Mecanismos de reconsolidación y extinción.pdf

MECANISMOS MOLECULARES DE LA RECONSOLIDACIÓN
Y LA EXTINCIÓN
Consolidación celular / molecular
Activación y reactivación de la memoria
Reconsolidación
Extinción en memorias asociativas y posible participación de
mecanismos tipo LTD
Contextual memory retieval may induce either
RECONSOLIDATION or EXTINCTION
depending on the length of context re-exposure
Behavioral output
Retrieval by
short
reexposure
(5 min)
Retrieval by
prolonged reexposure
(30 min)
reconsolidation
extinction
Original
memory
Extinction
memory
Testing session
Untrained or Amnesic Animal
Trained Animal
La extinción is una inhibición temporaria del comportamiento de
freezing
La recuperación expontánea ocurre algunos días después
Miedo Condicionado (fear conditioning)
Tanto la reconsolidación como la extinción dependen
de la síntesis de novo de proteínas durante un período crítico
Contextual fear conditioning
Inyección de anisomicina
Suzuki et al., 2004
Tanto la reconsolidación como la extinción dependen
de la síntesis de novo de proteínas durante un período crítico
Contextual fear conditioning
Inyección de anisomicina
Suzuki et al., 2004
Reconsolidación:
¿Cómo se labiliza la memoria reactivada?
¿Cómo se re-estabiliza?
Extinción:
¿La consolidación de la extinción es un proceso igual o similar al de la
memoria original?
¿Es un nuevo circuito que inhibe temporariamente la expresión del original?
¿Es un debilitamiento temporario del mismo circuito?
¿Ambas cosas?
¿Cuál es el mecanismo que determina si la memoria va a
reconsolidación o extinción después de la evocación?
1- NF-kB en la consolidación
Curso temporal de la actividad de NF-kB en el hipocampo
durante la consolidación
NF-B Inhibition by B Decoy DNA
Intrahipocampal injection of ds DNA oligonucleotide
containing the NF-B consensus sequence :
B Decoy :
5’-GAGGGGACTTTCCCA-3’
-CTCCCCTGAAAGGGTmutated B Decoy :
5’-GAGGCGACTTTCCCA-3’
-CTCCGCTGAAAGGGT-
Fluorescein - B Decoy entra en las neuronas 15 min después de la
inyeción
B Decoy, pero no mDecoy, inhibe NF-B
Boccia et al., J. Neurosci., 2007
La inhibición de NF-B en el hipocampo impide la consolidation de la
memoria
2- NF-kB en la reconsolidación
Actividad de NF-B durante la reconsolidación
***
*
de la Fuente et al, J. Neurosci. 2011
R
La inhibición de NF-B en
el hipocampo impide la
reconsolidación
de la Fuente et al, J. Neurosci. 2011
NoR
La inhibición de NF-kB no impide la “short-term reactivated memory”
3- NF-kB en la extinción
La inhibición de NF-B en el hipocampo retarda la recuperación
expontánea
E
NoE
de la Fuente et al, J. Neurosci. 2011
Curso temporal de la actividad de NF-B en el hipocampo durante y
después de la extinción
de la Fuente et al, J. Neurosci. 2011
Evidencias previas sugieren que la fosfatasa calcineurina
está involucrada en la extinción
La calcineurina es activada por Ca2+ - Calmodulina
P
Phosphatase activity
La calcineurina está presente en espinas dendriticas
Evidencias previas
Evidencias previas
Lin et al., J. Neurosci., 2003
Postulamos que calcineurina está involucrada en el hipocampo
en la memoria de extinción
La inhibición de calcineurina por el FK506 impide la extinción
E
NoE
de la Fuente et al, J. Neurosci. 2011
La inhibición de calcineurina no impide la reconsolidación
Hipothesis: durante la re-exposición prolongada (extinction)
la calcineurina es activada
y bloquea la activación de NF-B
La inhibición de calcineurina permite la activación de NF-B
después de la extinción
(como si fuera reconsolidación)
de la Fuente et al, J. Neurosci. 2011
Hay un target nuclear de calcineurina
para la memoria de extinción?
