Persistent up-regulation of polyribosomes at synapses during long-term memory,reconsolidation, and extinction of associative memory

Local protein synthesis at synapses can provide a rapid supply of proteins to support synaptic changes during consolidation of new memories, but its role in the maintenance or updating of established memories is unknown. Consolidation requires new protein synthesis in the period immediately following learning, whereas established memories are resistant to protein synthesis inhibitors. We have previously reported that polyribosomes are up-regulated in the lateral amygdala (LA) during consolidation of aversive-cued Pavlovian conditioning. In this study, we used serial section electron microscopy reconstructions to determine whether the distribution of dendritic polyribosomes returns to baseline during the long-term memory phase. Relative to control groups, long-term memory was associated with up-regulation of polyribosomes throughout dendrites, including in dendritic spines of all sizes. Retrieval of a consolidated memory by presentation of a small number of cues induces a new, transient requirement for protein synthesis to maintain the memory, while presentation of a large number of cues results in extinction learning, forming a new memory. One hour after retrieval or extinction training, the distribution of dendritic polyribosomes was similar except in the smallest spines, which had more polyribosomes in the extinction group. Our results demonstrate that the effects of learning on dendritic polyribosomes are not restricted to the transient translation-dependent phase of memory formation. Cued Pavlovian conditioning induces persistent synapse strengthening in the LA that is not reversed by retrieval or extinction, and dendritic polyribosomes may therefore correlate generally with synapse strength as opposed to recent activity or transient translational processes.

