alberini 2011). Furthermore,
IGF-II injected into rat hippocampus was found to enhance extinction
in mice (Alberini, Chen 2012; Agis-Balboa, Arcos-Diaz, Wittnam, Go-
vindarajan, Blom, Burkhardt, Haladyniak, Agbemenyah, Zovoilis, Sa-
linas-Riester, et al. 2011). IGF-II is part of the insulin-like growth fac-
tor system, which also includes insulin and insulin-like growth factor I
(IGF1 or IGF-I). Interestingly, IGF-I does not seem to have any
memory enhancement effect on the tested memories. The memory en-
hancing effect of IGF-II requires the IGF-II, but not IGF-I, receptor.
This is interesting because unlike IGF-I and insulin receptors, IGF-IIR,
which is identical to the cation-independent mannose-6-phosphate



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receptor, is not a tyrosine-kinase receptor, but a receptor that targets
proteins to endosomes and lysosomal degradation processes (Roth
1988). Very little is known about what downstream mechanisms cause
this persistent memory enhancement, but due to the receptor require-
ment and the different temporal dynamics, it seems likely to hypothe-
size that it uses mechanisms distinct from those of insulin or glucose.
Interestingly, IGF-II-mediated memory enhancement correlates with
increases in synaptic GluA1 receptor at 30 minutes after training, indi-
cating that endogenous targeting of AMPARs may be very effective in
promoting memory enhancement. IGF-II may also have an effect on
the cholinergic system. In hippocampal neurons, IGF-II potentiates ac-
etylcholine release (Hawkes, Jhamandas, Harris, Fu, MacDonald, Kar
2006); therefore, it is possible that an endogenous effect of IGF-II is
to potentiate acetylcholine release and action, in addition to regulating
other mechanisms. Though very little is known about the role of IGFII
in cognitive functions, the ability for IGF-II to pass the blood-brain-
barrier (Reinhardt, Bondy 1994) makes it a particularly exciting com-
pound for both preclinical and clinical studies.
    Other growth factors, for example brain-derived neurotrophic fac-
tor (BDNF), also regulate memory retention. A number of studies have
shown increased BDNF mRNA or protein levels following memory en-
hancement treatments (Slutsky, Abumaria, Wu, Huang, Zhang, Li,
Zhao, Govindarajan, Zhao, Zhuo 2010; Lynch 2002; van Praag 2009).
However, there seem to be no current evidence that BDNF itself can
enhance memory in a non-diseased animal when given close to the
time of training, as is the case with IGF-II. However, BDNF appears to
increase memory persistence. For example, BDNF injected into the dor-
sal rat hippocampus 12 hours after an IA training with a low footshock,
which produces a memory that would normally be forgotten by 7 days,
leads to   memory     persistence   (Bekinschtein, Cammarota, Igaz,
Bevilaqua, Izquierdo, Medina 1997). In disease models, BDNF may



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Sarah A. Stern, Cristina M. Alberini, Mechanisms of Memory Enhancement




reverse memory deficits, making it an attractive candidate for selective
enhancement of failing memories.


2.5. Behavioral Methods
In addition to pharmacological approaches, there are a number of be-
havioral manipulations that have been found to be effective in promot-
ing memory enhancement. First, repetition has long been known to
enhance memory performance, and it has been consistently shown that
repeated training trials and/or learning events are associated with bet-
ter memory (Pinsker, Hening, Carew, Kandel 1973). This method is
one that is employed during everyday learning, and is also known to
have benefits for cognitive disorders such as dementia.
      Similarly, memory can be enhanced by targeting retrieval-induced
reconsolidation, which occurs through repeated retrieval sessions.
When a memory is retrieved, it can again return to a labile state and
can undergo reconsolidation (Alberini, Milekic, Tronel 2006). It has
been suggested that a function of reconsolidation is to increase
memory strength (Sara 2000). Recently in our laboratory it was found
that, in IA, multiple memory reactivation by brief (10 sec) exposures
to the context results in memory enhancement in rats through recon-
solidation, whereas multiple retrievals consisting of a full testing ses-
sion can result in fear extinction (Inda, Muravieva, Alberini 2011). No-
tably memory changes over time, and in order to attain a memory
enhancing effect, retrievals must occur within a relatively short time-
span after training. Indeed the same multiple 10 second retrievals
which had lead to enhancement if given during the first week after
training, result in fear-extinction when given 4 weeks post-training,
indicating that memory strengthening is a function of the age/ stage of
the memory and that likewise, memory storage is dynamic and
changes over time. However, there is currently little knowledge about
the mechanisms by which these changes occur, or whether the



