A Mismatch-Based Model for Memory Reconsolidation and Extinction in Attractor Networks

The processes of memory reconsolidation and extinction have received increasing attention in recent experimental research, as their potential clinical applications begin to be uncovered. A number of studies suggest that amnestic drugs injected after reexposure to a learning context can disrupt either of the two processes, depending on the behavioral protocol employed. Hypothesizing that reconsolidation represents updating of a memory trace in the hippocampus, while extinction represents formation of a new trace, we have built a neural network model in which either simple retrieval, reconsolidation or extinction of a stored attractor can occur upon contextual reexposure, depending on the similarity between the representations of the original learning and reexposure sessions. This is achieved by assuming that independent mechanisms mediate Hebbian-like synaptic strengthening and mismatch-driven labilization of synaptic changes, with protein synthesis inhibition preferentially affecting the former. Our framework provides a unified mechanistic explanation for experimental data showing (a) the effect of reexposure duration on the occurrence of reconsolidation or extinction and (b) the requirement of memory updating during reexposure to drive reconsolidation

Long-Term Memory for Pavlovian Fear Conditioning Requires Dopamine in the Nucleus Accumbens and Basolateral Amygdala

The neurotransmitter dopamine (DA) is essential for learning in a Pavlovian fear conditioning paradigm known as fear-potentiated startle (FPS). Mice lacking the ability to synthesize DA fail to learn the association between the conditioned stimulus and the fear-inducing footshock. Previously, we demonstrated that restoration of DA synthesis to neurons of the ventral tegmental area (VTA) was sufficient to restore FPS. Here, we used a target-selective viral restoration approach to determine which mesocorticolimbic brain regions receiving DA signaling from the VTA require DA for FPS. We demonstrate that restoration of DA synthesis to both the basolateral amygdala (BLA) and nucleus accumbens (NAc) is required for long-term memory of FPS. These data provide crucial insight into the dopamine-dependent circuitry involved in the formation of fear-related memory

Dopamine in the dorsal hippocampus impairs the late-consolidation of cocaine-associated memory

Cocaine is thought to be addictive because it elevates dopamine levels in the striatum, reinforcing drug-seeking habits. Cocaine also elevates dopamine levels in the hippocampus, a structure involved in contextual conditioning as well as in reward function. Hippocampal dopamine promotes the late phase of consolidation of an aversive step-down avoidance memory. Here, we examined the role of hippocampal dopamine function in the persistence of the conditioned increase in preference for a cocaine-associated compartment. Blocking dorsal hippocampal D1-type receptors (D1Rs) but not D2-type receptors (D2Rs) 12 h after a single training trial extended persistence of the normally short-lived memory; conversely, a general and a specific phospholipase C-coupled D1R agonist (but not a D2R or adenylyl cyclase-coupled D1R agonist) decreased the persistence of the normally long-lived memory established by three-trial training. These effects of D1 agents were opposite to those previously established in a step-down avoidance task, and were here also found to be opposite to those in a lithium chloride-conditioned avoidance task. After returning to normal following cocaine injection, dopamine levels in the dorsal hippocampus were found elevated again at the time when dopamine antagonists and agonists were effective: between 13 and 17 h after cocaine injection. These findings confirm that, long after the making of a cocaine-place association, hippocampal activity modulates memory consolidation for that association via a dopamine-dependent mechanism. They suggest a dynamic role for dorsal hippocampal dopamine in this late-phase memory consolidation and, unexpectedly, differential roles for late consolidation of memories for places that induce approach or withdrawal because of a drug association.Fil: Kramar, Cecilia Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Chefer, Vladimir I.. National Institutes of Health; Estados UnidosFil: Wise, Roy A.. National Institutes of Health; Estados UnidosFil: Medina, Jorge Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; ArgentinaFil: Barbano, María Flavia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentin

Transient Increase in Zn2+ in Hippocampal CA1 Pyramidal Neurons Causes Reversible Memory Deficit

