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The occurrence of dreaming during rapid eye movement (REM) sleep prompts interest in the role of REM sleep in hippocampal-dependent episodic memory. Within the mammalian hippocampus, the dentate gyrus (DG) has the unique characteristic of exhibiting neurogenesis persisting into adulthood. Despite their small numbers and sparse activity, adult-born neurons (ABNs) in the DG play critical roles in memory; however, their memory function during sleep is unknown. Here, we investigate whether young ABN activity contributes to memory consolidation during sleep using Ca 2+ imaging in freely moving mice. We found that contextual fear learning recruits a population of young ABNs that are reactivated during subsequent REM sleep against a backdrop of overall reduced ABN activity. Optogenetic silencing of this sparse ABN activity during REM sleep alters the structural remodeling of spines on ABN dendrites and impairs memory consolidation. These findings provide a causal link between ABN activity during REM sleep and memory consolidation.

Decline in cognitive functions, including hippocampus-dependent spatial memory, is commonly observed at a later stage of aging (e.g., >20 months old in rodents) and typically studied after a discrete learning event. How normal aging, particularly at an early stage, affects the modulatory aspect of memory persistence is underinvestigated. Previous studies in young animals show that weak, fading memories can last longer if a modulating event, such as spatial novelty, is introduced around memory encoding. This is known as behavioral tagging and capture (BTC). Here, we investigated how early aging (10–13 months old) affects BTC in an appetitive delayed-matching-to-place task. We trained rats when they were young and middle aged and found that novelty facilitated long-term memory persistence in young but not in middle-aged rats. However, re-exposure to the encoded environment after learning improved memory persistence in middle-aged rats. BTC, combined with memory reactivation, facilitated memory persistence through reconsolidation. Our results point toward a weakened tagging and capture mechanism before reduction of plasticity-related proteins at an early stage of aging.

During a small-scale cell culture process producing a monoclonal antibody, a larger than expected difference was observed in the charge variants profile of the harvested cell culture fluid (HCCF) between the 2 L and larger scales (e.g., 400 L and 12 kL). Small-scale studies performed at the 2 L scale consistently showed an increase in acidic species when compared with the material made at larger scale. Since the 2 L bioreactors were made of clear transparent glass while the larger scale reactors are made of stainless steel, the effect of ambient laboratory light on cell culture process in 2 L bioreactors as well as handling the HCCF was carefully evaluated. Photoreactions in the 2 L glass bioreactors including light mediated increase in acidic variants in HCCF and formulation buffers were identified and carefully analyzed. While the acidic variants comprised of a mixture of sialylated, reduced disulfide, crosslinked (nonreducible), glycated, and deamidated forms, an increase in the nonreducible forms, deamidation and Met oxidation was predominantly observed under light stress. The monoclonal antibody produced in glass bioreactors that were protected from light behaved similar to the one produced in the larger scale. Our data clearly indicate that care should be taken when glass bioreactors are used in cell culture studies during monoclonal antibody production.

Our current understanding of brain mechanisms involved in learning and memory has been derived largely from studies using experimentally naïve animals. However, it is becoming increasingly clear that not all identified mechanisms may generalize to subsequent learning. For example, N-methyl-D-aspartate glutamate (NMDA) receptors in the dorsal hippocampus are required for contextual fear conditioning in naïve animals but not in animals previously trained in a similar task. Here we investigated how animals learn contextual fear conditioning for a second time-a response which is not due to habituation or generalization. We found that dorsal hippocampus infusions of voltage-dependent calcium channel blockers or the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) agonist impaired the first, not the second contextual learning. Only manipulations of the entire hippocampus led to an impairment in second learning. Specifically, inactivation of either the dorsal or ventral hippocampus caused the remaining portion of the hippocampus to acquire and consolidate the second learning. Thus, dorsal hippocampus seems necessary for initial contextual fear conditioning, but either the dorsal or ventral hippocampus is sufficient for subsequent conditioning in a different context. Together, these findings suggest that prior training experiences can change how the hippocampus processes subsequent similar learning.