The formation of long-term memory involves a consolidation phase in the period immediately after learning, during which new proteins are required to stabilize learning-induced synapse remodeling (Davis and Squire 1984; Mayford et al. 2012; Rosenberg et al. 2014; Segal 2017). There is evidence that local protein synthesis in dendrites is essential for consolidation of long-term memory and related forms of synaptic plasticity (Holt and Schuman 2013), but its exact role is not well understood. Dendritic translation can supply new proteins to synapses rapidly, and potentially with synapse-specific spatial precision. Thousands of mRNAs have been identified in dendrites, many of which encode synaptic proteins (Poon et al. 2006; Zhong et al. 2006; Cajigas et al. 2012; Tushev et al. 2018; Middleton et al. 2019), and mRNA is present in dendritic spines (Tiruchinapalli et al. 2003; Hafner et al. 2019). The ability of dendritic mRNAs to remain dormant until they are unmasked by synaptic activity (Doyle and Kiebler 2011; Buxbaum et al. 2014; Hutten et al. 2014) provides a mechanism for rapid and targeted translation at synapses. Synaptic activity during learning triggers a transient up-regulation of new synaptic proteins in dendrites (Redondo and Morris 2011; Moncada et al. 2015), and the spatiotemporal constraints on these new proteins strongly suggest that they are translated locally (Sajikumar et al. 2007; Doyle and Kiebler 2011). We have previously found by serial section transmission electron microscopy (ssTEM) volume reconstruction that polyribosomes and translation factors are up-regulated in dendritic spines in the rat lateral amygdala (LA) 1 h after cued aversive Pavlovian conditioning (Ostroff et al. 2010, 2017; Gindina et al. 2021). These polyribosomes presumably represent translation supporting consolidation, but no studies have addressed whether dendritic translation remains elevated or returns to baseline in the long-term memory phase.Cued aversive Pavlovian conditioning, also referred to as fear or threat conditioning, is an extensively studied learning paradigm in which a sensory cue is paired with an unpleasant stimulus—typically an auditory cue with a mild shock—to create an associative memory between the two (LeDoux 2000; Maren 2001). There is strong evidence that this memory is mediated by protein synthesis-dependent strengthening of LA synapses during a short window after learning. Enhanced synaptic transmission is observed in the LA after conditioning (McKernan and Shinnick-Gallagher 1997; Rogan et al. 1997; Sah et al. 2008), and consolidation requires protein synthesis in the LA immediately after training, but not 6 or 24 h later (Nader et al. 2000; Schafe and LeDoux 2000; Maren et al. 2003). The extracellular signal-regulated/mitogen-activated protein kinase (ERK/MAPK), which regulates translation (Kelleher et al. 2004), is transiently phosphorylated in the LA 1 h after learning, and this phosphorylation is required for both memory consolidation (Schafe et al. 2000) and synaptic plasticity in the LA (Huang et al. 2000; Schafe et al. 2008).Although dormant long-term memories are stable, retrieval induces a new labile phase called reconsolidation, during which the memory can be updated, weakened, or strengthened (Dudai 2012). As in consolidation, postretrieval inhibition of protein synthesis or ERK/MAPK phosphorylation in the LA impairs reconsolidation of the memory and associated synaptic plasticity (Nader et al. 2000; Duvarci et al. 2005; Doyere et al. 2007). A transient supply of necessary new proteins is available to synapses during reconsolidation (Orlandi et al. 2020), but whether these proteins are synthesized in dendrites is unknown. Both consolidation and reconsolidation are impaired by broad protein synthesis inhibitors, and there is substantial evidence that consolidation requires translation initiation, the step in which polyribosomes are formed (Gkogkas et al. 2010; Santini et al. 2014). Interestingly, one study found that inhibition of the predominant initiation process impaired consolidation but not reconsolidation, suggesting that the role of translation differs between the two processes (Hoeffer et al. 2011). Since polyribosomes can be stalled for later reactivation (Richter and Coller 2015), reconsolidation could rely on translation of pre-existing polyribosomes.Reconsolidation is triggered by a small number of retrieval cues, but retrieval with a large number of cues induces extinction learning, in which the cue loses its ability to elicit defensive responses (Myers and Davis 2007). There is ample evidence that plasticity important for extinction occurs in the basolateral amygdala (BLA; which includes the LA), though it is unclear exactly how this relates to the original memory trace in the dorsal LA (Bouton et al. 2021). For instance, consolidation of extinction is impaired by pretraining systemic inhibition of protein synthesis (Suzuki et al. 2004) and by pretraining inhibition of protein synthesis or ERK/MAPK in the BLA (Lin et al. 2003c; Herry et al. 2006). However, the Lin et al. (2003c) study measured the effects of protein synthesis inhibition in the BLA 30 min after extinction training, which is typically thought to reflect short-term memory. Subsequent work by another group found that postextinction training inhibition of protein synthesis impaired reconsolidation, making it difficult to assess the effects on extinction consolidation (Duvarci et al. 2006). There are also ongoing debates about the relative contribution of “erasure” versus “new learning” processes in extinction. Evidence that protein synthesis-dependent depotentiation of CS inputs to the LA contributes to extinction suggests up-regulation of polyribosomes in the LA pyramidal cells storing the original trace (Lin et al. 2003a,b,c; Kim et al. 2009). However, up-regulation of polyribosomes is also possible if extinction plasticity occurs in other cells or regions of the brain, as repeated retrieval trials may strongly trigger reconsolidation processes. Complicating things further, it appears that extinction can halt reconsolidation (Suzuki et al. 2004).To investigate the dynamics of local translation in the context of an established memory, we used ssTEM to quantify dendritic polyribosome distribution in the LA during the long-term memory phase of Pavlovian conditioning, reconsolidation, and consolidation of extinction. We hypothesized that polyribosomes would not be up-regulated in the long-term memory condition relative to controls, since memory maintenance is resistant to protein synthesis inhibition at this time point. We also hypothesized that both retrieval and extinction would induce up-regulation of polyribosomes, but in different patterns; for example, reconsolidation processes could be reflected in polyribosomes near large synapses, but extinction could result in loss of these synapses and perhaps more generalized polyribosome distribution.     