144
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behavioral effect based on reconsolidation would be useful in aging
and/or AD.
    Interestingly, the reconsolidation process does not promote
memory enhancement by behavioral repetitions only. Memory en-
hancement can be in fact promoted via pharmacological manipulations
given in concert with reconsolidation. Thus, injections of nicotine, β-
adrenergic receptor agonists, PKA activators, phosphodiesterase type
5 inhibitors, angiotensin and IGF-II all enhance memory when injected
after retrieval (Alberini, Chen 2012; Dębiec, Bush, LeDoux 2011; Tian,
Huang, Li, Li, Zhou, Deng, Yang 2011). This suggests that memories
can be enhanced even after they are consolidated, and indicates po-
tential new directions for developing treatments for cognitive disorders
that targets in addition to deficits of encoding/consolidation also defi-
cits of already formed memories.
    Another behavioral approach that has been recently found to be
effective in enhancing memories is physical exercise. Numerous stud-
ies over the past two decades in rodents have shown conclusively that
exercise can improve memory in a number of tasks, including the spa-
tial task water maze, the fear task IA and the non-aversive task novel
object recognition. This effect may be more pronounced in aged rats,
and has numerous possible underlying mechanisms, including increase
of the neurotrophin brain derived neurotrophin factor (BDNF), neuro-
genesis, IGF-I, glucocorticoids, and CAMKII activation (van Praag
2009), suggesting once again that echanisms involved in memory con-
solidation may be the best targets to achieve memory enhancement or
prevent memory decay. Though it is generally accepted that exercise
is beneficial in regards to general health, extended lifespan and aging,
the extent and type of exercise needed in humans to attain a benefit
specifically for memory enhancement is not yet mechanistically well
understood, and excessive forms of exercise may actually be deleteri-
ous for declarative, hippocampal-dependent memories by causing



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Sarah A. Stern, Cristina M. Alberini, Mechanisms of Memory Enhancement




extreme stress, as noted above (Eich, Metcalfe 2009). Behavioral
methods for enhancing memory are an exciting avenue of research,
and may be extremely useful in clinical practice with more basic
knowledge of how best to implement their practice, as well as whether
they can be even further augmented through pharmacological means,
as with reconsolidation-mediated enhancement.


3. Sidebar title Behavioral Tasks in Rodents
Pavlovian Fear Conditioning pairs an unconditioned stimulus (US),
which elicits an automatic response (ie. a mild footshock elicits fear
behaviors), with a conditioned stimulus (CS), which has no inherent
valance but subsequently elicits the same behavior as the US (ie. a
tone). Common versions of this task are auditory fear conditioning
(AFC) and contextual fear conditioning (CFC), which pairs a tone and
context, respectively, with a footshock. Memory is measured as the %
time spent freezing during the test.
      Inhibitory Avoidance (IA) trains the animal to avoid the dark side
of a two-chamber apparatus in which it was previously given a foot-
shock. During testing, memory is measured as the latency to enter the
dark compartment.
      Extinction extends fear-based tasks in which the animal learns
through subsequent presentations of the CS without the US that the
previously fearful CS is now safe.
      Morris Water Maze trains animals to find an escape platform in a
circular water maze. Memory during probe trials can be measured as
the percentage of time spent in the correct quadrant or latency to find
the platform.
      Novel Object Recognition (nOR) exploits rodent’s natural tendency
to explore novel objects. Animals are trained with two identical objects,
and during testing, memory is measured as the % time spent with the
novel object. This task can also be modified to ask if animals remember



146
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“where” versus “what” by moving one of the objects rather than re-
placing it with a new object (known as Object Placement).
    Radial Arm Maze trains animals to go to specific arms of an 8-arm
maze to obtain a food reward. Arms may be cued or contextual cues in
the room may guide animals to use the correct strategy to obtain the
reward.


4. Conclusion
There are a number of promising avenues in the field of memory en-
hancement, some of which have been discussed in this Review. There
is now a significant amount of information regarding molecular path-
ways that are likely to be among the most important targets for en-
hancing memories; however, much remains to be understood to trans-
late this knowledge into clinical trials. For example, most studies in
animal models examine effects in males, but a number of studies have
shown that there may indeed be sex differences (Leuner, Shors 2004;
Mizuno, Giese 2010). This is an important outstanding question that
needs to be addressed further.
    The strategies that have promoted memory enhancement in ani-
mal models thus far have primarily relied on mechanisms of memory
consolidation, such as the CREB-C/EBP pathway and receptor traffick-
ing, which have been mainly studies in aversive or spatial memory
tasks. These are mechanisms that are thought to be important for en-
hancing hippocampal-dependent memories and contrasting cognitive
decline in aging and AD. Other studies have focused on the effects of
treatments to enhance working memories, such as targeting dopamine
neuromodulation that will be useful for diseases such as PD.
    Importantly, cognitive enhancement therapies may be useful in
some situations, but not others. Some may be beneficial in enhancing
memory in healthy adults and during normal aging. Others may com-
pensate for disease-related changes, or may instead restore those