The neurobiology of memory formation has been studied primarily in experimentally naive animals, but the majority of learning unfolds on a background of prior experience. Considerable evidence now indicates that the brain processes initial and subsequent learning differently. In rodents, a first instance of contextual fear conditioning requires NMDA receptor (NMDAR) activation in the dorsal hippocampus, but subsequent conditioning to another context does not. This shift may result from a change in molecular plasticity mechanisms or in the information required to learn the second task. To clarify how related events are encoded, it is critical to identify which aspect of a first task engages NMDAR-independent learning and the brain regions that maintain this state. Here, we show in rats that the requirement for NMDARs in hippocampus depends neither on prior exposure to context nor footshock alone but rather on the procedural similarity between two conditioning tasks. Importantly, NMDAR-independent learning requires the memory of the first task to remain hippocampus dependent. Furthermore, disrupting memory maintenance in the anterior cingulate cortex after the first task also reinstates NMDAR dependency. These results reveal cortico-hippocampal interactions supporting experience-dependent learning.

Consistent cell culture performance is a prerequisite to ensure product quality consistency and achieve productivity goals for the manufacture of recombinant protein therapeutics, including monoclonal antibodies. Here a peculiar observation is reported where high levels of intracellular BiP in seed train cultures are consistently predictive of poor cell culture performance in the subsequent inoculum and production cultures for a monoclonal antibody produced in CHO cells. This investigation suggests that in this cell line the high intracellular BiP levels in the seed train are triggered by a slightly lower culture pH, which interferes with proper antibody folding and secretion. While the seed train culture does not display any obvious signs of the problem at slightly lower culture pH, inoculum trains, and production cultures sourced from these low pH seed trains display significantly lower cell growth and cell size. High intracellular BiP levels may interfere with UPR signaling, thereby hampering a proper and timely UPR response in the production media. Studies of other problematic cell lines have shown a similar correlation between intracellular BiP accumulation and poor production performance. The authors believe intracellular BiP levels in seed train should hence be low in order to increase the success rate in production.

This review, focusing on work using animals, updates a theoretical approach whose aim is to translate neuropsychological ideas about the psychological and anatomical organization of memory into the neurobiological domain. It is suggested that episodic-like memory consists of both automatic and controlled components, with the medial temporal mediation of memory encoding including neurobiological mechanisms that are primarily automatic or incidental. These ideas, in the cognitive and behavioral domain, are linked to neurophysiological ideas about cellular consolidation concerning synaptic potentiation, particularly the relationship between protein synthesis-dependent long-term changes and shorter-lasting post-translational mechanisms. Ideas from psychology about mental schemas are considered in relation to the phenomenon of systems consolidation and, specifically, about how prior knowledge can alter the rate at which consolidation occurs. Finally, the hippocampal-neocortical interactions theory is updated in relation to reconsolidation, a process that enables updating of stored memory traces in response to novelty.

Memory reconsolidation has been demonstrated in various tasks and species, suggesting it is a fundamental process. However, there are experimental parameters that can inhibit reconsolidation from occurring (boundary conditions). These conditions and their mechanisms remain poorly defined. Here, we characterize the ability of strong training to inhibit reconsolidation at the behavioral, systems and molecular levels. We demonstrate that strong memories in rats initially are resistant to reconsolidation, but after sufficient time will undergo reconsolidation, suggesting that boundary conditions can be transient. At the systems level, we show that the hippocampus is necessary for inhibiting reconsolidation in the amygdala. At the molecular level, we demonstrate that NR2B NMDA-receptor subunits which are critical for the induction of reconsolidation of auditory memories in the amygdala, are downregulated only under conditions when strong memories do not undergo reconsolidation. This suggests that one molecular mechanism for mediating boundary conditions is through downregulation of reconsolidation induction mechanisms.

