Hatıra sağlamlaşması - Hatırla ve değiştir · Hatıra sağlamlaşması - Hatırla ve değiştir Sinaptik ve sistem ... 24 Part I / The Neurobiology of Behavior “birleştiren”

Hatıra sağlamlaşması - Hatırla ve değiştir

Sinaptik ve sistem (yeniden) sağlamlaşması[Synaptic and systems memory (re)consolidation]

Monday, November 7, 2011

Hayvanların deneyimlerini kaydedebilme ve bu deneyimlerin doğasına göre davranışlarını değiştirebilme

yetenekleri net bir şekilde biyolojinin en önemli ve heyecan verici fenomenlerinden biri durumundadır

(James L. McGaugh, 1966, Science)


Konular


Konular

•Nöronlar ve sinapslar


Konular

•Nöronlar ve sinapslar•Öğrenmeyi mümkün kılan nöral süreçler


Konular

•Nöronlar ve sinapslar•Öğrenmeyi mümkün kılan nöral süreçler•Hatıraların sağlamlaştırılmaları (sabitlenmeleri)


Konular

•Nöronlar ve sinapslar•Öğrenmeyi mümkün kılan nöral süreçler•Hatıraların sağlamlaştırılmaları (sabitlenmeleri)•Hafıza her hatırlandığında yeniden mi yazılıyor?


Konular

•Nöronlar ve sinapslar•Öğrenmeyi mümkün kılan nöral süreçler•Hatıraların sağlamlaştırılmaları (sabitlenmeleri)•Hafıza her hatırlandığında yeniden mi yazılıyor? •Hatıraların yeniden sağlamlaştırılmaları


Bir nöron

24 Part I / The Neurobiology of Behavior

Figure 2-4 Neurons can be classified as unipolar, bipolar, or multipolar accord- ing to the number of processes that originate from the cell body. A. Unipolar cells have a single process, with different segments serving as recep- tive surfaces or releasing terminals. Unipolar cells are characteristic of the invertebrate nervous system. B. Bipolar cells have two processes that are functionally specialized: the dendrite carries information to the cell, and the axon transmits information to other cells. C. Certain neurons that carry sensory information, such as information about touch or stretch, to the spinal cord belong to a subclass of bipolar cells designated as pseudo-unipolar. As such cells develop, the two processes of the embryonic bipolar cell become fused and emerge from the cell body as a single process. This out- growth then splits into two processes, both of which function as axons, one going to peripheral skin or muscle, the other going to the central spinal cord. D. Multipolar cells have an axon and many dendrites. They are the most common type of neuron in the mammalian nervous system. Three examples illustrate the large diversity of these cells. Spinal motor neurons (left) innervate skeletal muscle fibers. Pyramidal cells (middle) have a roughly triangular cell body; dendrites emerge from both the apex (the apical dendrite) and the base (the basal dendrites). Pyramidal cells are found in the hippocampus and throughout the cerebral cortex. Purkinje cells of the cerebellum (right) are characterized by the rich and ex- tensive dendritic tree in one plane. Such a structure permits enormous synaptic in- put. (Adapted from Ramon y Cajal 1933.)

A Unipolar cell B Bipolar cell

-Cell body

Axon

Invertebrate neuron Bipolar cell of retina

D Three types of multipolar cells

Motor neuron of s p n a cord

Unipolar neurons are the simplest nerve cells because they have a single primary process, which usually gives rise to many branches. One branch serves as the axon; other branches function as dendritic receiving struc- tures (Figure 2-4A). These cells predominate in the nervous systems of invertebrates; in vertebrates they occur in the autonomic nervous system.

Bipolar neurons have an oval-shaped soma that gives rise to two processes: a dendrite that conveys information from the periphery of the body, and an axon that carries information toward the central nervous system (Figure 2-4B). Many sensory cells are bipolar cells, including those in the retina of the eye and in the olfactory

Pyramidal cell of h~ppocampus

Peripheral axon to s k n and muscle

S n g e bifurcated 11- process

Central

Ganglion cell of dorsal root

Axon

Purknje cell of cerebellum

epithelium of the nose. The mechanoreceptors that con- vey touch, pressure, and pain to the spinal cord are vari- ants of bipolar cells called pseudo-unipolar cells. These cells develop initially as bipolar cells; later the two cell processes fuse to form one axon that emerges from the cell body. The axon then splits into two; one branch runs to the periphery (to sensory receptors in the skin, joints, and muscle), the other to the spinal cord (Figure 2-4C).

Multipolar neuvons predominate in the nervous system of vertebrates. They have a single axon and, typically, many dendrites emerging from various points around the cell body (Figure 2-4D). Multipolar cells vary greatly in shape, especially in the length of their




-Cell body

Axon









Central


Axon




Hücre gövdesi

Mesaj yönü

Akson uçları (ileticiler)


Bir nöron

•Duysal hücreler, hareket hücreleri, ve aralarında onları “birleştiren” sinir hücreleri (nöronlar)24 Part I / The Neurobiology of Behavior



-Cell body

Axon









Central


Axon







-Cell body

Axon









Central


Axon




Hücre gövdesi

Mesaj yönü



Bir nöron

•Duysal hücreler, hareket hücreleri, ve aralarında onları “birleştiren” sinir hücreleri (nöronlar)

•Nöron doktrini: Bireysel nöronlar, sinir sisteminin iletişim birimleridir. (Cajal)




-Cell body

Axon









Central


Axon







-Cell body

Axon









Central


Axon




Hücre gövdesi

Mesaj yönü



Bir nöron

•Duysal hücreler, hareket hücreleri, ve aralarında onları “birleştiren” sinir hücreleri (nöronlar)

•Nöron doktrini: Bireysel nöronlar, sinir sisteminin iletişim birimleridir. (Cajal)




-Cell body

Axon









Central


Axon







-Cell body

Axon









Central


Axon




Hücre gövdesi

Mesaj yönü



Hücreyi saran yarı geçirgen zar

Hücre dışı

Hücre içi


Hücreye iyon girişi sağlayan kanallar

Hücre dışı

Hücre içi

Kapalı

Açık


Nöronlar konuşurken...