Calcineurin – NFAT pathway
NFAT es un factor de transcripción evolutivamente relacionado with NF-B
La inhibición de NFAT impide la extinción
E
NoE
de la Fuente et al, J. Neurosci. 2011
La inhibición de NFAT no impide la reconsolidación
Calcineurin y NFAT translocan al nucleo 45 min después de la sesión de
extinction
de la Fuente et al, J. Neurosci. 2011
La inhibición de calcineurina impide la translocación de NFAT
FK/DMSO
de la Fuente et al, J. Neurosci. 2011
Transcription factor switch between reconsolidation and extinction
The transcription factor NF-kB is activated 15 min after a brief reexposure to the training context, and induces its target
genes expression. This brief stimulus leads to reconsolidation. In contrast, if the stimulus is prolonged, phosphatase CaN is
activated and blocks NF-kB activation. CaN also activates NFAT transcription factor by direct dephosphorylation. This, in
turn, would activate its target genes expression. CaN and NFAT translocate to the nucleus as a complex, thus impeding the
NFAT rephosphorylation. In this case, extinction of memory takes place.
Reconsolidation and extinction are dissociable and mutually exclusive processes: behavioral and
molecular evidence.
Merlo E1, Milton AL, Goozée ZY, Theobald DE, Everitt BJ.
J. Neurosci 2014
At training, rats received two CS–US pairings. Twenty-four hours later, the animals were re-exposed to 1 or 10 CSs to reactivate or
extinguish the fear memory (n = 8 per group). The following day at the retention test, all the animals were presented with one CS.C, The
same behavioral procedure , but with the inclusion of a non-reactivated Ctr group that was trained identically to the 1CS and 10CS
groups but during the re-exposure session remained in the home cage. Twenty (pERK1/2) or 60 (CaN) minutes after re-exposure, or
straight from the home cage (Ctr groups), animals were killed and the cytoplasmic protein extracts from the BLA obtained (all groups, n=
8). D, E, Representative Western blot results and analysis showing the cytosolic levels of pERK1/2 (D) or CaN (E) after 1 or 10 CS
presentations. Data are presented as means ± SEM. *p < 0.05, **p < 0.01.
Reconsolidation and extinction are dissociable and mutually exclusive processes: behavioral and
molecular evidence.
Merlo E1, Milton AL, Goozée ZY, Theobald DE, Everitt BJ.
J. Neurosci 2014
A CaN increase induced by 10 CSs is
required for consolidation of the fear
extinction memory. A, Animals with fully
consolidated fear memory received
microinfusions of ASO or Scr ODN
sequences in the BLA (see Fig. 2) 2.5 h
before the presentation of 1 CS (n = 10 per
group) or 10 CSs (Scr ODN, n = 10; ASO, n =
8). Four days later, all groups were tested
for long-term fear or extinction memory
retention by the presentation of one CS.
*p < 0.005. B, Animals with fully
consolidated fear memory were
microinfused with ASO (n = 5) or Scr ODN
(n = 4) 2.5 h before 10 CS presentations.
One hour after the 10 CS presentations,
they were killed and the BLA cytoplasmic
extract was obtained. A representative
result of the Western blot analysis along
with the quantification of CaN levels in the
BLA is shown. Data are presented as means
± SEM. *p < 0.05.
Reconsolidation and extinction are dissociable and mutually exclusive processes: behavioral and
molecular evidence.
Merlo E1, Milton AL, Goozée ZY, Theobald DE, Everitt BJ.
J. Neurosci 2014
NMDAR agonist and antagonist treatments differentially affect the behavioral transition between reconsolidation and extinction. A,
Experimental design. One day after training, the rats received an intraperitoneal injection of the NMDAR partial agonist DCS (15 mg/kg) or
the antagonist MK-801 (0.1 mg/kg). B–E, One quarter of each group received 1 CS (B), 4 CS (C), 7 CS (D), or 10 CS (E) presentations (line
graphs). Twenty-four hours later, freezing behavior was measured in all groups by the presentation of one CS (bar graphs). Data are
presented as means ± SEM. MK-801 groups: 1 CS, n = 12; 4 CSs, n = 9; 7 CSs, n = 9; and 10 CSs, n = 11. DCS groups: 1 CS, n = 7; 4 CSs, n = 8; 7
CS, n = 8; and 10 CSs, n = 8. *p < 0.05, **p < 0.01.
Models of the transition
from reconsolidation to
extinction of fear
memories. A, Gradual
model. B, Step function
model. C, Three-phase
model. R, Reconsolidation
process; E, extinction
process; y-axis, sensitivity
to NMDAR activity
manipulations; x-axis,
number of CS
presentations.