To this day, it remains unresolved whether experimental amnesia reflects failed memory storage or the inability to retrieve otherwise intact memory. Methodological as well as conceptual reasons prevented deciding between these two alternatives: The absence of recovery from amnesia is typically taken as supporting storage impairment interpretations; however, this absence of recovery does not positively demonstrate nonexistence of memory, allowing for alternative interpretations of amnesia as impairment of memory retrieval. To address this shortcoming, we present a novel approach to study the nature of amnesia that makes positive, i.e., falsifiable, predictions for the absence of memory. Applying this paradigm, we demonstrate here that infusing anisomycin into the dorsal hippocampus induces amnesia by impairing memory storage, not retrieval.

Background The conditions under which memory generalization occurs are not well understood. Although it is believed that fear memory generalization is gradually established after learning, it is not clear whether experiences soon after learning affect generalization. Results Using a contextual fear conditioning paradigm in mice, we found that fear memory generalization occurred when mice were exposed to a familiar, unconditioned context soon after fear learning. Conclusions Our results suggest that the familiarity of contexts and the timing of their exposure influences memory generalization, which increases our understanding of the mechanisms of generalization. Electronic supplementary material The online version of this article (doi:10.1186/s13041-015-0184-0) contains supplementary material, which is available to authorized users.

Many insignificant events in our daily life are forgotten quickly but can be remembered for longer when other memory-modulating events occur before or after them. This phenomenon has been investigated in animal models in a protocol in which weak memories persist longer if exploration in a novel context is introduced around the time of memory encoding. This study aims to understand whether other types of rewarding or novel tasks, such as rewarded learning in a T-maze and novel object recognition, can also be effective memory-modulating events. Rats were trained in a delayed matching-to-place task to encode and retrieve food locations in an event arena. Weak encoding with only one food pellet at the sample location induced memory encoding but forgetting over 24 h. When this same weak encoding was followed by a rewarded task in a T-maze, the memory persisted for 24 h. Moreover, the same persistence of memory over 24 h could be achieved by exploration in a novel box or by a rewarded T-maze task after a “non-rewarded” weak encoding. When the one-pellet weak encoding was followed by novel object exploration, the memory did not persist at 24 h. Together, the results confirm that place encoding is possible without explicit reward, and that rewarded learning in a separate task lacking novelty can be an effective memory-modulating event. The behavioral and neurobiological implications are discussed.

In considering the heterogeneous function of the nucleus accumbens (NAC), the present work evaluated the conditioned place preference (CPP) after local infusion of d-amphetamine (AMP; 10, 15 microg/side) or cocaine (COC; 50, 100 microg/side) into two subareas of NAC, core and shell. A regular two-compartment CPP apparatus was used to test the place conditioning effects after 6 pairings of drug in one compartment and 6 pairings of vehicle in the other one. Significant CPP was observed with either AMP infused in the core area or COC infused into the shell area. Neither AMP in shell nor COC in core significantly produced CPP. These results indicate important differences between two neural substrates within NAC for the rewarding effects of AMP and COC on the CPP task.

In humans and in animals, mental schemas can store information within an associative framework that enables rapid and efficient assimilation of new information. Using a hippocampal-dependent paired-associate task, we now report that the anterior cingulate cortex is part of a neocortical network of schema storage with NMDA receptor-mediated transmission critical for information updating, and AMPA receptor-mediated transmission required for the expression and updating of stored information.

