A Arte de esquecer

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A Arte de esquecer
Iván IzquierdoInstituto de Pesquisas
BiomédicasCentro de MemóriaPontifícia
Universidade Católica de Rio Grande do SulPorto
Alegre, RS, Brasil
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• O aspecto mais notável da memória é o
  esquecimento James McGaugh
• De fato, esquecemos a imensa maioria das
  informações que adquirimos
• Os mecanismos da memória se saturam
• Funes o Memorioso Jorge Luis Borges

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• Há memórias que nos perturbam (medos,
  humilhações, maus momentos)
• Há outras que nos prejudicam (fobias)ou nos
  perseguem (estresse pós-traumático)
• Há memórias que nos impedem adquirir outras novas
  ou recordar outras antigas, mais importantes
• ...novamente Funes o Memorioso ...incapaz de
  esquecer para poder pensar, e para pensar é
  necessário esquecer para poder fazer
  generalizações (Borges)

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• Formas de esquecimento
• Extinção
• Repressão voluntária e involuntária
• Memórias que não ultrapassam a memória de
  trabalho OU AS FASES INICIAIS DA MEMÓRIA DE CURTA
  DURAÇÃO só duram poucos minutos ou horas.
• Memórias que duram poucos dias e depois
  desaparecem
• Esquecimento real (as memórias desaparecem por
  atrofia sináptica (falta de uso).

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One-trial, step-down, inhibitory avoidance (IA)
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One-trial, step-down, inhibitory avoidance (IA)
Características
1. La memoria asociada con esta tarea es
adquirida en apenasuna sesión de entrenamiento,
lo que la hace ideal para el estudiode las
cascadas bioquímicas activadas durante la
consolidaciónde memorias, sin la contaminación
proveniente del proceso deexpresión que ocurre
durante el aprendizaje de paradigmas desesiones
múltiplas.
2. Representa una forma rápida y simple de
aprendizaje queinvolucra una forma universal
de memoria. Esto permite quelos eventos
biquímicos iniciados por el entrenamiento puedan
serseguidos de manera precisa y que los
resultados obtenidospuedan ser extrapolados a
otros sistemas.
?
ENTRENAMIENTO
TESTE
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The inhibition of acquired fearNeurotoxicity
Research, 6 2004
Fig 1 Extinction of IA memory requires the
normal functionality of several signaling
pathways in thehippocampus and
amygdala.Animals with cannulae implanted in the
CA1 region of the dorsal hippocampus or into the
baso-lateral amygdala were trained (Tr) in IA
using a 0.5 mA, 2 s footshock and submitted to 4
daily extinction sessions (T1 to T4).Fifteen min
before T1 the animals received through the
implanted cannulae bilateral infusions of the RNA
pol II inhibitor, DRB, theprotein synthesis
inhibitor, anisomycin (ANI), the blocker of
ERK1/2 activation, PD098059 or the PKA inhibitor,
Rp-cAMPs.
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The entorhinal cortex plays a role in
extinctionNeurobiology of Learning and Memory,
86, 192-197, 2006
Animals trained in IA were submitted to 4
non-reinforced test sessions at 24, 48, 72 and 96
h after training (T1 to T4). Immediately after T1
animals received bilateral infusions of 10 DMSO
in saline (VEH), AP5 (25 nmol/side), anisomycin
(ANI 300 nmol/side), PD98059 (5 nmol/side) or
KN-93 (10 nmol/side) into the entorhinal cortex.
Values are expressed as median ? interquartile
range of step-down latency. n14-22 per group
plt0.01 and plt0.001 vs T1 in Dunns multiple
comparisons after Friedman test for repeated
measures. Please note in the upper right corner
the schematic drawing taken the Atlas of Paxinos
and Watson (1986) showing the location of the
infusion sites in the entorhinal cortex (light
gray)
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Inhibition of mRNA and protein synthesis in the
CA1 region of the dorsalhippocampus blocks
reinstatement of an extinguished conditionedfear
response Journal of Neuroscience, 23 2003
Fig 2 Presentation of the CS after enhanced
extinction does not induce spontaneous recovery
of the original CR.Unimplanted animals were
trained (T) in IA and tested for 5 consecutive
days (TT1 TT5 first test 24 h after training).
During testsessions, animals were allowed to
freely explore the training box for 30 sec after
they stepped down from the platform.To evaluate
the spontaneous recovery of the avoidance
response, animals were tested once again 8 d
after the fifth extinctionsession (TT6). Data
are expressed as median interquartile range of
the step down latency (i.e. the time the animals
spendon the platform before stepping down to the
grid). plt0.01 vs T in Dunns poc hoc comparison
after Kruskal-Wallis test.
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Inhibition of mRNA and protein synthesis in the
CA1 region of the dorsalhippocampus blocks
reinstatement of an extinguished conditionedfear
response Journal of Neuroscience, 23 2003
Fig 3 Retrieval enhancers are unable to recover
the expressionof the original CR after enhanced
extinction.A. Animals bilaterally implanted
with cannulae aimed to the CA1 region of
thedorsal hippocampus were trained in IA and
tested without reinforcer for 5consecutive days
(TT1-TT5 first test 24 h after training).
Fifteen minutesbefore TT5 the animals received
bilateral intra-CA1 infusions of either
saline(VEH), Sp-cAMPs (Sp), SKF38393 (SKF),or
oxotremorine (OXO), or anintraperitoneal
administration of saline (Sal) or ACTH1-24. B.
Animals bilaterally implanted with cannulae aimed
at the CA1 region weretrained as in A and, 15
min before a test session performed 24h after
trainingthey received bilateral infusions of
VEH, Sp, SKF or OXO, or an intraperitonealadminis
tration of SAL or ACTH. plt0.05 vs TT1 in a
Mann-Whitney two-tailedtest.
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Inhibition of mRNA and protein synthesis in the
CA1 region of the dorsalhippocampus blocks
reinstatement of an extinguished conditionedfear
response Journal of Neuroscience, 23 2003
Fig 4 Intrahippocampal ANI and DRB block
reinstatement of the avoidance response after
enhanced extinction.Animals bilaterally
implanted with cannulae aimed to the CA1 region
on the dorsal hippocampus were trained in IA and
tested for 4consecutive days (TT1 TT4 first
test 24 h after training. After that the animals
were randomly assigned to four different
groups.Fifteen minutes before the fifth session
(TT5), each experimental group received bilateral
intra-CA1 infusions of saline (Sal),anisomycin
(ANI), 0.1 DMSO in saline (VEH) or DRB. During
this session, instead of being allowed to freely
explore the trainingbox, rats received a
scrambled electric footshock equal to that
received in the training session immediately
after they stepped downto the grid. Retention
was measured in a subsequent test session
performed 24 h later (TT6). plt0.001 vs VEH or
Sal groupsat TT6 in a Mann-Whitney two-tailed
test.
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(No Transcript)
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Relationship between short- and long-term memory
andshort- and long-term extinction Neurobiology
of Learning Memory, 8425-32, 2005
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Conclusions on extinction

