M.C. Krawczyk

HIPPOCAMPAL ALPHA7 NICOTINIC RECEPTORS MODULATE MEMORY RECONSOLIDATION OF AN INHIBITORY AVOIDANCE TASK IN MICE

CF-1 male mice were trained in an inhibitory avoidance (IA) task using either a mild or a high footshock (0.8 or 1.2 mA, 50 Hz, 1 s). A retention test was given 48 h later. Immediately after the retention test, mice were given intra-dorsal hippocampus infusions of either choline (Ch, an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, 0.08-1.30 μg/hippocampus), or methyllycaconitine (MLA, an α7nAChR antagonist, 1.0-30.0 μg/hippocampus). Memory retention was tested again 24 h later. Methyllycaconitine impaired retention performance regardless of footshock intensity and its effects were long lasting. Ch impaired retention performance only in those mice trained with a high footshock. On the contrary, Ch enhanced retention performance when mice were trained with a mild footshock. These effects were long lasting and dose- and time-dependent. Retention performance was not affected in drug-treated mice that were not subjected to memory reactivation, suggesting that the performance effects could not be attributable to non-specific effects of the drugs. Methyllycaconitine effects were dose-dependently reversed by choline, suggesting that MLA and Ch interact at the α7nAChR. Altogether, results suggest that hippocampal α7nAChRs play a critical role in reconsolidation of an IA response in mice, and may also have important implications for dynamic memory processes. This is the first presentation, to our knowledge, indicating that a specific receptor (α7nAChR) is able to modulate consolidated memories after retrieval.

Neuropharmacology of memory consolidation and reconsolidation: Insights on central cholinergic mechanisms

Central cholinergic system is critically involved in all known memory processes. Endogenous acetylcholine release by cholinergic neurons is necessary for modulation of acquisition, encoding, consolidation, reconsolidation, extinction, retrieval and expression. Experiments from our laboratory are mainly focused on elucidating the mechanisms by which acetylcholine modulates memory processes. Blockade of hippocampal alpha-7-nicotinic receptors (α7-nAChRs) with the antagonist methyllycaconitine impairs memory reconsolidation. However, the administration of a α7-nAChR agonist (choline) produce a paradoxical modulation, causing memory enhancement in mice trained with a weak footshock, but memory impairment in animals trained with a strong footshock. All these effects are long-lasting, and depend on the age of the memory trace. This review summarizes and discusses some of our recent findings, particularly regarding the involvement of α7-nAChRs on memory reconsolidation.

Sildenafil, a selective phosphodiesterase type 5 inhibitor, enhances memory reconsolidation of an inhibitory avoidance task in mice.

Intracellular levels of the second messengers cAMP and cGMP are maintained through a balance between production, carried out by adenyl cyclase (AC) and guanylyl cyclase (GC), and degradation, carried out by phosphodiesterases (PDEs). Recently, PDEs have gained increased attention as potential new targets for cognition enhancement, with particular reference to phosphodiesterase type 5 (PDE5A). It is accepted that once consolidation is completed memory becomes permanent, but it has also been suggested that reactivation (memory retrieval) of the original memory makes it sensitive to the same treatments that affect memory consolidation when given after training. This new period of sensitivity coined the term reconsolidation. Sildenafil (1, 3, and 10mg/kg, ip), a cGMP-PDE5 inhibitor, facilitated retention performance of a one-trial step-through inhibitory avoidance task, when administered to CF-1 male mice immediately after retrieval. The effects of sildenafil (1mg/kg, ip) were time-dependent, long-lasting and inversely correlated with memory age. The administration of sildenafil (1mg/kg, ip) 30 min prior to the 2nd retention test did not affect retention of mice given post-retrieval injections of either vehicle or sildenafil (1mg/kg, ip). Finally, an enhancement of retention was also observed in CF-1 female mice receiving sildenafil (1mg/kg, ip) immediately, but not 180 min after retrieval. In the present paper we reported for the first time that systemic administration of sildenafil after memory reactivation enhances retention performance of the original learning. Our results indirectly point out cGMP, a component of the NO/cGMP/PKG pathway, as a necessary factor for memory reconsolidation.

