Role of prediction error and the cholinergic system on memory reconsolidation processes in mice.

The ability to make predictions based on stored information is a general coding strategy. A prediction error (PE) is a mismatch between expected and current events. Our memories, like ourselves, are subject to change. Thus, an acquired memory can become active and update its content or strength by a labilization-reconsolidation process. Within the reconsolidation framework, PE drives the updating of consolidated memories. In the past our lab has made key progresses showing that a blockade in the central cholinergic system during reconsolidation can cause memory impairment, while reinforcement of cholinergic activity enhances it. In the present work we determined that PE is a necessary condition for memory to reconsolidate in an inhibitory avoidance task using both male and female mice. Depending on the intensity of the unconditioned stimulus (US) used during training, a negative (higher US intensity) or positive (lower US intensity/no US) PE on a retrieval session modified the behavioral response on a subsequent testing session. Furthermore, we demonstrated that the cholinergic system modulates memory reconsolidation only when PE is detected. In this scenario administration of oxotremorine, scopolamine or nicotine after memory reactivation either enhanced or impaired memory reconsolidation in a sex-specific manner.

Critical role of hippocampal muscarinic acetylcholine receptors on memory reconsolidation in mice.

Over the years, experimental and clinical evidence has given support to the idea that acetylcholine (Ach) plays an essential role in mnemonic phenomena. On the other hand, the Hippocampus is already known to have a key role in learning and memory. What is yet unclear is how the Ach receptors may contribute to this brain region role during memory retrieval. The Ach receptors are divided into two broad subtypes: the ionotropic nicotinic acetylcholine receptors and the metabotropic muscarinic acetylcholine receptors. Back in 2010, we demonstrated for the first time the critical role of hippocampal α7 nicotinic acetylcholine receptors in memory reconsolidation process of an inhibitory avoidance response in mice. In the present work, we further investigate the possible implication of hippocampal muscarinic Ach receptors (mAchRs) in this process using a pharmacological approach. By specifically administrating agonists and antagonists of the different mAchRs subtypes in the hippocampus, we found that M1 and M2 but not M3 subtype may be involved in memory reconsolidation processes in mice.

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

Persistence is an attribute of long-term memories (LTM) that has recently caught researcher's 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 training's 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.

A dedicated system for topographical working memory: evidence from domain-specific interference tests.

In the present study, we used single- and dual-task conditions to investigate the nature of topographical working memory to better understand what type of task can hamper performance during navigation. During dual-task conditions, we considered four different sources of interference: motor (M), spatial motor (SM), verbal (i.e. articulatory suppression AS) and spatial environmental (SE). In order to assess the nature of topographical working memory, we used the Walking Corsi Test, asking the participants to perform two tasks simultaneously (M, SM, AS and SE). Our results showed that only spatial-environmental interference hampers the execution of a topographical working memory task, suggesting a task-domain-specific effect. We also found general gender differences in the topographical working memory capabilities: men were more proficient than women, regardless of the type of interferences. However, like men, women performed worse when a spatial-environmental interference was present.

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.

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.

Oxytocin-Cholinergic Central Interaction: Implications for Non-Social Memory Formation.

Oxytocin (OT) and vasopressin (AVP) are two closely related neuropeptides implicated in learning and memory processes, anxiety, nociception, addiction, feeding behavior and social information processing. Regarding learning and memory, OT has induced long-lasting impairment in different behaviors, while the opposite was observed with AVP. We have previously evaluated the effect of peripheral administration of OT or its antagonist (AOT) on the inhibitory avoidance response of mice and on the modulation of cholinergic mechanisms. Here, we replicate and validate those results, but this time through central administration of neuropeptides, considering their poor passage through the blood-brain barrier (BBB). When we delivered OT (0.10 ng/mouse) and its antagonist (0.10 ng/mouse) through intracerebroventricular (ICV) injections, the neuropeptide impaired and AOT enhanced the behavioral performance on an inhibitory avoidance response evaluated 48 h after training in a dose-dependent manner. On top of that, we investigated a possible central interaction between OT and the cholinergic system. Administration of anticholinesterases inhibitors with access to the central nervous system (CNS), the activation of muscarinic acetylcholine (Ach) receptors and the increase of evoked ACh release using linopirdine (Lino) (3-10 µg/kg, IP), reversed the impairment of retention performance induced by OT. Besides, either muscarinic or nicotinic antagonists with unrestricted access to the CNS reduced the magnitude of the performance-facilitating effect of AOT's central infusion. We suggest that OT might induce a cholinergic hypofunction state, resulting in an impairment of IA memory formation, a process for which the cholinergic system is crucially necessary.