The translocation of synaptic Zn2+ to the cytosolic compartment has been studied to understand Zn2+ neurotoxicity in neurological diseases. However, it is unknown whether the moderate increase in Zn2+ in the cytosolic compartment affects memory processing in the hippocampus. In the present study, the moderate increase in cytosolic Zn2+ in the hippocampus was induced with clioquinol (CQ), a zinc ionophore. Zn2+ delivery by Zn-CQ transiently attenuated CA1 long-term potentiation (LTP) in hippocampal slices prepared 2 h after i.p. injection of Zn-CQ into rats, when intracellular Zn2+ levels was transiently increased in the CA1 pyramidal cell layer, followed by object recognition memory deficit. Object recognition memory was transiently impaired 30 min after injection of ZnCl2 into the CA1, but not after injection into the dentate gyrus that did not significantly increase intracellular Zn2+ in the granule cell layer of the dentate gyrus. Object recognition memory deficit may be linked to the preferential increase in Zn2+ and/or the preferential vulnerability to Zn2+ in CA1 pyramidal neurons. In the case of the cytosolic increase in endogenous Zn2+ in the CA1 induced by 100 mM KCl, furthermore, object recognition memory was also transiently impaired, while ameliorated by co-injection of CaEDTA to block the increase in cytosolic Zn2+. The present study indicates that the transient increase in cytosolic Zn2+ in CA1 pyramidal neurons reversibly impairs object recognition memory

GSK-3β Is Required for Memory Reconsolidation in Adult Brain

Activation of GSK-3β is presumed to be involved in various neurodegenerative diseases, including Alzheimer's disease (AD), which is characterized by memory disturbances during early stages of the disease. The normal function of GSK-3β in adult brain is not well understood. Here, we analyzed the ability of heterozygote GSK-3β knockout (GSK+/−) mice to form memories. In the Morris water maze (MWM), learning and memory performance of GSK+/− mice was no different from that of wild-type (WT) mice for the first 3 days of training. With continued learning on subsequent days, however, retrograde amnesia was induced in GSK+/− mice, suggesting that GSK+/− mice might be impaired in their ability to form long-term memories. In contextual fear conditioning (CFC), context memory was normally consolidated in GSK+/− mice, but once the original memory was reactivated, they showed reduced freezing, suggesting that GSK+/− mice had impaired memory reconsolidation. Biochemical analysis showed that GSK-3β was activated after memory reactivation in WT mice. Intraperitoneal injection of a GSK-3 inhibitor before memory reactivation impaired memory reconsolidation in WT mice. These results suggest that memory reconsolidation requires activation of GSK-3β in the adult brain

Synergistic Activation of Dopamine D1 and TrkB Receptors Mediate Gain Control of Synaptic Plasticity in the Basolateral Amygdala

Fear memory formation is thought to require dopamine, brain-derived neurotrophic factor (BDNF) and zinc release in the basolateral amygdala (BLA), as well as the induction of long term potentiation (LTP) in BLA principal neurons. However, no study to date has shown any relationship between these processes in the BLA. Here, we have used in vitro whole-cell patch clamp recording from BLA principal neurons to investigate how dopamine, BDNF, and zinc release may interact to modulate the LTP induction in the BLA. LTP was induced by either theta burst stimulation (TBS) protocol or spaced 5 times high frequency stimulation (5xHFS). Significantly, both TBS and 5xHFS induced LTP was fully blocked by the dopamine D1 receptor antagonist, SCH23390. LTP induction was also blocked by the BDNF scavenger, TrkB-FC, the zinc chelator, DETC, as well as by an inhibitor of matrix metalloproteinases (MMPs), gallardin. Conversely, prior application of the dopamine reuptake inhibitor, GBR12783, or the D1 receptor agonist, SKF39393, induced robust and stable LTP in response to a sub-threshold HFS protocol (2xHFS), which does not normally induce LTP. Similarly, prior activation of TrkB receptors with either a TrkB receptor agonist, or BDNF, also reduced the threshold for LTP-induction, an effect that was blocked by the MEK inhibitor, but not by zinc chelation. Intriguingly, the TrkB receptor agonist-induced reduction of LTP threshold was fully blocked by prior application of SCH23390, and the reduction of LTP threshold induced by GBR12783 was blocked by prior application of TrkB-FC. Together, our results suggest a cellular mechanism whereby the threshold for LTP induction in BLA principal neurons is critically dependent on the level of dopamine in the extracellular milieu and the synergistic activation of postsynaptic D1 and TrkB receptors. Moreover, activation of TrkB receptors appears to be dependent on concurrent release of zinc and activation of MMPs