Scopolamine prevents retrograde memory interference between two different learning tasks

Subjects exposed to learning experiences could store the new information through memory consolidation process. If consolidation is interfered by exposing the experimental subjects to another novel stimulus, memory of the first learning situation is sometimes disrupted. The cholinergic system is critically involved in acquisition of new information. Here, we use low doses of the muscarinic cholinergic receptor antagonist scopolamine (SCOP) to disrupt acquisition of new information, but sparing memory consolidation of previous memories. Mice were consecutively exposed to two learning situations: the inhibitory avoidance (IA) and the nose-poke habituation (NPH) tasks. The exposure of mice to the NPH task, after being trained in the IA apparatus, impairs consolidation of the avoidance memory in a manner related to the duration of the exposure to the NPH task. If the exposure to the NPH task occurred after reactivation of the avoidance memory, reconsolidation was impaired. Blockade of acquisition of the NPH task by SCOP allowed consolidation and reconsolidation of the avoidance memory. Results indicate that cholinergic system blockade by SCOP impairs acquisition but is less able to affect memory consolidation. The mere exposure and perception of a novel situation are not sufficient conditions to cause impairment of retention performance about previously learned information, but effective processing leading to acquisition of the NPH task information is necessary to cause the interference between both learning situations.

Decrease of ERK/MAPK Overactivation in Prefrontal Cortex Reverses Early Memory Deficit in a Mouse Model of Alzheimer's Disease

Alzheimers disease (AD) can be considered as a disease of memory in its initial clinical stages. Amyloid-β (Aβ) peptide accumulation is central to the disease initiation leading later to intracellular neurofibrillary tangles (NFTs) of cytoskeletal tau protein formation. It is under discussion whether different Aβ levels of aggregation, concentration, brain area, and/or time of exposure might be critical to the disease progression, as well as which intracellular pathways it activates. The aim of the present work was to study memory-related early molecular and behavioral alterations in a mouse model of AD, in which a subtle deregulation of the physiologic function of Aβ can be inferred. For this purpose we used triple-transgenic (3xTg) mice, which develop Aβ and tau pathology resembling the disease progression in humans. Memory impairment in novel object recognition task was evident by 5 months of age in 3xTg mice. Hippocampus and prefrontal cortex extra-nuclear protein extracts developed differential patterns of Aβ aggregation. ERK1/MAPK showed higher levels of cytosolic activity at 3 months and higher levels of nuclear activity at 6 months in the prefrontal cortex. No significant differences were found in JNK and NF-κB activity and in calcineurin protein levels. Finally, intra-PFC administration of a MEK inhibitor in 6-month-old 3xTg mice was able to reverse memory impairment, suggesting that ERK pathway alterations might at least partially explain memory deficits observed in this model, likely as a consequence of memory trace disruption.

Choline reverses scopolamine-induced memory impairment by improving memory reconsolidation

It is widely known that pre-training systemic administration of the muscarinic antagonist scopolamine (SCP) (0.5mg/kg, i.p.) leads to anterograde memory impairment in retention tests. The administration of the α(7)-nicotinic receptor agonist choline (Ch) in the dorsal hippocampus (0.8μg/hippocampus) immediately after memory reactivation allowed recovery from scopolamine-induced memory impairment. This effect of Ch was time-dependent, and retention performance was not affected in drug-treated mice that were not subjected to memory reactivation, suggesting that the performance effects are not due to non-specific effects of the drug. The effects of Ch also depended on the age of the reactivated memory. Altogether, our results suggest that Ch exerts its effects by modulating memory reconsolidation, and that the memory impairment induced by low doses of SCP is a memory expression failure and not a storage deficit. Therefore, reconsolidation, among other functions, might serve to change memory expression in later tests. Summarizing, our results open new avenues about the behavioral significance and the physiological functions of memory reconsolidation, providing new strategies for recovering memories from some types of amnesia.

Hippocampal α7-nicotinic cholinergic receptors modulate memory reconsolidation: a potential strategy for recovery from amnesia.