No evidence of family history as a risk factor for herpes zoster in patients with post-herpetic neuralgia.

Little is known about reactivation of latent varicella zoster virus as herpes zoster in individuals with no underlying immunosuppression. Risk factors include age, sex, ethnicity, exogenous boosting of immunity from varicella contacts, underlying cell-mediated immune disorders, mechanical trauma, psychological stress, and immunotoxin exposure. An association between herpes zoster and family history of zoster has been proposed. A case-control study involving patients affected by post-herpetic neuralgia, which usually follows more severe acute herpes zoster, was performed. The patients with post-herpetic neuralgia were enrolled at the Pain Clinic of the Policlinico Tor Vergata in Rome, Italy, within 1 year from the onset of acute zoster. The controls matched for sex and age were chosen among healthy subjects without a history of herpes zoster presenting at the Internal Medicine Outpatient Clinic for hypertension in the same time period. All the participants in the study gave informed consent and were interviewed by medically trained and blinded investigators using a questionnaire. Similar proportions of the patients and the controls reported a family history of herpes zoster irrespective of the degree of relationship, i.e., 17.4% and 18.2%, respectively, by analyzing only the first-degree relatives [RR 1.03 (CI 95%: 0.78-1.37)], and 28.4% and 29.6%, respectively, by analyzing the total number of relatives [RR 1.03 (CI 95%: 0.81-1.31)]. Further and larger prospective cohort studies are needed to ascertain whether a family history of herpes zoster is really an independent predictor of zoster in different geographical settings.

Basal Forebrain Cholinergic System and Memory.

Basal forebrain cholinergic neurons constitute a way station for many ascending and descending pathways. These cholinergic neurons have a role in eliciting cortical activation and arousal. It is well established that they are mainly involved in cognitive processes requiring increased levels of arousal, attentive states and/or cortical activation with desynchronized activity in the EEG. These cholinergic neurons are modulated by several afferents of different neurotransmitter systems. Of particular importance within the cortical targets of basal forebrain neurons is the hippocampal cortex. The septohippocampal pathway is a bidirectional pathway constituting the main septal efferent system, which is widely known to be implicated in every memory process investigated. The present work aims to review the main neurotransmitter systems involved in modulating cognitive processes related to learning and memory through modulation of basal forebrain neurons.

Extinction and recovery of an avoidance memory impaired by scopolamine.

Pre-training administration of scopolamine (SCP) resembles situations of cholinergic dysfunction, leading to memory impairment of mice trained in an inhibitory avoidance task. We suggest here that SCP does not impair memory formation, but acquisition is affected in a way that reduces the strength of the stored memory, thus making this memory less able to control behavior when tested. Hence, a memory trace is stored, but is poorly expressed during the test. Although weakly expressed, this memory shows extinction during successive tests, and can be strengthened by using a reminder. Our results indicate that memories stored under cholinergic dysfunction conditions seem absent or lost, but are in fact present and experience common memory processes, such as extinction, and could be even recovered by using appropriate protocols.

Neural foundation of human moral reasoning: an ALE meta-analysis about the role of personal perspective.