•İki nöronun “konuştuğu” noktaya sinaps denir•“Sinaptik benlik” hipotezi (Changeux)


İletişimin iki yüzü

Part 111



•Elektriksel

Part 111



•Elektriksel

Part 111



•Elektriksel

• Kimyasal

Part 111



•Elektriksel

• Kimyasal

Part 111

Chapter 10 / Overview of Synaptic Transmission 183

Presynaptic acton potential

Excitatory postsynaptic potential

Act~on potenta n nerve termnal opens Ca2+channels

ca2+ entry causes vesicle fuson and transmtter release

Receptor-channels open, Nat enters the postsynaptic cell and vesces recycle

@ e' e @

N a i Na+ NaT cell

Figure 10-7 Synapt ic t ransmission at chemical synapses involves several steps. An action potential arriving at the terminal of a presynaptic axon causes voltage-gated Ca2+ channels at the active zone to open. The influx of Ca2- produces a high concentration of Ca2+ near the active zone, which in turn causes vesicles containing neurotransmitter t o fuse with the presynaptic cell membrane and release their contents into the synaptic cleft (a process termed exocytosis). The released neurotransmitter molecules then diffuse across the synaptic

Chemical Transmitters Bind to Postsynaptic Receptors

Chemical synaptic transmission can be divided into two steps: a tvnnsmitting step, in which the presynaptic cell releases a chemical messenger, and a veceptiue step, in which the transmitter binds to the receptor molecules in the postsynaptic cell.

The transmitting process resembles the release process of an endocrine gland, and chemical synaptic transmission can be seen as a modified form of hormone secretion. Both endocrine glands and presynaptic terminals release a chemical agent with a signaling function, and both are examples of regulated secretion (Chapter 4). Similarly, both endocrine glands and neurons are usually some distance from their target cells. There is one important difference, however. The hormone released by the gland travels through the blood stream until it interacts with all cells that contain an appropri- ate receptor. A neuron, on the other hand, usually com- municates only with specific cells, the cells with which it forms synapses. Communication consists of a presynaptic neuron sending an action potential down its axon to the axon terminal, where the electrical signal triggers

cleft and bind to specific receptors on the post-synaptic membrane. These receptors cause ion channels to open (or close), thereby changing the membrane conductance and membrane potential of the postsynaptic cell. The complex process of chemical synaptic transmission is responsible for the delay between action potentials in the pre- and post-synaptic cells com- pared wi th the virtually instantaneous transmission of signals at electrical synapses (see Figure 10-2B). The gray filaments represent the docking and release sites of the active zone.

the focused release of the chemical transmitter onto a target cell. Thus the chemical signal travels only a small distance to its target. Neuronal signaling, therefore, has two special features: It is fast and precisely directed.

To accomplish this highly directed or focused release, most neurons have specialized secretory machin- ery, the active zones. In neurons without active zones the distinction between neuronal and hormonal transmission becomes blurred. For example, the neurons in the autonomic nervous system that innervate smooth muscle reside at some distance from their postsynaptic cells and do not have specialized release sites in their terminals. Synaptic transmission between these cells is slower and more diffuse. Furthermore, at one set of terminals a transmitter can be released at an active zone, as a conventional transmitter acting directly on neighbor- ing cells; at another locus it can be released in a less focused way as a modulator, producing a more diffuse action; and at a third locus it can be released into the blood stream as a neurohormone.

Although a variety of chemicals serve as neuro- transmitters, including both small molecules and pep- tides (see Chapter 15), the action of a transmitter in the


Öğrenmenin “Hebb Kuralı”•Öğrenmenin (hafızanın) hücresel temeli, sinaps sonrası nöron ateşlenirken her defasında aktif olan sinapsın güçlendirilmesidir

Sinaps öncesi

Sinaps sonrası


“Hebb Kuralı”

•Birlikte ateş eden nöronlar birbirlerine bağlanırlar•Neurons that fire together, wire together


Nereden başlayalım? Hippokampus (deniz atı)


Sinaptik plastisite

•LTP = Uzun süreli potansiyalizasyon: Bir nöronun belli bir sinaptik girdi sayesinde harekete geçirilebilirliğinde bu girdinin yüksek frekansta tekrarlanması sonucu oluşan uzun süreli artış


Ne gerekiyor?

1) Bir sinapsin uyarılması

2) Sonraki hücrede aynı anda depolarizasyon


Nasıl?

AP zaten güçlü sinapsın

ileticisine geliyor (depolarizasyona

yol açıyor)

Güçlü sinaps

Depolarizasyon sonraki hücrenin ateş etmesi için

yeterli

Geri ateşleme dendrit boyunca geri dönüyor ve buradaki NMDA

reseptörlerini “hazırlıyor”

Zayıf sinapstan gelen AP geri ateşleme ile

karşılaşınca LTP meydana geliyor

LTP gerçekleşiyor ve sinaps güçleniyor


Sinaps nasıl güçlenir?

•Nitrik-oxit sayesinde salgılanan NT (haberleşme kimyasalı) miktarı artıyor (burada soru işaretleri yok değil)

•Uzun süreli değişiklikler

•Reseptör artışı (AMPA)

•Yapısal değişiklikler


“O” sinaps nasıl tanınıyor?•LTP’nin protein sentezi ile daha da uzun süreli kılınması (erken LTP’den geç LTP’ye) •Frey & Morris’in ‘tagleme’ hipotezi

LTP bu sinapsta

gerçekleştiBu olduktan

sonra kimyasal ‘tag’ler

üretiliyor

Çekirdeğe protein sentezlenmesi için

mesaj gidiyor

Proteinler tagler bu etiketler sayesinde

yakalanıyor


Büyük resim

Duysal bilgi

Kısa dönem hafıza

Sağlamlaşma

Uzun dönem hafıza

Tekrar

Geri çağırma


Hatıra Sağlamlaşması

•Uzun süreli hafızanın edinildikten sonra giderek daha sabit bir hale gelmesi, ve bu sabitlenmenin içerisinde gerçekleştiği bellek süreçleri (Dudai, 2002, 2004)•Sinaptik: Kısa sürede (dakikalardan saatlere)•Sistemsel: Uzun sürede (saatlerden yıllara)

2 Dec 2003 18:37 AR AR207-PS55-03.tex AR207-PS55-03.sgm LaTeX2e(2002/01/18) P1: GCE

54 DUDAI

ON THE TERMINOLOGY OF CONSOLIDATION

The term “consolidation” is currently used in the neuroscience literature to re-fer to two types of processes, or a family of processes (Dudai 1996, Dudai &Morris 2000; Figure 1). One type is accomplished within the first minutes tohours after the encoding has occurred or practice ended. Ample evidence indicatesthat this relatively fast type of process takes place in local nodes in the neuronal

Figure 1 Types of consolidation. (A) The time course of synaptic (cellular, local) con-solidation, determined by measuring the sensitivity of memory to the inhibition of proteinsynthesis. Consolidated memory is defined as treatment-resistant long-term memory. Thedata are from experiments on shuttle-box learning in the goldfish (Agranoff et al. 1966).The protein synthesis inhibitor was administered to separate groups of fish at the indicatedtime points after training. The sensitivity of memory to protein synthesis inhibition was overby about one hour. A consolidation process that depends on protein synthesis during andimmediately after training is a universal property of the nervous system. (B) The time courseof system consolidation, determined by measuring the sensitivity of long-term memory tohippocampal damage. The data are from experiments on contextual fear conditioning in therat (Kim & Fanselow 1992). The lesion was inflicted to separate groups at the indicated timepoints after training. The dependence of long-term memory on the hippocampus in this casewas over by about one month. System consolidation, lasting weeks or longer, during whichthe memory becomes independent of the hippocampus, is observed in declarative memory.(Figure adapted from Dudai 2002a.)