Endurance factors improve hippocampal neurogenesis and spatial memory in mice

Physical activity improves learning and hippocampal neurogenesis. It is unknown whether compounds that increase endurance in muscle also enhance cognition. We investigated the effects of endurance factors, peroxisome proliferator-activated receptor δ agonist GW501516 and AICAR, activator of AMP-activated protein kinase on memory and neurogenesis. Mice were injected with GW for 7 d or AICAR for 7 or 14 d. Two weeks thereafter mice were tested in the Morris water maze. AICAR (7 d) and GW improved spatial memory. Moreover, AICAR significantly, and GW modestly, elevated dentate gyrus neurogenesis. Thus, pharmacological activation of skeletal muscle may mediate cognitive effects.     

Hormonal and monoamine signaling during reinforcement of hippocampal long-term potentiation and memory retrieval

Recently it was shown that holeboard training can reinforce, i.e., transform early-LTP into late-LTP in the dentate gyrus during the initial formation of a long-term spatial reference memory in rats. The consolidation of LTP as well as of the reference memory was dependent on protein synthesis. We have now investigated the transmitter systems involved in this reinforcement and found that LTP-consolidation and memory retrieval were dependent on β-adrenergic, dopaminergic, and mineralocorticoid receptor (MR) activation, whereas glucocorticoid receptors (GRs) were not involved. Blockade of the β-adrenergic signaling pathway significantly increased the number of reference memory errors compared with MR and dopamine receptor inhibition. In addition, β-adrenergic blockade impaired the working memory. Therefore, we suggest that β-adrenergic receptor activation is the main signaling system required for the retrieval of spatial memory. In addition, other modulatory interactions such as dopaminergic as well as MR systems are involved. This result points to specific roles of different modulatory systems during the retrieval of specific components of spatial memory. The data provide evidence for similar integrative interactions between different signaling systems during cellular memory processes.     

The effects of hippocampal lesions on learning, memory, and reward expectancies

The hippocampus appears to be critical for the formation of certain types of memories. Hippocampal-lesioned animals fail to exhibit some spatial, contextual, and relational associations. After aspiration lesions of the hippocampus and/or cortex, male rats were allowed to recover for three weeks before being trained on a matching-to-position task. The matching-to-position task was altered to influence the type of cognitive strategies a subject would use to solve the task. The main behavioral manipulation was the reinforcement contingency assignment: Use of a differential outcomes procedure (DOP) or a nondifferential outcomes procedure (NOP). The DOP involves correlating each to-be-remembered event with a distinct reward condition via Pavlovian trace conditioning, whereas the NOP results in random reward contingency. We found that hippocampal lesions did retard learning the matching rule, regardless of the reinforcement contingency assignment. However, when delay intervals were added to the task memory performance of subjects with hippocampal lesions was dramatically impaired--if subjects were not trained with the DOP. When subjects were trained with the DOP, the hippocampal lesion had a marginal effect on delayed memory performance. These findings demonstrate two important points regarding lesions of the hippocampus: (1) hippocampal lesions have a minimal effect on the on the ability of rats to use reward information to solve a delayed discrimination task; (2) rats with hippocampal lesions have the ability to learn about reward information using Pavlovian trace conditioning procedures.     

Reversible hippocampal lesions disrupt water maze performance during both recent and remote memory tests

Conventional lesion methods have shown that damage to the rodent hippocampus can impair previously acquired spatial memory in tasks such as the water maze. In contrast, work with reversible lesion methods using a different spatial task has found remote memory to be spared. To determine whether the finding of spared remote spatial memory depends on the lesion method, we reversibly inactivated the hippocampus with lidocaine either immediately (0-DAY) or 1 mo (30-DAY) after training in a water maze. For both the 0-DAY and 30-DAY retention tests, rats that received lidocaine infusions exhibited impaired performance. In addition, when the 0-DAY group was retested 2 d later, (when the drug was no longer active), the effect was reversed. That is, rats that had previously received lidocaine performed as well as control rats did. These findings indicate that the rodent hippocampus is important for both recent and remote spatial memory, as assessed in the water maze. What determines whether remote spatial memory is preserved or impaired following disruption of hippocampal function appears to be the type of task used to assess spatial memory, not the method used to disrupt the hippocampus.     