Moral sense is defined as a feeling of the rightness or wrongness of an action that knowingly causes harm to people other than the agent. The large amount of data collected over the past decade allows drawing some definite conclusions about the neurobiological foundations of moral reasoning as well as a systematic investigation of methodological variables during fMRI studies. Here, we verified the existence of converging and consistent evidence in the current literature by means of a meta-analysis of fMRI studies of moral reasoning, using activation likelihood estimation meta-analysis. We also tested for a possible neural segregation as function of the perspective used during moral reasoning i.e., first or third person perspectives. Results demonstrate the existence of a wide network of areas underpinning moral reasoning, including orbitofrontal cortex, insula, amygdala, anterior cingulate cortex as well as precuneus and posterior cingulate cortex. Within this network we found a neural segregation as a function of the personal perspective, with 1PP eliciting higher activation in the bilateral insula and superior temporal gyrus as well as in the anterior cingulate cortex, lingual and fusiform gyri, middle temporal gyrus and precentral gyrus in the left hemisphere, and 3PP eliciting higher activation in the bilateral amygdala, the posterior cingulate cortex, insula and supramarginal gyrus in the left hemisphere as well as the medial and ventromedial prefrontal cortex in the right hemisphere. These results shed some more light on the contribution of these areas to moral reasoning, strongly supporting a functional specialization as a function of the perspective used during moral reasoning.

Maternal behavior deficits in nulliparous oxytocin knockout mice.

The first observations of postpartum oxytocin knockout (OTKO) mice found no maternal behavior deficits. However, it is unclear how detailed those observations were. In this study, we compared maternal behavior exhibited by OTKO and wild-type (WT) nullipara toward six 2-4-day-old foster pups during test sessions conducted on 3 successive days. Each day, subjects were placed in a clean cage 30 min prior to introduction of pups which were deposited in a clump adjacent to the middle of a long wall of each test cage. Behavior was measured for 3.5 h after which pups and test subjects were returned to their home cages. On test days 1 and 3, a significantly smaller proportion of OTKO females retrieved pups to a corner of their cage. Also, significantly fewer pups were retrieved to corners by OTKO females. In contrast to most WTs, most OTKO females mothered pups in the center of the cage where they were initially deposited. Pup-licking frequencies were significantly lower in OTKO females. Their self-grooming frequencies also trended toward being lower. Latencies to retrieve and lick pups, latencies to and frequencies of still crouching over pups and proportion of time in nest did not differ between groups. Our findings suggest that OT stimulates a significant proportion of pup-licking in nulliparous mice, a situation similar to lactating rat mothers. Our results also indicate that OT may play a role in the motivation to retrieve pups to a more secure location.

Vasopressin interactions with oxytocin in the control of female sexual behavior.

Previous studies have found that central administration of arginine vasopressin and arginine vasopressin receptor V1a antagonists respectively inhibited and stimulated receptivity but did not examine effects on other aspects of female sexual behavior. Central oxytocin facilitates both proceptive and receptive components of sexual behavior and diminishes male-directed agonistic behavior. The present study examined i.c.v.-administered arginine vasopressin and V1a antagonist effects on proceptive, receptive and agonistic behaviors, and interactions with oxytocin. In experiment 1, rats were primed s.c. with 2 microg estradiol benzoate x 2 days and with 500 microg of progesterone on day 3. Arginine vasopressin (0.2, 0.4 microg) or normal saline vehicle was administered 5 h after progesterone treatment and sexual and agonistic behavior measured 30, 60 and 90 min later. Compared with saline, both doses of arginine vasopressin significantly decreased lordosis responses to mounting and hop-dart proceptive behavior and trended toward significantly increasing agonistic behaviors. In experiment 2, oxytocin (2 microg) infusion just after arginine vasopressin (0.4 microg) significantly increased lordoses and decreased agonistic behaviors but did not affect hopping and darting. In experiment 3, conducted in ovariectomized rats primed with estradiol benzoate (1 microg/day s.c. x 2 days), i.c.v. infusion of 0.5 and 1.0 microg of the selective V1a antagonist, d(CH2)5Tyr-(Me)arginine vasopressin on day 3 significantly increased lordoses and trended toward increasing hopping and darting 4 and 6 h after i.c.v. treatment. In experiment 4, 1 microg of the selective oxytocin antagonist, d(CH2)5[Tyr(Me)2, Thr4, Tyr-NH2(9)]OVT given 1 h before d(CH2)5Tyr-(Me)arginine vasopressin (1 microg) significantly decreased lordoses. Previous studies indicate that arginine vasopressin contributes to light phase inhibition of female sexual behavior. Our findings suggest that arginine vasopressin may exert this effect through interactions that decrease oxytocin stimulation of sexual behavior and raise the question whether sex steroid conditions that stimulate sexual behavior may suppress central arginine vasopressin and V1a receptor activity.