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Protein sentezi engellemesi

(balık)

Hipokampus hasarı (sıçan)


Sürecin bozulması

•Ögrenme sonrasi amnezik (unutkanlik yaratan) bir müdahelenin yarattığı etkinin gücü zamanın bir fonksiyonu olmalı


54 DUDAI

ON THE TERMINOLOGY OF CONSOLIDATION

The term “consolidation” is currently used in the neuroscience literature to re-fer to two types of processes, or a family of processes (Dudai 1996, Dudai &Morris 2000; Figure 1). One type is accomplished within the first minutes tohours after the encoding has occurred or practice ended. Ample evidence indicatesthat this relatively fast type of process takes place in local nodes in the neuronal

Figure 1 Types of consolidation. (A) The time course of synaptic (cellular, local) con-solidation, determined by measuring the sensitivity of memory to the inhibition of proteinsynthesis. Consolidated memory is defined as treatment-resistant long-term memory. Thedata are from experiments on shuttle-box learning in the goldfish (Agranoff et al. 1966).The protein synthesis inhibitor was administered to separate groups of fish at the indicatedtime points after training. The sensitivity of memory to protein synthesis inhibition was overby about one hour. A consolidation process that depends on protein synthesis during andimmediately after training is a universal property of the nervous system. (B) The time courseof system consolidation, determined by measuring the sensitivity of long-term memory tohippocampal damage. The data are from experiments on contextual fear conditioning in therat (Kim & Fanselow 1992). The lesion was inflicted to separate groups at the indicated timepoints after training. The dependence of long-term memory on the hippocampus in this casewas over by about one month. System consolidation, lasting weeks or longer, during whichthe memory becomes independent of the hippocampus, is observed in declarative memory.(Figure adapted from Dudai 2002a.)

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Protein sentezi engellemesi

(balık)

Hipokampus hasarı (sıçan)


Sinaptiğe dair


Sinaptiğe dair

•Öğrenmenin ardından belirli bir süre içinde çesitli müdaheleler hatıralarda amnezik etki yaratıyor, süre sonunda ise etkisizler (ECS, davranışsal dikkat bozucular, çeşitli ilaçlar)


Sinaptiğe dair


•Müdaheleler ya hep ya hiç değil, dereceli bir etki gösteriyor.


Sinaptiğe dair


•Müdaheleler ya hep ya hiç değil, dereceli bir etki gösteriyor. •RNA veya protein sentezini engelleyen maddeler, gen ekspresyonunun öğrenme ardından durdurulması USB’in oluşmasını engellerken, algı, KSB, hatıranın saklanması, ve geri çağırılmasında etkili değil.


Ne sorun ne söyleyeyim


58 DUDAI

involve coordination between the activated synapse and the nucleus, whichpossibly optimize exploitation of the metabolic resources of the neuron andthe specificity of the long-term change (Dudai & Morris 2000).

f. The long-term changes in the synapse involve trafficking of new receptormolecules and possibly other proteins into the synaptic membrane, and al-teration in the association of receptors with cellular cytoskeleton and signaltransduction cascades (e.g., El-Husseini et al. 2002, Shi et al. 1999). In ad-dition, there is evidence that long-term synaptic plasticity and long-termmemory are correlated with morphological changes in synapses (e.g., Bailey& Kandel 1993, Weiler et al. 1995).

THE STANDARD MODEL OF SYNAPTIC CONSOLIDATION

The above and additional findings served as the basis for the formulation of thestandard model of synaptic consolidation (Figure 2). This model posits that mem-ory traces can exist in at least two forms: short-term and labile, and long-term and

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Sisteme dair

•Sadece MTL hasarı genelde geriye doğru (retrograde) dereceli unutkanlık gösterirken, neokorteks hasarı da varsa unutkanlık düz olabiliyor

Beyin hasar öncesi olaylar

hatırlanmıyor

Beyin hasarının gerçekleştiği

an

Beyin hasarı sonrası olaylar KSB

sonrası hatırlanamıyor


Geriye dönük hafıza kaybı

Sağlıklı kontrollerGeriye dönük hafıza kaybı hastaları

Toplumsal olayın yaşandığı onyıl

Hat

ırla

ma

oran

ı


Ne oluyor?


62 DUDAI

Figure3 The standardmodel of systemconsolidation is depicted in aflowchart. Initialstorage, i.e., encoding and registration of the perceived information (Dudai 2002a),occurs in both the hippocampal system and the neocortical system. Sh(0) and Sc(0)represent the strength of the initial hippocampal and neocortical traces, respectively.These traces are expected to differ, with the hippocampal one probably representinga compressed version of the internal representation. The hippocampal representationlater becomes active either in explicit recall, or in implicit processes such as sleep.This gives rise to reinstatement of the corresponding neocortical memory, resulting inincremental adjustment of neocortical connections, probably involving local, synapticconsolidation. In parallel, memory also decays, faster in the hippocampus (Dh) than inthe cortex (Dc). The net result is that memories initially dependent on the hippocampusgradually become independent of it. In reality this happens over weeks or longer. Thehippocampal system can hence be viewed not only as a memory store but also as ateacher of the neocortical system. This process (C, rate of consolidation) is proposed toallow the hippocampal system to rapidly learn new information without disrupting oldmemory stored in the neocortex, while at the same time allowing gradual integration ofthe new information into the older, structured information. Adapted from McClellandet al. (1995).

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Ne oluyor?

•Algılanan olay hem hippokampusta hem neokortekste iz bırakıyor


62 DUDAI


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Ne oluyor?

•Algılanan olay hem hippokampusta hem neokortekste iz bırakıyor•Hippokampustaki iz diğerinden çok daha güçlü


62 DUDAI


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Ne oluyor?

•Algılanan olay hem hippokampusta hem neokortekste iz bırakıyor•Hippokampustaki iz diğerinden çok daha güçlü •Hippokampus izi, gerek hatırlama, gerekse uykuda yeniden aktifleşince neokorteks bağlantıları da ayarlanıyor


62 DUDAI


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Ne oluyor?