Cholinergic dependence of taste memory formation: evidence of two distinct processes

Learning the aversive or positive consequences associated with novel taste solutions has a strong significance for an animal's survival. A lack of recognition of a taste's consequences could prevent ingestion of potential edibles or encounter death. We used conditioned taste aversion (CTA) and attenuation of neophobia (AN) to study aversive and safe taste memory formation. To determine if muscarinic receptors in the insular cortex participate differentially in both tasks, we infused the muscarinic antagonists scopolamine at distinct times before or after the presentation of a strong concentration of saccharin, followed by either an i.p. injection of a malaise-inducing agent or no injection. Our results showed that blockade of muscarinic receptors before taste presentation disrupts both learning tasks. However, the same treatment after the taste prevents AN but not CTA. These results clearly demonstrate that cortical cholinergic activity participates in the acquisition of both safe and aversive memory formation, and that cortical muscarinic receptors seem to be necessary for safe but not for aversive taste memory consolidation. These results suggest that the taste memory trace is processed in the insular cortex simultaneously by at least two independent mechanisms, and that their interaction would determine the degree of aversion or preference learned to a novel taste.     

Foreground contextual fear memory consolidation requires two independent phases of hippocampal ERK/CREB activation

Fear conditioning is a popular model for investigating physiological and cellular mechanisms of memory formation. In this paradigm, a footshock is either systematically associated to a tone (paired conditioning) or is pseudorandomly distributed (unpaired conditioning). In the former procedure, the tone/shock association is acquired, whereas in the latter procedure, the context/shock association will prevail. Animals with chronically implanted recording electrodes show enhanced amplitude of the extracellularly recorded field EPSP in CA1 pyramidal cells for up to 24 h after unpaired, but not paired, fear conditioning. This is paralleled by a differential activation of the ERK/CREB pathway in CA1, which is monophasic in paired conditioning (0-15 min post-conditioning), but biphasic (0-1 h and 9-12 h post-conditioning) in unpaired conditioning as revealed by immunocytochemistry and Western blotting. Intrahippocampal injection of the MEK inhibitor U0126 prior to each phase prevents the activation of both ERK1/2 and CREB after unpaired conditioning. Block of any activation phase leads to memory impairment. We finally reveal that the biphasic activation of ERK/CREB activity is independently regulated, yet both phases are critically required for the consolidation of long-term memories following unpaired fear conditioning. These data provide compelling evidence that CA1 serves different forms of memory by expressing differential cellular mechanisms that are dependent on the training regime.     

Role of hippocampal signaling pathways in long-term memory formation of a nonassociative learning task in the rat

Long-term habituation to a novel environment is one of the most elementary forms of nonassociative learning. Here we studied the effect of pre- or posttraining intrahippocampal administration of drugs acting on specific molecular targets on the retention of habituation to a 5-min exposure to an open field measured 24 h later. We also determined whether the exposure to a novel environment resulted in the activation of the same intracellular signaling cascades previously shown to be activated during hippocampal-dependent associative learning. The immediate posttraining bilateral infusion of CNQX (1 μg/side), an AMPA/kainate glutamate receptor antagonist, or of muscimol (0.03 μg/side), a GABA_A receptor agonist, into the CA1 region of the dorsal hippocampus impaired long-term memory of habituation. The NMDA receptor antagonist AP5 (5 μg/side) impaired habituation when infused 15 min before, but not when infused immediately after, the 5-min training session. In addition, KN-62 (3.6 ng/side), an inhibitor of calcium calmodulin-dependent protein kinase II (CaMKII), was amnesic when infused 15 min before or immediately and 3 h after training. In contrast, the cAMP-dependent protein kinase (PKA) inhibitor Rp-cAMPS, the mitogen-activated protein kinase kinase (MAPKK) inhibitor PD098059, and the protein synthesis inhibitor anisomycin, at doses that fully block memory formation of inhibitory avoidance learning, did not affect habituation to a novel environment. The detection of spatial novelty is associated with a sequential activation of PKA, ERKs (p44 and p42 MAPKs) and CaMKII and the phosphorylation of c-AMP responsive element-binding protein (CREB) in the hippocampus. These findings suggest that memory formation of spatial habituation depends on the functional integrity of NMDA and AMPA/kainate receptors and CaMKII activity in the CA1 region of the hippocampus and that the detection of spatial novelty is accompanied by the activation of at least three different hippocampal protein kinase signaling cascades.     