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Sarah A. Stern, Cristina M. Alberini, Mechanisms of Memory Enhancement




changes to their original, healthy state. Thus, all potential enhancers
must be tested for their mechanisms of action.
      One important aspect that remains to be deeply investigated is
the question of specificity and flexibility – not all possible memories
require or benefit from enhancement, and it is unclear if/when memory
enhancement interferes with new learning and the consolidation of new
memories. To date, very little attention in animal studies has been
given to enhancement of memory retrieval and to enhancement of re-
mote memories, both of which may be important areas of study with
very important translational potential.
      The study of memory enhancement holds the potential for great
progress in the treatment of numerous diseases of the mind, and for
developing strategies for more efficient learning and cognitive func-
tions.




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Acknowledgments
Many thanks to Dhananjay Bambah-Mukku, Sarah Johnson, Xiaojing
Ye and Michael Garelick for their comments to the manuscript. The
writing and part of the work included in this review are supported by
the National Institutes of Health (R01-MH074736 and R01-MH065635
to C.M.A. and F31-MH090636 to S.A.S.




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Box A. Behavioral Tasks in Rodents
Pavlovian Fear Conditioning – An task pairing an unconditioned stimu-
lus (US), which elicits an automatic response (ie. a mild footshock that
elicits fear behaviors), with a conditioned stimulus (CS), which has no
inherent valance but subsequently elicits the same behavior as the US
(such as a tone). Two common versions of this task are auditory fear
conditioning (AFC) and contextual fear conditioning (CFC), which pairs
a tone and context, respectively, with a footshock. Memory is meas-
ured as the % time spent freezing during the test.
Inhibitory Avoidance (IA) – A one-trial task in which the animal learns
to avoid the dark side two-chamber apparatus in which it was previ-
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mean latency to enter the dark compartment. Extinction – An exten-
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Morris Water Maze – A task of hippocampal-dependant memory in
which animals are trained to find an escape platform in a circular water




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maze. Memory during probe trials can be measured as the percentage
of time spent in the correct quadrant.
Novel Object Recognition (nOR) – A non-aversive task which exploits
rodent’s natural tendency to explore novel objects. Animals are trained
with two identical objects, and during testing, memory is measured as
the % time spent with the novel object. This task can also be modified
to ask if animals remember “where” versus “what” by moving one of
the objects rather than replacing it with a new object (known as Object
Placement).




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Figure 1. Multiple memory systems as targets of memory enhancement
Modified from Squire 1992
Memory consists of multiple stages and types. A number of different stages (in blue)
are involved in acquiring, storing and retrieving a memory. A number of cognitive
disorders (in red) have symptoms that are associated with deficits in specific stages,
while others may have deficits that are more general or unclear in nature (such as
those in cognitive decline over aging). Long-term memory can be subdivided into a
number of different types which rely on different brain regions (in purple). Impair-
ments of these different memories are also associated with different disorders. Puta-
tive memory enhancers may be associated with the the improvement of a specific
stage or memory type, which will therefore affect the clinical population that will
receive therapeutic benefit. WM: working memory; STM: short-term memory; LTM:
long-term memory. Copyright © [1992] by the American Psychological Association.
Adapted with permission. Squire, L. R. (1992). Memory and the hippocampus: A
synthesis from findings with rats, monkeys, and humans. Psychological Review,
99(2), 195–231. doi:10.1037/0033-295X.99.2.195 The use of APA information does
not imply endorsement by APA.