•Algılanan olay hem hippokampusta hem neokortekste iz bırakıyor•Hippokampustaki iz diğerinden çok daha güçlü •Hippokampus izi, gerek hatırlama, gerekse uykuda yeniden aktifleşince neokorteks bağlantıları da ayarlanıyor

•İz hippokampusta daha hızlı kayboluyor


62 DUDAI


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Sisteme dair

•Amnezi hastaları•Laboratuvar hayvanlarında hippokampus hasarı sonrası aynı dereceli unutkanlığın gözlenmesi •Hippokampal hemodinamik aktivite 3 yıl öncesi gibi yakın zamanlı olaylarda bir kaç on yıl önceki olaylarin hatırlanmasına oranla çok daha aktif (Smith & Squire, 2009)

•Derhal gen ekspresyonu (IEG) öğrenme sonrasındaki haftalarda hippokampal formasyondan neokorteks kayıyor


Sağlamlaşma akla yatkın mı?

•Hafıza değişebilir demedik mi?•Sahte hafızalar vs.


Peki bu ne anlama geliyor?

•Misanin, Miller & Lewis; 1968

Hafıza yok

Öğrenme

Öğrenme

Öğrenme Sadece koşullu uyaran uyarılması

Hafıza var

Hafıza yok


Yeniden sağlamlaşma!

•Sağlamlaşma esnasında hatıranın değişebilir, zarar görebilir olduğunu gördük

•Bu aşamadan sonra ise hatıranın bir daha değismemek üzere sabitlendiği fikri 100 yıla yakın doğru kabul edildi•Ama bu hafızanin dinamik şekilde değişebildiği bulguları ile uyumlu değil•Son deneyde ise bir gün sonra hatırlatılan ögrenmenin yeniden aynı kırılgan, değişebilir duruma geldiğini gördük•30 sene kadar uyuyan bu erken bulgular 2000’de mihen taşı bir çalışma ile şu anda çok yoğun bir şekilde yeniden ele alınır oldu

Nader, 2003, TiNSMonday, November 7, 2011

Korkuyu silmek

•Kullanılan bilgiler

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© 2000 Macmillan Magazines Ltd

Nature, 2000

Protein sentezi sadece LBA’da engellenecek!


Sonuçlar

•Nader et al., 2000, Nature

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Sonuçlar

•Nader et al., 2000, Nature

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Gereklilikler

•Hatıranın sağlamlaşmış olduğundan emin ol•Hatırlama olmazsa amnezik etkinin görülmediğinden emin ol

•Kısa süreli bellek (ve tabi diğer hafıza süreçleri)

Memory traces unboundKarim Nader

Department of Psychology, McGill University, Montreal, Quebec, Canada H3A 1B1

The idea that new memories are initially ‘labile’ andsensitive to disruption before becoming permanentlystored in the wiring of the brain has been dogma for>100 years. Recently, we have revisited the hypothesisthat reactivation of a consolidated memory can return itto a labile, sensitive state – in which it can be modified,strengthened, changed or even erased! The data gener-ated from some of the best-described paradigms inmemory research, in conjunction with powerful neuro-biological technologies, have provided striking supportfor a very dynamic neurobiological basis of memory,which is beginning to overturn the old dogma.

For .100 years, generations of behavioural paradigmsand technologies have been used to address questionsabout the mechanisms that mediate learning and memory[1–3]. Repeatedly, evidence has been found to suggest thatthe properties of the memory trace change in a time-dependent manner, such that new memories are initiallyin a dynamic ‘labile’ form for a short time [short-termmemory (STM)], after which the memory trace is ‘fixed’ or‘consolidated’ into the physical structure of the brain [long-term memory (LTM)] [4–6]. For example, electroconvul-sive shock (ECS) is effective in inducing amnesia ifpresented shortly after training (during STM) but not ifgiven a few hours later (during LTM) [7]. Time-dependenteffects such as these are the cornerstone of memoryconsolidation theory (now called cellular consolidationtheory [8]). During the past 40 years, incredible effortshave been made to describe across all levels of analysisthe processes that contribute to the transformation of atrace from being labile to being fixed [9,10]. Of note isthe finding that the transcription factor Ca2!-response-element-binding protein (CREB), transcription and trans-lation all seem to be universal neuronal requirements fortraces to enter LTM [11–15] (Fig. 1a).

Early studies on reconsolidationIn 1968, the view that memories are consolidated overtime into a permanent state was challenged by Lewisand colleagues [16]. In agreement with previous studies,when ECS was given 24 h after fear conditioning it wasineffective in generating amnesia. However, if the memorywas reactivated before ECS administration, amnesia wasobserved the following day. Given that amnesia was notproduced in the absence of memory reactivation, thememory is defined as being consolidated by that time.Therefore, reactivation of a consolidated memory presum-ably returned it to a labile state, which initiated another

time-dependent memory process similar to that seen afternew learning. This phenomenon is now referred to asreconsolidation [17–19]. Lewis’ study defined a paradigmfor experimentally differentiating consolidation and recon-solidation: a necessary criterion if an effect is to be attri-buted to reconsolidation is that the amnesic agent must be

Fig. 1. Two models of memory processing. (a) The traditional consolidation theory,which posits a labile, short-term memory (STM) state and a later, consolidatedlong-term memory (LTM) state. Once fixed in LTM, the memory is posited to bepermanent. Below each memory state is a list that is typically used to describesome of the properties of the two states. (b) The memory model proposed byLewis [33]. The active state (AS) and inactive state (IS) are analogous to STM andLTM, respectively. The molecular descriptors in brackets were not part of theoriginal model but have been inserted for comparison with (a). New memoriesenter a labile AS and then with time enter the IS [top red arrow, again similar to(a)]. Reactivation of memories that are in an IS returns them to the AS (bottom redarrow). Both new and reactivated memories require protein-synthesis-dependentmechanisms in order to enter the IS. Contrary to consolidation theory, whichcannot explain the reconsolidation data, this model incorporates both the datafrom consolidation and reconsolidation experiments.

TRENDS in Neurosciences

Short-term memory (STM)

• Lasts for seconds to hours

• ‘Labile’ (sensitive to disruption)

• Does not require new RNA or protein synthesis

Active state (AS)

• Lasts for seconds to hours

• ‘Labile’ (sensitive to disruption)

(Does not require new RNA or protein synthesis)

Long-term memory (LTM)

• Lasts for days to weeks

• Consolidated (insensitive to disruption)

• Does require new RNA or protein synthesis

Inactive state (IS)

• Lasts for days to weeks

• Inactive (insensitive to disruption)

(Does require new RNA or protein synthesis)

(a)

(b)

Corresponding author: Karim Nader ([email protected]).