Characterization of long-term memory, resistance to extinction, and influence of temperament during two instrumental tasks in horses

The present study investigated the influence of temperament on long-term recall and extinction of 2 instrumental tasks in 26 horses. In the first task (backward task), horses learned to walk backward, using commands given by an experimenter, in order to obtain a food reward. In the second task (active avoidance task), horses had to cross an obstacle after a bell rang in order to avoid emission of an air puff. Twenty-two months after acquisition, horses exhibited perfect recall performance in both tasks. Accordingly, no influence of temperament on recall performance could be observed for either task. In contrast, in the absence of positive or negative outcomes, the horses’ ability to extinguish their response to either task was highly variable. Resistance to extinction was related to some indicators of temperament: The most fearful horses tended to be the most resistant to extinction in the backward task, while the least sensitive horses tended to be the most resistant to extinction in the active avoidance task. These findings reveal extensive long-term memory abilities in horses and suggest an influence of temperament on learning processes other than acquisition.     

Medial prefrontal cortex and hippocampal activity differentially contribute to ordinal and temporal context retrieval during sequence memory

Remembering sequences of events defines episodic memory, but retrieval can be driven by both ordinality and temporal contexts. Whether these modes of retrieval operate at the same time or not remains unclear. Theoretically, medial prefrontal cortex (mPFC) confers ordinality, while the hippocampus (HC) associates events in gradually changing temporal contexts. Here, we looked for evidence of each with BOLD fMRI in a sequence task that taxes both retrieval modes. To test ordinal modes, items were transferred between sequences but retained their position (e.g., AB3). Ordinal modes activated mPFC, but not HC. To test temporal contexts, we examined items that skipped ahead across lag distances (e.g., ABD). HC, but not mPFC, tracked temporal contexts. There was a mPFC and HC by retrieval mode interaction. These current results suggest that the mPFC and HC are concurrently engaged in different retrieval modes in support of remembering when an event occurred.