Memory for inconsequential events fades, unless these happen before or after other novel or surprising events. However, our understanding of the neurobiological mechanisms of novelty-enhanced memory persistence is mainly restricted to aversive or fear-associated memories. We now outline an “everyday appetitive” behavioral model to examine whether and how unrelated novelty facilitates the persistence of spatial memory coupled to parallel electrophysiological studies of the persistence of long-term potentiation (LTP). Across successive days, rats were given one trial per day to find food in different places and later had to recall that day's location. This task is both hippocampus and NMDA receptor dependent. First, encoding with low reward induced place memory that decayed over 24 h; in parallel, weak tetanization of CA1 synapses in brain slices induced early-LTP fading to baseline. Second, novelty exploration scheduled 30 min after this weak encoding resulted in persistent place memory; similarly, strong tetanization—analogous to novelty—both induced late-LTP and rescued early- into late-LTP on an independent but convergent pathway. Third, hippocampal dopamine D1/D5 receptor blockade or protein synthesis inhibition within 15 min of exploration prevented persistent place memory and blocked late-LTP. Fourth, symmetrically, when spatial memory was encoded using strong reward, this memory persisted for 24 h unless encoding occurred under hippocampal D1/D5 receptor blockade. Novelty exploration before this encoding rescued the drug-induced memory impairment. Parallel effects were observed in LTP. These findings can be explained by the synaptic tagging and capture hypothesis.

Although the clarity of many memories fades with time, some memories may maintain their original precision. Here we used a context discrimination procedure to evaluate whether the hippocampus is important in maintaining precision as memories mature. Spared discrimination in hippocampal-lesioned mice indicated that precise, remote context memories may be supported by extra-hippocampal brain regions.

Chronic pain hypersensitivity depends on N-methyl-D-aspartate receptors (NMDARs). However, clinical use of NMDAR blockers is limited by side effects resulting from suppression of the physiological functions of these receptors. Here we report a means to suppress pain hypersensitivity without blocking NMDARs, but rather by inhibiting the binding of a key enhancer of NMDAR function, the protein tyrosine kinase Src. We show that a peptide consisting of amino acids 40-49 of Src fused to the protein transduction domain of the HIV Tat protein (Src40-49Tat) prevented pain behaviors induced by intraplantar formalin and reversed pain hypersensitivity produced by intraplantar injection of complete Freund's adjuvant or by peripheral nerve injury. Src40-49Tat had no effect on basal sensory thresholds, acute nociceptive responses or cardiovascular, respiratory, locomotor or cognitive functions. Thus, through targeting of Src-mediated enhancement of NMDARs, inflammatory and neuropathic pain are suppressed without the deleterious consequences of directly blocking NMDARs, an approach that may be of broad relevance to managing chronic pain.

Summary The genetic mechanisms that regulate neurodegeneration are only poorly understood. We show that the loss of one allele of the p53 family member, p73, makes mice susceptible to neurodegeneration as a consequence of aging or Alzheimer's disease (AD). Behavioral analyses demonstrated that old, but not young, p73 +/− mice displayed reduced motor and cognitive function, CNS atrophy, and neuronal degeneration. Unexpectedly, brains of aged p73 +/− mice demonstrated dramatic accumulations of phospho-tau (P-tau)-positive filaments. Moreover, when crossed to a mouse model of AD expressing a mutant amyloid precursor protein, brains of these mice showed neuronal degeneration and early and robust formation of tangle-like structures containing P-tau. The increase in P-tau was likely mediated by JNK; in p73 +/− neurons, the activity of the p73 target JNK was enhanced, and JNK regulated P-tau levels. Thus, p73 is essential for preventing neurodegeneration, and haploinsufficiency for p73 may be a susceptibility factor for AD and other neurodegenerative disorders.

Incentive learning is the process via which animals update changes in the value of rewards. Current evidence suggests that, for food rewards in rats, this learning process involves the amygdala. However, it remains unclear whether this learning undergoes protein synthesis-dependent consolidation and “reconsolidation” processes in the lateral and basal nuclei of amygdala. Accordingly, we examined this hypothesis by local infusion of protein-synthesis inhibitor after devaluation of a food reward induced by a shift from a food-deprived to a food-sated state in an instrumental conditioning paradigm. Our results show that intra-amygdala infusions of anisomycin, whether given after the initial devaluation or after a second devaluation session, abolished the changes in the value of the food reward produced by incentive learning. This study provides direct evidence that instrumental incentive learning depends on protein synthesis within the amygdala for both consolidation and reconsolidation and extends the demonstrations of protein synthesis-dependent reconsolidation to reward-related memories.