Opinion TRENDS in Neurosciences Vol.26 No.2 February 2003 65

http://tins.trends.com 0166-2236/03/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved. PII: S0166-2236(02)00042-5

Nader, 2003, TiNS

KSBSaniyelerden saatlere

Hasara açık Yeni RNA veya protein sentezine ihtiyaç yok

USBGünlerden haftalaraHasara kapalı (sabit)

Yeni RNA veya protein sentezine ihtiyaç var

Aktif DurumSaniyelerden saatlere


İnaktif DurumSaniyelerden saatlere



Hem sinaptik hem sistem

Neuron, Vol. 36, 527–538, October 24, 2002, Copyright !2002 by Cell Press

Cellular and Systems Reconsolidationin the Hippocampus

studies demonstrating that amnesia could also occur ifa fully consolidated and stable LTM was reactivatedprior to amnesic treatments (Misanin et al., 1968). This

Jacek Debiec,1,2 Joseph E. LeDoux,2

and Karim Nader3,4

1Department of Psychiatryphenomenon has been described in a large number ofJagiellonian University Collegium Medicumspecies, using a wide array of behavioral paradigms andCracow 31-501amnesic agents (Sara, 2000). These findings suggestedPolandthat old, reactivated memories undergo another round of2 W.M. Keck Foundation Laboratory of Neurobiologyconsolidation, a process referred to as reconsolidationCenter for Neural Science(Nader et al., 2000b; Przybyslawski and Sara, 1997).New York UniversityConsistent with the reconsolidation hypothesis is ourNew York, New York 10003recent demonstration that consolidated memories for3 Department of Psychologyauditory fear conditioning, which are stored in the amyg-McGill Universitydala (Fanselow and LeDoux, 1999; Maren, 2001; SchafeMontreal, Quebec H3A 1B1et al., 2000), undergo protein synthesis-dependent re-Canadaconsolidation in the amygdala and that this process iscontingent on memory reactivation (Nader et al., 2000a).Indeed, reconsolidation and consolidation have beenSummaryfound to share a number of common properties, includ-ing: (1) requirement of protein synthesis in order forCellular theories of memory consolidation posit thatthe memory to persist, (2) time windows during whichnew memories require new protein synthesis in orderprotein synthesis blockade is effective, and (3) that pro-to be stored. Systems consolidation theories posit thattein synthesis blockage in the same brain region, thethe hippocampus has a time-limited role in memoryamygdala, disrupts both. Given these similarities, itstorage, after which the memory is independent of theseemed parsimonious to conclude that a new memoryhippocampus. Here, we show that intra-hippocampaland a reactivated, consolidated memory share a com-infusions of the protein synthesis inhibitor anisomycinmon memory state, as originally proposed by Lewiscaused amnesia for a consolidated hippocampal-(1979). Thus, instead of just occurring once, memorydependent contextual fear memory, but only if thestorage may instead be a process that is reiterated withmemory was reactivated prior to infusion. The effecteach use of the memory.occurred even if reactivation was delayed for 45 days

A key issue is whether reconsolidation also occursafter training, a time when contextual memory is inde-in other brain systems. The most extensively studiedpendent of the hippocampus. Indeed, reactivation ofmemory system of the brain involves the hippocampus.a hippocampus-independent memory caused the traceResults from previous studies have suggested thatto again become hippocampus dependent, but onlymemories for hippocampus-dependent tasks can un-for 2 days rather than for weeks. Thus, hippocampaldergo reconsolidation (Mactutus et al., 1979; Przybys-memories can undergo reconsolidation at both thelawski et al., 1999; Schneider and Sherman, 1968). Forcellular and systems levels.example, using a radial arm maze, systemic postreacti-vation injections of propranol were effective at produc-Introductioning amnesia if the memory was first reactivated (Przy-byslawski et al., 1999). Because the treatment wasThe formation of long-term memory (LTM) is generallysystemic, however, it is not known whether the effectsbelieved to involve a process by which a labile short- of the drug on reconsolidation occurred in the hippo-

term memory (STM) is converted into a lasting stable campus or in some other structure that contributes totrace (Ebbinghaus, 1885; Hebb, 1949; Muller and Pil- this task. Similarly, recent findings that disruption ofzecker, 1900). Evidence for this time-dependent process CREB-mediated transcription in the forebrain interfereshas come from numerous studies, showing that treat- with the reconsolidation of contextual fear memoriesments such as electroconvulsive shock (ECS) produce (Kida et al., 2002) suffer from the same drawback. Inamnesia shortly after learning, but the same treatment support of the possibility that memories stored withinseveral hours later has no effect (Duncan, 1949; McGaugh, the hippocampus itself might undergo reconsolidation1966). The dominant view of how the conversion from are the recent findings showing that reactivation of con-STM to LTM occurs is that new RNA and proteins are textual memories induces the expression of zif268, asynthesized and transform temporary alterations in syn- gene implicated in consolidation of new hippocampal-aptic transmission into persistent modifications of syn- dependent memories (Hall et al., 2001).aptic architecture (Davis and Squire, 1984; Flexner et In the present study, we first asked if hippocampal-al., 1965; Goelet et al., 1986). This is called consolidation mediated memories undergo protein synthesis-depen-theory, or more precisely, cellular consolidation theory dent reconsolidation in the hippocampus. The task we(Dudai and Morris, 2000). used was contextual fear conditioning, a variant of audi-

Cellular consolidation theory was challenged by early tory fear conditioning in which the footshock comes tobe associated with the chamber (context) in which theshock occurred. The hippocampus is thought to estab-4 Correspondence: [email protected]


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•Olmadı ise böyle birşey yok

Reconsolidation of episodic memories: A subtlereminder triggers integration of new informationAlmut Hupbach,1,3 Rebecca Gomez,1 Oliver Hardt,2 and Lynn Nadel11Department of Psychology, The University of Arizona, Tucson, Arizona 85721, USA; 2Department of Psychology, McGillUniversity, Montreal, Quebec H3A 2T5, Canada

Recent demonstrations of “reconsolidation” suggest that memories can be modified when they are reactivated.Reconsolidation has been observed in human procedural memory and in implicit memory in infants. This study askswhether episodic memory undergoes reconsolidation. College students learned a list of objects on Day 1. On Day 2,they received a reminder or not, and then learned a second list. Memory for List 1 was tested immediately on Day 2(Experiment 2) or on Day 3 (Experiment 1). Although the reminder did not moderate the number of items recalledfrom List 1 on either day, subjects who received a reminder incorrectly intermixed items from the second list whenrecalling List 1 on Day 3. Experiment 2 showed that this effect does not occur immediately and thus istime-dependent. The reminder did not affect memory for List 2 on Day 3 (Experiment 3), demonstrating thatmodification occurred only for the original memory (List 1). The study demonstrates the crucial role of remindersfor the modification of episodic memory, that reconsolidation of episodic memory is time-dependent, and, incontrast to previous reconsolidation findings, that reconsolidation is also a constructive process, one that supportsthe incorporation of new information in memory.