Memory for sequences of events is a fundamental component of episodic memory (Tulving 1984, 2002; Allen and Fortin 2013; Howard and Eichenbaum 2013; Eichenbaum 2017). While different experiences share overlapping elements, the sequence of events is unique. Remembering the order of events allows us to disambiguate episodes with similar content and make detailed predictions supporting decision-making.At least two complementary memory processes contribute to the retrieval of events in the correct sequence: ordinal (Orlov et al. 2002) and temporal context (Howard and Kahana 2002) retrieval modes. Whether these disparate retrieval modes operate coincidently or not remains an open question with consequences for understanding basic mechanisms of how we remember the events that unfold throughout our day. According to an ordinal retrieval mode, items are remembered by their position within an event sequence (DuBrow and Davachi 2013; Allen et al. 2014; Long and Kahana 2019), providing sequential memory through well-established semantic or abstracted relationships (first, second, third, etc.). While for a temporal context retrieval mode, events are remembered through a gradually changing temporal context within which specific items have been associated. According to temporal contexts, when an element of a sequence is presented or retrieved (e.g., “C” in ABCDEF), items that are more proximal in the sequence (e.g., the “D” in the sequence) have a higher retrieval rate compared with items that are further away (e.g., the “F” in the sequence). These temporal contexts result from item associations that are dependent on time varying neural activity (e.g., Eichenbaum 2014), and contribute to sequence memory through the reactivation of neighboring items during retrieval (DuBrow and Davachi 2013; Long and Kahana 2019).The medial prefrontal cortex (mPFC) and hippocampus (HC) are thought to contribute to sequence memory through ordinal representations and temporal contexts, respectively (Agster et al. 2002; Fortin et al. 2002; Kesner et al. 2002; DeVito and Eichenbaum 2011; Allen et al. 2016; Jenkins and Ranganath 2016). In rodents, mPFC disruptions impair sequence memory (DeVito and Eichenbaum 2011; Jayachandran et al. 2019), mPFC “time cells” are evident (Tiganj et al. 2017), and positions within a sequence can be the main determinant of differential activity in mPFC neurons during spatial sequences (Euston and McNaughton 2006). In humans, mPFC activation is sensitive to temporal order memory (Preston and Eichenbaum 2013), and codes for information about temporal positions within image sequences regardless of the image itself (Hsieh and Ranganath 2015). HC activations are also generally associated with temporal order memory (Kumaran and Maguire 2006; Ekstrom and Bookheimer 2007; Lehn et al. 2009; Ross et al. 2009; Jenkins and Ranganath 2010; Tubridy and Davachi 2011; Kalm et al. 2013; Hsieh et al. 2014; Goyal et al. 2018). Prior evidence further shows that the medial temporal lobe, specifically the HC formation, plays a critical role in the use of a TCM retrieval mode in the brain (Manns et al. 2007; Hsieh et al. 2014; Bladon et al. 2019). The HC binds events within temporal contexts (Eichenbaum et al. 2007; DuBrow and Davachi 2013; Bladon et al. 2019) through a gradually changing neural context (Manns et al. 2007; Mankin et al. 2012). Similarly, medial temporal lobe neuronal and BOLD activations in humans have demonstrated evidence for gradually evolving temporal contexts (Howard et al. 2012; Kalm et al. 2013; Kragel et al. 2015).Here we tested the contributions of the mPFC and HC during a visual sequence memory task that provides behavioral evidence of both ordinal and temporal context retrieval modes (see Fig. 1A; task modified from Allen et al. 2014). Briefly, participants first memorized six visual sequences (six images each) in a single passive viewing phase, and then were instructed to make judgments as to whether individual items were subsequently presented in sequence (InSeq) or out of sequence (OutSeq) over 240 self-paced presentations of each of the six items from each sequence. In the task, the two retrieval modes are parsed using probe trials that place conflicting demands on ordinal (Orlov et al. 2000; Allen et al. 2014, 2015) and temporal context modes (Jayachandran et al. 2019). We first evaluated ordinal retrieval modes using items that were transferred from one sequence to another while retaining their ordinal position (Ordinal Transfers) (Fig. 1B). Evidence for an ordinal-based retrieval mode occurs when these probes are identified as in sequence, because they occur in the same ordinal position as their original sequence. mPFC activations (but not HC) was strongest for these ordinal retrievals. Second, we evaluated a temporal context retrieval mode using items that skipped ahead (Skips) (Fig. 1B) with shorter lag distances (ABCFEF) compared with larger lag distances (AFCDEF). Skips should be most difficult to detect on the shortest lag distances because proximal items in a sequence are more likely to be retrieved (Howard and Kahana 2002; Kragel et al. 2015) and thus judged as InSeq. HC activations (but not mPFC) tracked with lag distance, providing evidence the HC is more reflective of a temporal context-based retrieval mode. Importantly, a significant interaction was observed such that mPFC and HC differentially activated for ordinal and temporal context retrievals. Altogether, our data show that sequence memory involves both retrieval modes. In line with these results, we suggest that understanding episodic memory requires more insight into the neurobiology of ordinal processing, in addition to the more often studied temporal contexts, in the mPFC and HC system.Open in a separate windowFigure 1.Sequence memory task and overall performance levels. Participants were tested on a sequence memory task that differentially burdens different retrieval modes using different out of sequence probe trial types. (A) An example sequence set that included six sequences. Two sequences were low memory demand sequences and four were high memory demand sequences. (B) There were three out of sequence probe trial types: items that were repeated in the sequence (Repeats), items that were presented too early in the sequence (Skips), and items that transferred from one sequence to another, while remaining in their ordinal position (Ordinal Transfers). Repeats and Skips occurred throughout the whole task, whereas Ordinal Transfers occurred during the second half only. (C) Accuracy throughout the task (error bars = ±1SD). Participants performed best on Repeats, then Skips, and poorest on Ordinal Transfers. (D,E) Distributions of response times for all InSeq trials (D, gray bars) and for all OutSeq trials (E, gray bars) for all participants with a fitted two-term Gaussian curve (black line). (F) A bimodal Gaussian curve fit better than a unimodal curve for InSeq and OutSeq trials. A trimodal curve did not improve the fit and increased the root mean squared error (not shown), suggesting distinct decisions decision-making between two decisions. It was rare to observe responses outside of the two distributions.     