When subjects are exposed to new learning experiences, the novel information could be acquired and eventually stored through memory consolidation process. The exposure of mice to a novel experience (a hole-board) after being trained in an inhibitory avoidance apparatus is followed by impaired performance of the avoidance memory in subsequent tests. The same impairing effect is produced when mice are exposed to the novel environment after the reactivation of the avoidance memory. This interfering effect is due to impaired consolidation or reconsolidation of the avoidance memory. The administration of the α7-nicotinic receptor agonist choline (Ch) in the dorsal hippocampus (0.8 μg/hippocampus) immediately after the inhibitory avoidance memory reactivation, allowed memory recovery. This effect of Ch was time-dependent, and retention performance was not affected in drug-treated mice that were not subjected to memory reactivation, suggesting that the effects on performance are not due to non-specific effects of the drug. The effects of Ch also depended on the age of the reactivated memory. Altogether, our results suggest that Ch exerts its effects by modulating memory reconsolidation, and that the memory impairment induced by new learning is a memory expression failure and not a storage deficit. Therefore, reconsolidation, among other functions, might serve to change whether a memory will be expressed in later tests. Summarizing, our results open new avenues about the behavioral significance and the physiological functions of memory reconsolidation, providing new strategies for recovering memories from some types of amnesia.

Reconsolidation-induced memory persistence: Participation of late phase hippocampal ERK activation.

Persistence is an attribute of long-term memories (LTM) that has recently caught researchers attention in search for mechanisms triggered by experience that assure memory perdurability. Up-to-date, scarce evidence of relationship between reconsolidation and persistence has been described. Here, we characterized hippocampal ERK participation in LTM reconsolidation and persistence using an inhibitory avoidance task (IA) at different time points. Intra-dorsal-hippocampal (dHIP) administration of an ERK inhibitor (PD098059, PD, 1.0μg/hippocampus) 3h after retrieval did not affect reconsolidation of a strong IA, when tested 24h apart. However, the same manipulation impaired performance when animals were tested at 7d, regardless of the trainings strength; and being specific to memory reactivation. To the best of our knowledge, this is the first report showing that persistence might be triggered after memory reactivation involving an ERK/MAPK-dependent process.

Toward a better understanding on the role of prediction error on memory processes: From bench to clinic

HighlightsPrediction error is the driven‐force for memory acquisition and reconsolidation.Proteasome, CAMKII, NR2B NMDA receptor are involved in memory destabilization.Dopamine, Noradrenaline and Acetylcholine are involved in labilization.Prediction error minimization strategies are crucial in psychiatry disorders. Abstract Experimental psychology defines Prediction Error (PE) as a mismatch between expected and current events. It represents a unifier concept within the memory field, as it is the driving force of memory acquisition and updating. Prediction error induces updating of consolidated memories in strength or content by memory reconsolidation. This process has two different neurobiological phases, which involves the destabilization (labilization) of a consolidated memory followed by its restabilization. The aim of this work is to emphasize the functional role of PE on the neurobiology of learning and memory, integrating and discussing different research areas: behavioral, neurobiological, computational and clinical psychiatry.

Memory reconsolidation of an inhibitory avoidance task in mice involves cytosolic ERK2 bidirectional modulation

Reconsolidation has been defined as the process of memory stabilization after retrieval involving, among others, gene expression regulation and post-translational modifications. Many of these mechanisms are shared with memory consolidation. Here, we studied hippocampal ERK participation on memory reconsolidation of an inhibitory avoidance task in CF-1 mice. We found a retrieval-induced cytosolic ERK2 activation in the hippocampus (HIP) 15 min after memory reactivation, and an inhibition at 45 min. PD098059, a MEK1/2 (MAPK/ERK kinase) inhibitor, administered in the HIP immediately after retrieval impaired memory in a dose-dependent fashion. However, infusions of the highest dose of PD098059 performed 40 min after retrieval enhanced memory in mice trained with a weaker footshock. These results suggest for the first time that ERK2 is involved in memory reconsolidation in a biphasic fashion. Furthermore, the inhibition of ERK could either impair or enhance mice performance depending on ERK state of activation.