Consolidation theory assumes that memories are labile during alimited window after encoding, but as time passes, memories areconsolidated and become resistant to change (e.g., McGaugh2000). The rediscovery of reactivation-induced reconsolidationhas challenged this view (cf. Przybyslawski and Sara 1997; Sara2000; Nader 2003; cf. Lewis et al. 1968; Misanin et al. 1968, forearly demonstrations of the reconsolidation phenomenon). Incontrast to the consolidation account, reactivation is thought toreturn memories to a labile state, which allows them to change.In the normal course of events, reactivated memories are retainedthrough a process similar to initial consolidation, i.e., reconsoli-dation. This view of memory formation as a dynamic processrather than a static one has implications for theories of memoryand for our understanding of memory change.

Nader et al. (2000) showed that memories are labile by dem-onstrating that fear memory in the rat can be severely impairedat the time the memory is recalled. Rats received several tone-footshock pairings on Day 1. The following day, half of the ani-mals were again exposed to the tone. The tone elicited freezing,indicating that the rats recalled the conditioned fear memory. Allrats were then injected with a protein-synthesis inhibitor or itsvehicle into the amygdala. When tested for fear memory in re-sponse to the tone on Day 3, rats who had received the remind-ing tone before injection of the inhibitor showed less freezingthan the vehicle-injected rats and, most importantly, than ratswho were not reminded. This demonstrated that reactivation ofthe fear memory returned the memory to a labile state, whichlike a newly acquired, nonconsolidated memory requires de novoprotein-synthesis in order to be maintained. The protein-synthesis inhibitor blocked reconsolidation, and thus led tomemory impairment. This finding has now been replicated in avariety of species and paradigms (see Dudai and Eisenberg 2004;Alberini 2005).

Walker et al. (2003) recently demonstrated reconsolidation

effects in humans. Participants were trained on a procedural mo-tor-skill task that involved finger-tapping a simple sequence (e.g.,4-1-3-2). Twenty-four hours later they briefly rehearsed the se-quence (reactivating it) and learned a second sequence (e.g., 2-3-1-4). When tested on Day 3, accuracy performance for Sequence1 was significantly impaired in comparison to a group of partici-pants who did not rehearse Sequence 1 before learning Sequence2. This shows that the reactivation of the memory for Sequence1 on Day 2 destabilized it such that a competing motor patterncould interfere.

Galluccio (2005) and Galluccio and Rovee-Collier (2005) in-vestigated the fate of reactivated memories in infants trained tokick their foot to activate a mobile. After a delay, infants werereminded of the event: The moving mobile was presented for abrief period during which it was no longer attached to the baby’sfoot. After reactivation, one group of infants learned to move anovel mobile. One day later, infants who were exposed to thenovel mobile showed a modification of the reactivated memoryin that they no longer recognized the original mobile and solelyreacted to the novel one.

Thus, reconsolidation effects have been shown in humans,but only for procedural memory (Walker et al. 2003) and condi-tioning (Galluccio 2005). These are both forms of implicitmemory that do not require conscious recollection, making itimportant to ask whether reconsolidation also applies to explicitmemory, a form of memory that allows for the conscious recol-lection of events (episodic memory) and facts (semanticmemory).

Although the idea of fixed consolidated memory traces hasbeen the dominant view in neurobiology, it has long beenknown in cognitive psychology that episodic memories can bereconstructed. For instance, Bartlett’s (1932) classic study inwhich participants were repeatedly asked to recall a NativeAmerican folktale showed that, over time, participants recon-structed their recall to better fit their own cultural schema. It isalso well known, from the study of retroactive interference, thata subsequent learning experience can impair performance forpreviously acquired material (e.g., Barnes and Underwood 1959;Delprato 2005). And we know that episodic memories can be

3Corresponding author.E-mail [email protected]; fax (520) 621-9306.Article published online in January 2007. Article and publication date are athttp://www.learnmem.org/cgi/doi/10.1101/lm.365707.

Research

14:47–53 ©2007 by Cold Spring Harbor Laboratory Press ISSN 1072-0502/07; www.learnmem.org Learning & Memory 47www.learnmem.org

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Learning & Memory, 2007


Hafıza değişimi•Sağlamlaşma => BDNF (beyin-türetilmiş nörotrofik faktör

•Yeniden sğlamlaşma => zif268•Lee, 2008, Nature Neuroscience

fear-conditioning procedure was used, in which both trials werecondensed into a single session, memory consolidation remaineddependent on hippocampal BDNF and not on zif268 (Fig. 1b,c andSupplementary Fig. 5 online). ANOVA revealed an overall significantsession! gene! ASO interaction (F2,44 " 11.11, Po 0.001). Analysisof the zif268 groups alone revealed nomain effect of ASO (F1,12" 1.05,P " 0.32) or session ! ASO interaction (F2,24 " 1.23, P " 0.31),whereas analysis of the BDNF groups revealed a significant session !ASO interaction (F2,20 " 19.95, P o 0.001) that was driven by asignificant effect of ASO during the long-term memory (LTM) tests(simple effects one-way ANOVA, Po 0.05), with no effect on the STMtest. Therefore, these data reveal a double dissociation between thecellular mechanisms of initial memory consolidation (BDNF) andmemory strengthening through additional learning (zif268). Moreover,the selective dependence of the two processes on their relative cellularmechanisms was not a result of nonspecific or quantitative factors.A further contention might be that zif268 is not required for

memory strengthening per se, but is instead required for synapticplasticity in neural circuits that have been modified recently bybehavioral experience. Thus, the selective dependence of additionallearning on zif268may result not from the factthat an existing memory is being updated andstrengthened, but arises because some learn-ing experience, which need not have beenrelated, engaged the dorsal hippocampus onthe previous day. To test this hypothesis, wefirst conditioned rats in a separate context(different operant chambers12), before return-ing them to the standard fear-conditioningapparatus (context 2) for the second day oftraining. Infusion of zif268 ASO into thedorsal hippocampus before this second con-ditioning trial had no effect on subsequentconditioned freezing in context 2, whereasknockdown of hippocampal BDNF resultedin severe amnesia (Fig. 2a and Supplemen-tary Fig. 6 online). Although ANOVArevealed no gene ! ASO interaction duringthe first conditioning session (F o 1), therewas an overall significant session ! gene !ASO interaction in context 2 (F1,22 " 11.31,P " 0.003). Analysis of the zif268 groupsalone revealed no main effect of ASO or