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Figure 2. Schematic representation of the CREB-C/EBP pathway targeted for memory
enhancement
Taken from: Alberini, Chen, 2012. A number of intracellular signal transduction pathways are activated
upon learning by diverse stimuli, such as stress, neurotransmitters, growth factors and membrane depo-
larization, and lead to activation of the CREB-C/EBP pathway. Growth factors bind to and signal via dimer-
ized receptor tyrosine kinase (RTK), which induces activation of both the Ras/Raf/mitogen-activated pro-
tein kinase (MAPK)/MAP kinase kinase (MEK) pathway and the phosphatidylinositol 3-kinase (PI3K)-de-
pendent pathway. Activation of these pathways recruit additional protein kinases, including p90 ribosomal
S6 kinase (RSK2) and mitogen- and stress-activated protein kinase (MSK) for the MAPK-dependent path-
way and Akt and p70S6 kinase(p70S6K) for the PI3K-dependent pathway to catalyze phosphorylation of
CREB (pCREB) in its Ser-133 residue, which is an important step for its activation. Another route of CREB
phosphorylation is through neurotransmitters binding to their receptors, through which they can couple
cAMP by regulating adenylyl cyclase (AC) activity. cAMP recruits protein kinase A (PKA) as the main kinase
for CREB phosphorylation. Phosphodiesterase (PDE) can catalyze the hydrolysis of cAMP and inhibit its
signaling. Additionally, increases in intracellular Ca2+ influx through voltage- or ligandgated cation chan-
nels, such as voltage-sensitive calcium channels (VSCCs) or NMDA receptors (NMDARs), can also lead to
CREB phosphorylation via different calciumdependent protein kinases. Once phosphorylated, CREB recruits
its transcription coactivator CREB-binding protein (CBP) to promote transcription of CREB-target genes,
such as the immediate early gene, C/EBP. C/EBP, in turn, regulates a number of late-response genes, for
example, IGF-II. Targeting any of these upstream pathways in a manner that leads to increased CREB or
C/EBP activation, or targeting CREB-C/EBP target genes (as in the case of IGF-II), may in turn lead to
long-term memory enhancement.
Reprinted from Trends in Neuroscience 35(5), Alberini CM, Chen DY. Memory Enhancement: consolidation,
reconsolidation and insulin-like growth factor 2., 274–283 Copyright (2012).




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Figure 3. Synaptic remodeling that occurs with learning
Taken from Rao and Finkbeiner 2007.
Presynaptic activity that occurs with learning or stimulation leads to a release of
glutamate onto NMDA and AMPA receptors, which depolarizes the membrane. This
leads to a number of intracellular changes, including activation of transcription fac-
tors, and translation of their downstream targets (Left Panel). These in turn lead to
growth initiation, including protein synthesis (for example, of Arc), which then lead
to the addition (Middle Panel) and stabilization (Right Panel) of new spines through
insertion of new NMDA and AMPA receptors. Targeting synaptic remodeling mecha-
nisms to increase receptor insertion may be an effective route for memory enhance-
ment. Reprinted from Trends in Neuroscience 30(6), Rao VR, Finkbeiner S. NMDA
and AMPA receptors: old channels, new tricks., 284–291 Copyright (2007).




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Table 1
Summary of memory enhancement effects presented in the present review, including species and tasks
tested.

             Name            Species                              Tasks                   Relevant
                                                                                         References
 CREB-C/EBP Pathway

 CREB                        Aplysia      Synaptic facilitation                               24
                            Drosophila    Conditioned odor avoidance                          25
           Downstream        Rodent       Fear potentiated startle, water maze              26, 27

             C/EBP
                              Aplysia     Synaptic Facilitation                              29
                              Rodent      MWM                                                30
 IGF-II                       Rodent      IA, CFC, Extinction                               36,89

            Upstream
             MAPK                                                                            31
               PKA                                                                           31
              cAMP                                                                           31
           Calcineurin        Aplysia     Tail-shock sensitization                           34
                              Rodent      nOR, MWM, radial arm maze                          33

 PDE4                         Rodent      CFC                                                35

  Synaptic Remodeling

 NMDA
                              Rodent      nOR, AFC, CFC, Extinction, MWM                    39,47
                                          working memory                                     40
          D-Cycloserine       Human       FC (cued fear conditioning)                        46

 AMPA

           Ampakines          Rodent      AFC                                                52

                               NHP        Delayed-non-match-to-Sample                        52

                              Human       Delayed Recall                                     52

            PKMzeta           Rodent      Conditioned Taste Aversion                         50

 Arc                          Rodent      IA                                                36,56

 CNF1                         Rodent      MWM, AFC                                           58
 NCAM                         Rodent      MWM, AFC                                           59
 Neuromodulation

 Dopamine                     Rodent                IA, nOR, Sptial working memory          66, 67
                               NHP                   Delayed-non-match-to-sample              64


 Glucocorticoids             Rodents                           IA, nOR                      69, 72
       Corticosteroid        Humans                     Cued-fear conditioning                69

                              Rodents     AFC, IA                                            73
 Noradrenaline

 Amphetamines
                             Humans       Delayed Recall, Spatial working memory,        10,75,76
       Methylphenidate                    Sustained Attention
                              Rodent      MWM, Radial Arm Maze                               77
 Acetylcholine
                             Humans       cognitive scales and examinations                  78
    Donepezil
 Endogenous

 Glucose                      Rodent                               IA                        84
                              Human                     Verbal Episodic Memory               83

 Insulin                      Rodent                        Radial Arm Maze                  85
                              Human                        Delayed score recall             86,87
 Behavioral

 Reconsolidation          Rodent          IA, AFC, CFC                                   28,98,99,100
 Exercise                 Rodent          MWM, IA, nOR                                   94




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