Where does brain neural activation in aesthetic responses to visual art occur? Meta-analytic evidence from neuroimaging studies.

Here we aimed at finding the neural correlates of the general aspect of visual aesthetic experience (VAE) and those more strictly correlated with the content of the artworks. We applied a general activation likelihood estimation (ALE) meta-analysis to 47 fMRI experiments described in 14 published studies. We also performed four separate ALE analyses in order to identify the neural substrates of reactions to specific categories of artworks, namely portraits, representation of real-world-visual-scenes, abstract paintings, and body sculptures. The general ALE revealed that VAE relies on a bilateral network of areas, and the individual ALE analyses revealed different maximal activation for the artworks' categories as function of their content. Specifically, different content-dependent areas of the ventral visual stream are involved in VAE, but a few additional brain areas are involved as well. Thus, aesthetic-related neural responses to art recruit widely distributed networks in both hemispheres including content-dependent brain areas of the ventral visual stream. Together, the results suggest that aesthetic responses are not independent of sensory, perceptual, and cognitive processes.

Memory consolidation and reconsolidation of an inhibitory avoidance task in mice: effects of a new different learning task.

CF-1 male mice were trained in an inhibitory avoidance task using a high footshock (1.2mA, 50Hz, 1 s) in order to reduce the influence of extinction on retention performance. A single session of 5 min exposure to a hole-board (nose-poke behavior), either immediately after training or the first retention test (memory reactivation) impaired retention performance over two consecutive days. The effects were time-dependent since they were not observed when the exposure to the hole-board was delayed 3 h. When mice were habituated to the hole-board (5 min/day, 5 days), and then trained in an inhibitory avoidance task, the immediately post-training or memory reactivation exposure to the hole-board did not modify retention performance over two consecutive days. The effects of the post-reactivation acute exposure to the hole-board were long-lasting (21 days). Reinstatement was not observed in our experimental conditions. The non-spontaneous recovery of retention performance over 21-days and the lack of reinstatement, suggest that the impairment of retention performance observed was not probably due to a deficit in memory retrieval. These findings suggest that the exposure to a potential new learning situation impairs not only memory consolidation but also memory reconsolidation of the original learning task.

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.

Do you like Arcimboldo's? Esthetic appreciation modulates brain activity in solving perceptual ambiguity.

Esthetic experience is a unique, affectively colored, self-transcending subject-object relationship in which cognitive processing is felt to flow differently than during everyday experiences. Notwithstanding previous multidisciplinary investigations, how esthetic experience modulates perception is still obscure. We used Arcimboldo's ambiguous portraits to assess how the esthetic context organizes ambiguous percepts. The study was carried out using functional magnetic resonance imaging (fMRI) in healthy young volunteers (mean age 25.45; S.D. 4.51; 9 females), during both an explicit esthetic judgment task and an artwork/non-artwork classification task. We show that a distinct neural mechanism in the fusiform gyrus contributes to the esthetic experience of ambiguous portraits, according to the valence of the esthetic experience. Ambiguous artworks eliciting a negative esthetic experience lead to more pronounced activation of the fusiform face areas than ambiguous artworks eliciting a positive esthetic experience. We also found an interaction between task and ambiguity in the right superior parietal lobule. Taken together, our results demonstrate that a neural mechanism in the content-dependent brain regions of face processing underlies the esthetic experience of ambiguous portraits. Furthermore, they suggest that esthetic experience interacts with perceptual qualities of stimuli in the right superior parietal lobe, supporting the idea that esthetic experience arises from the interaction between top-down orienting of attention and bottom-up perceptual facilitation.