session ! ASO interaction (F values o 1), whereas the BDNF groupshad a significant session ! ASO interaction (F1,12 " 22.17, Po 0.001)that was driven by a significant effect of ASO during the LTM test(simple effects one-way ANOVA, Po 0.05). Thus, even when there hasbeen recent synaptic plasticity in the hippocampus, contextual-fearconditioning functionally recruits consolidation, but not reconsolida-tion, mechanisms. Moreover, these results provide strong evidence thatmemory strengthening has underlying mechanisms that are separatefrom those of memory acquisition and consolidation.If the mechanisms of reconsolidation are the same as those that

strengthen the memory trace, impairing memory destabilizationshould prevent the modification of memory strength. It has beenshown recently that hippocampal synaptic protein degradation is acritical process in the destabilization of contextual-fear memories8.Infusion of the proteasome inhibitor clasto-Lactacystin-b-lactone intothe dorsal hippocampus prevented the amnesic action of anisomycin ina standard memory reconsolidation setting. Thus, although anisomy-cin infusion alone, immediately after contextual re-exposure, resultedin subsequent amnesia, the co-infusion of blac rendered the memoryinvulnerable to protein synthesis inhibition8.

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Figure 1 The cellular mechanisms of memory consolidation and strengthening differ. (a) Knockdown of zif268, but not BDNF, during a second conditioningsession resulted in subsequent amnesia. Rats were fear conditioned on 2 consecutive days (Cond1 and Cond2) and were tested 24 h later (Test). Behavioralmeasurements are shown for the periods before foot shock presentation during conditioning and for the whole test (n " 5–6 per group). (b,c) Knockdown ofBDNF (b), but not zif268 (c), during a single two-trial conditioning session resulted in subsequent amnesia. Behavioral measurements are shown for the STMtest (3 h after conditioning) and for two LTM tests (24 h, LTM; 7 d, LTM2; n " 6–7 per group). Data presented as mean ± s.e.m.

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Figure 2 Memory strengthening requires destabilization and reconsolidation. (a) Knockdown of BDNF,but not zif268, during fear conditioning to a changed context resulted in subsequent amnesia. Rats werefear conditioned first to context 1 (CX1, Cond1), then to CX2 on the next day (Cond2), and were tested24 h later (Test) in CX2. Behavioral measurements are shown for the periods before foot shockpresentation during conditioning and for the whole test (n " 6–7 per group). (b) Proteasome inhibitionprotected a contextual-fear memory against both additional learning and amnesia. Rats were fearconditioned on 2 consecutive days (Cond1 and Cond2), and were tested 24 h later (Test). Behavioralmeasurements are shown for the periods before foot shock presentation during conditioning and for thewhole test (n " 7 per group). Data presented as mean ± s.e.m. MSO, control missenseoligodeoxynucleotide sequences; Veh, vehicle.

NATURE NEUROSCIENCE VOLUME 11 [ NUMBER 11 [ NOVEMBER 2008 1265

BR I E F COMMUNICAT IONS


Kısaca

Brief Communications

Sensory-Specific Associations Stored in the LateralAmygdala Allow for Selective Alteration of Fear Memories

Lorenzo Díaz-Mataix,1 Jacek Debiec,1,2,3 Joseph E. LeDoux,1,4 and Valerie Doyere1,5,6

1Center for Neural Science, New York University, New York, New York 10003, 2New York University Child Study Center, New York, New York 10016,3Copernicus Center for Interdisciplinary Studies, Krakow 30387, Poland, 4Emotional Brain Institute, Nathan S. Kline Institute for Psychiatry Research,Orangeburg, New York 10962, 5Universite Paris-Sud, Centre de Neurosciences Paris-Sud, UMR 8195, Orsay F-91405, France, and 6CNRS, Orsay F-91405,France

Consolidated long-term fear memories become labile and can be disrupted after being reactivated by the presentation of the uncondi-tioned stimulus (US). Whether this is due to an alteration of the conditioned stimulus (CS) representation in the lateral amygdala (LA) isnot known. Here, we show in rats that fear memory reactivation through presentation of the aversive US, like CS presentation, triggers aprocess which, when disrupted, results in a selective depotentiation of CS-evoked neural responses in the LA in correlation with a selectivesuppression of CS-elicited fear memory. Thus, an aversive US triggers the reconsolidation of its associated predictor representation in LA.This new finding suggests that sensory-specific associations are stored in the lateral amygdala, allowing for their selective alteration byeither element of the association.

IntroductionIn Pavlovian auditory fear conditioning, an initially neutral con-ditioned acoustic stimulus (CS), after being associated with anaversive unconditioned stimulus (US), typically electric shock,acquires the ability to induce conditioned fear responses (Pavlov,1927). This form of associative learning critically involves thelateral nucleus of the amygdala (LA). Although the LA is believedto be a storage site for such fear memories (Davis, 1997; Fanselowand LeDoux, 1999; LeDoux, 2000; Maren, 2001; Fanselow andPoulos, 2005), the nature of the information stored in LA is un-clear. A key issue is whether CS–US associations encoding spe-cific sensory features of both stimuli are stored in the LA.

After consolidation of the fear memory, presentation of theUS triggers a reconsolidation process which, when disrupted,leads to a decrease in CS-evoked behavioral fear memory in anamygdala-dependent manner (Debiec et al., 2010). It has beenproposed that the neural representation of the CS activatessensory-specific representations of the US, which, in turn, elicitsthe corresponding behavioral conditioned responses (Konorski,1967). Thus, the loss of fear behavior when US-triggered recon-solidation is disrupted may conceivably result from the disruption of

either CS or US neural representation. Using a second-order con-ditioning paradigm, we have previously shown that not allthe fear associations are rendered labile in an amygdala-dependent manner after reactivation of one of them (Debiec etal., 2006). It is therefore possible, as one could argue, thatalthough amygdala-dependent, the behavioral disruption mayreflect alteration of processes in brain networks other than theLA. Furthermore, even if some altered processes reside in theLA, they may not necessarily affect the CS representation, as adisrupted US representation may solely be responsible for the loss ofbehavioral-conditioned responses after disruption of US-triggeredreconsolidation processes. Alternatively, stored first-order CS–USassociation in the LA could permit the CS representation to be ren-dered labile after US reactivation and produce a sensory-specific fearmemory loss. A selective updating of CS representation would pro-vide evidence that specific CS–US associations linked through neuralplasticity are stored in the LA.