• Extinction is generated at the first CS-no US
  test through mechanisms involving NMDA receptors,
  CaMKII, PKA, ERKs, gene expression and protein
  synthesis in CA1, and PKA, gene expression and
  protein synthesis in the BLA and in the
  entorhinal cortex.
• In fear-motivated tasks protein synthesis and
  cell firing in the medial prefrontal cortex also
  plays a role in extinction. In other tasks other
  brain regions may also be involved (insula CTA)
  in some aversive tasks the hippocampus is not
  involved.
• Extinction can be increased by enhancing the no
  US component. This is useful for
  psychotherapeutic purposes. It causes a
  suppression of the original task that may be
  viewed as very close to forgetting.
• There is a short form of extinction. There is
  continuity between short- and long-term
  extinction, established when short-term
  extinction begins.
• Extinction is the treatment of choice for fobias
  and PTSD

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REPRESSÃO

• O cérebro costuma reprimir a evocação de memórias
  prejudiciais, ruins ou desagradáveis, de maneira
  inconsciente (without awareness)
• Também podemos conseguir isto de forma consciente
  , forçando-nos voluntariamente a esquecer esse
  tipo de memórias (não quero lembrar da cara
  dessa pessoa, etc.)

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• Em ambos tipos de repressão intervém
  provavelmente o córtex prefrontal medial
  (locusda memória de trabalho e do gerente
  geral de informações na hora da aquisição ou
  evocação de memórias.
• Esse córtex age inibindo a atividade do
  hipocampo, principal locusda evocação de
  memórias

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• Extinction and repression are in general
  processes which cause a reduction of retrieval,
  not real forgetting
• They might, however, reduce retrieval so much
  that they effectively function as forms of
  forgetting (or pseudo-forgetting)
• What about real forgetting due to a rapid decay
  of WM or STM? Many memories are retained for
  only a few hours one often forgets what
  happened the day before, or a few hours ago. This
  is easily explained by deficient LTM formation.
• Other memories are retained for a few days and
  then forgotten Recent experiments suggest that
  there are delayed post-acquisition maintenance
  processes that also depend on hippocampal protein
  synthesis.

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Delayed memory processing
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Early and delayed memory processing Effects of
antibody against BDNF
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• Loss of memory after a few days may be viewed as
  real forgetting and does not (necessarily) result
  from synaptic loss or atrophy.
• It might instead obey to a failure or deficit of
  further, delayed posttraining hippocampal protein
  synthesis- and BDNF-mediated events.

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• Martin Cammarota (PUCRS)
• Monica Vianna (PUCRS)
• Lia Bevilaqua (PUCRS)
• Janine Rossato (PUCRS)
• Juliana Bonini (PUCRS)
• Jorge Medina (UBA)
• Pedro Beckinschtein (UBA)
• Lionel Müller Igaz (UBA)
• FONCYT (Argentina), FAPERGS, CNPQ (Brasil)