Hippocampal dynamics of synaptic NF-kappa B during inhibitory avoidance long-term memory consolidation in mice.

Since the discovery that long-term memory is dependent on protein synthesis, several transcription factors have been found to participate in the transcriptional activity needed for its consolidation. Among them, NF-kappa B is a constitutive transcription factor whose nuclear activity has proven to be necessary for the consolidation of inhibitory avoidance in mice. This transcription factor has a wide distribution in the nervous system, with a well-reported presence in dendrites and synaptic terminals. Here we report changes in synaptosomal NF-kappa B localization and activity, during long-term memory consolidation. Activity comparison of synaptosomal and nuclear NF-kappa B, indicates different dynamics for both localizations. In this study we identify two pools of synaptosomal NF-kappa B, one obtained with the synaptoplasm (free fraction) and the second bound to the synaptosomal membranes. During the early steps of consolidation the first pool is activated, as the membrane associated transcription factor fraction increases and concomitantly the free fraction decreases. These results suggest that the activation of synaptic NF-kappa B and its translocation to membranes are part of the consolidation of long-term memory in mice.

Memory consolidation and reconsolidation of an inhibitory avoidance response in mice: effects of i.c.v. injections of hemicholinium-3.

The immediate post-training i.c.v. administration of hemicholinium-3 (HC-3) (1 microg), a specific inhibitor of the high-affinity choline uptake (HACU) in brain cholinergic neurons, impaired retention test performance of a one-trial step-through inhibitory avoidance response in adult male CF-1 mice. The effect was observed in mice that received a footshock (0.8 mA, 50 Hz, 1 s) on the learning trial, and not only 48 h after training, but also 7 days after it. After the completion of the retention test at each of the training-test interval that were studied, the HACU in the hippocampus of HC-3-treated mice was not significantly different from that of saline-injected (1 microl) control groups. Mice that were over-reinforced (1.2 mA, 50 Hz, 1 s) on the learning trial, exhibited a high retention performance 48 h after training. The immediate i.c.v. injection of HC-3 (1 microg) after the retention test, that is, after memory reactivation, significantly impaired retention performance over 4 consecutive days, whereas the saline-injected control group shown a slight, but significant performance decrease only at the last retention test. Retention performance was unchanged in HC-3-treated mice not undergoing memory reactivation session. These results, taken together, indicate that HC-3, not only impaired consolidation, but also reconsolidation of an inhibitory avoidance task in mice, suggesting a critical participation of central cholinergic mechanisms in both memory processes.

Brief vs. long maternal separations in infancy: contrasting relationships with adult maternal behavior and lactation levels of aggression and anxiety.

We compared the effects of daily long (3 h), brief (15 min) or no maternal separation (LMS, BMS, NMS) on postnatal days 2-14 on maternal behavior, aggression and anxiety levels during lactation in adulthood. Animals subjected to LMS received less maternal grooming than animals subjected to BMS. Maternal behaviors, including nursing, pup-grooming (PG) frequency and proportion of total grooming (PG+self-grooming) and nest-building during the immediate postpartum period and on postpartum days 2 and 5 were lower in dams with LMS experience compared to dams with BMS experience. LMS dams attacked male rats placed in their home cages less quickly and less often than did BMS or NMS dams. LMS dams also exhibited more anxiety than BMS dams in the elevated plus maze test. Thus, maternal separation during the postnatal period (or associated changes in the amount of maternal grooming received) affected subsequent adult maternal behavior, aggression and anxiety. The mechanism for this remains to be discovered, however, it seems likely to involve alteration of the development of oxytocin receptors in the brain.