In the present study, we thus asked whether US reactivation trig-gers an update of the CS fear representation in the LA and producesa reconsolidation process during which the CS representation is de-stabilized. To do this, we recorded CS-evoked field potentials in LAand tracked the effects of US-induced reconsolidation blockade onthe CS representation in the LA. We used an MAPK inhibitor toblock the reconsolidation process, allowing the comparison of ourresult with previous data showing that the MAPK/ERK pathway isinvolved in reconsolidation triggered by the CS (Duvarci et al., 2005;Doyere et al., 2007). To control for the selectivity of the effects, weused a dual-fear conditioning protocol in which rats were trained totwo different conditioned stimuli paired with two different aversiveunconditioned stimuli (Debiec et al., 2010). We found that theblockade of US-triggered reconsolidation results in a selective era-sure of the CS neural representation previously linked to that US butnot of the CS linked to the other US.

Received Nov. 4, 2010; revised April 16, 2011; accepted May 9, 2011.Author contributions: L.D.-M., J.D., and V.D. designed research; L.D.-M. and V.D. performed research; L.D.-M. and

V.D. analyzed data; L.D.-M., J.E.L., and V.D. wrote the paper.This work was supported by the National Institute for Mental Health Grants R01 MH46516 and R01 MH38774, and

McDonnell Foundation Grant 220020155. L.D.-M. was recipient of a Fulbright-Spanish Ministry of Science postdoc-toral fellowship. We thank Dr. Joshua Johansen for his helpful suggestions revising the manuscript and Claudia Farbfor her excellent assistance with histology.

The authors declare no competing financial interests.This article is freely available online through the J Neurosci Open Choice option.Correspondence should be addressed to Lorenzo Díaz-Mataix, Center for Neural Science, New York University, 4

Washington Place, Room 809, New York, NY 10003. E-mail: [email protected]:10.1523/JNEUROSCI.5808-10.2011

Copyright © 2011 the authors 0270-6474/11/319538-06$15.00/0

9538 • The Journal of Neuroscience, June 29, 2011 • 31(26):9538 –9543

2011, Haziran

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NATURE NEUROSCIENCE ADVANCE ONLINE PUBLICATION 1

A R T I C L E S

Aversive associative memories formed by the association between a neutral conditioned stimulus and an aversive unconditioned stimulus are progressively made permanent by a process of consolidation1. However, upon retrieval, intervention by amnestic agents2–7, either before or immediately after retrieval, results in disruption of the pre-viously consolidated fear memory. This suggests that a consolidated memory returns to a transient destabilized state shortly after reac-tivation, necessitating a dynamic time-dependent process of recon-solidation to persist further. During this reconstruction, a memory is vulnerable to experimental intervention8–10 leading to amnesia, but can also be enhanced11–13 or modified in the long-term14–16, thereby updating the previous memory with new information14–17. In clini-cal terms, the bidirectional and adaptive nature of reconsolidation is ideally placed to mediate the modification of both memory strength12 and memory content16,18, rendering this process a promising thera-peutic target for counteracting the hyper-responsive fear system. To fully exploit reconsolidation-based therapies that adapt the content of fear memories, leading to a loss of fear response in the long term, it is crucial to elucidate the molecular underpinnings of reconsolidation, which remain obscure.

Long-lasting changes in synaptic efficacy brought about by gene transcription, protein synthesis and changes in strength of hippo-campal glutamatergic synapses through AMPA receptor trafficking are believed to be the cellular substrates of learning and memory19–21. Although reconsolidation is not merely a recapitulation of the initial consolidation process22, it has been shown that transcription, de novo protein synthesis and synaptic protein degradation in the hippocampus

are necessary for memory remodeling after retrieval4,7,17,23–25. Here, we investigated whether the temporal profile of reconsolidation, which is hypothesized to be limited to a 6 h time window5,8, reflects a sequential profile of defined dorsohippocampal AMPA receptor synaptic plastic-ity that is crucial to the synaptic remodeling that underlies subsequent fear expression (changes in memory strength) and reinterpretation of fear memory after retrieval (changes in memory content).

RESULTSMemory recall induces acute hippocampal AMPAR endocytosisTo analyze whether glutamate receptors are regulated during reconsolida-tion in mice receiving the unconditioned stimulus and retrieval (US-R), we dissected the dorsal hippocampus at 1 and 4 h after retrieval and analyzed the synaptic membrane fraction, including membrane-bound proteins and associated proteins26,27, by immunoblotting for subunits of AMPA receptors. A no-shock group experiencing retrieval (NS-R) was used to control for the specificity of an aversive associative memory (Supplementary Fig. 1). These two time points were chosen because they fall within the 6-h time window after retrieval during which the memory undergoes reconsolidation5. After retrieval, subsequent recon-solidation requires protein synthesis for the memory to persist further7 (Supplementary Fig. 1). First, the 1 h time point was analyzed. All AMPAR subunits (GluA1–GluA3) were downregulated (31.4%, 16.4% and 50.20%, respectively; P < 0.05), indicating a weakened state of the synapse28,29 (Fig. 1a,b and Supplementary Fig. 2). The observed downregulation was specific to retrieval of an associative contextual conditioned stimulus–unconditioned stimulus representation, with

1Department of Molecular & Cellular Neurobiology, Center for Neurogenomics & Cognitive Research, Neuroscience Campus Amsterdam, VU University (Vrije Universiteit), Amsterdam, The Netherlands. 2Department of Integrative Neurophysiology, Center for Neurogenomics & Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands. 3Department of Functional Genomics, Center for Neurogenomics & Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands. 4These authors contributed equally to this work. Correspondence should be addressed to S.S. ([email protected]).

Received 2 May; accepted 18 July; published online 11 Septmber 2011; doi:10.1038/nn.2907

Retrieval-specific endocytosis of GluA2-AMPARs underlies adaptive reconsolidation of contextual fearPriyanka Rao-Ruiz1,4, Diana C Rotaru1,2,4, Rolinka J van der Loo1, Huibert D Mansvelder2, Oliver Stiedl1,3, August B Smit1 & Sabine Spijker1

Upon retrieval, fear memories are rendered labile and prone to modification, necessitating a restabilization process of reconsolidation to persist further. This process is also crucial for modulating both strength and content of an existing memory and forms a promising therapeutic target for fear-related disorders. However, the molecular and cellular mechanism of adaptive reconsolidation still remains obscure. Here we show that retrieval of fear memory induces a biphasic temporal change in GluA2-containing AMPA-type glutamate receptor (AMPAR) membrane expression and synaptic strength in the mouse dorsal hippocampus. Blockade of retrieval-induced, regulated, GluA2-dependent endocytosis enhanced subsequent expression of fear. In addition, this blockade prevented the loss of fear response after reconsolidation-update of fear memory content in the long-term. Thus, endocytosis of GluA2-containing AMPARs allows plastic changes at the synaptic level that exerts an inhibitory constraint on memory strengthening and underlies the loss of fear response by reinterpretation of memory content during adaptive reconsolidation.

2011, Eylül


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