A model of hippocampal neurogenesis in memory and mood disorders

The mounting evidence for neurogenesis in the adult hippocampus has fundamentally challenged the traditional view of brain development. The intense search for clues as to the functional significance of the new neurons has uncovered a surprising connection between neurogenesis and depression. In animal models of depression, neurogenesis is reduced, whereas many treatments for depression promote neurogenesis. We speculate on why the hippocampus, traditionally viewed as a memory structure, might be involved in mood disorders, and what specific role the new neurons might have in the pathogenesis of and recovery from depression. The proposed role of neurogenesis in contextual-memory formation predicts a specific pattern of cognitive deficits in depression and has important implications for treatment of this highly prevalent and debilitating disorder.     

Identification of genes expressed in the amygdala during the formation of fear memory

In this study we describe changes of gene expression that occur in the basolateral complex of the mouse amygdala (BLA) during the formation of fear memory. Through the combination of a behavioral training scheme with polymerase chain reaction-based expression analysis (subtractive hybridization and virtual Northern analysis) we were able to identify various gene products that are increased in expression after Pavlovian fear conditioning and are of potential significance for neural plasticity and information storage in the amygdala. In particular, a key enzyme of monoamine metabolism, aldehyde reductase, and the protein sorting and ubiquitination factor Praja1, showed pronounced and learning-specific induction six hours after fear conditioning training. Aldehyde reductase and Praja1, including a novel alternatively spliced isoform termed Praja1a, were induced in the BLA depending on the emotional stimulus presented and showed different expression levels in response to associative conditioning, training stress, and experience of conditioned fear. Stress and fear were further found to induce various signal transduction factors (transthyretin, phosphodiesterase1, protein kinase inhibitor-alpha) and structural reorganization factors (e.g., E2-ubiquitin conjugating enzyme, neuroligin1, actin, UDP-galactose transporter) during training. Our results show that the formation of Pavlovian fear memory is associated with changes of gene expression in the BLA, which may contribute to neural plasticity and the processing of information about both conditioned and unconditioned fear stimuli.     

Prefrontal and hippocampal contributions to encoding and retrieval of spatial memory

The prefrontal cortex is thought to be critical for goal-directed action and the hippocampus is known to be importantly involved in spatial memory. Several studies have been suggestive of a role for the orbitofrontal cortex (OFC) in spatial navigation. However, the medial prefrontal cortex (mPFC) receives projections directly from the intermediate CA1 (iCA1) region of hippocampus and this link may be critical for spatial navigation. The purpose of the present investigation was to test the performance of rats receiving bilateral or disconnection infusions of lidocaine into OFC, mPFC, or iCA1 to determine the contribution of these structures to encoding and retrieval of spatial memory using the Hebb–Williams maze. A total of 92 male Long-Evans rats received chronic bilateral, contralateral, or ipsilateral implantation of cannulas into OFC, mPFC, or iCA1. Prior to testing on day 1 or day 2, subjects received central infusions of saline or lidocaine. The number of errors committed on the first five trials compared to the second five trials of day 1 was used to determine encoding, whereas retrieval was determined by comparing the second five trials of day 1 with the first five trials of day 2. The present findings suggest that mPFC and iCA1 are necessary and interact during encoding and retrieval; however, the OFC does not appear to be essential for either process. While the nature of the interaction between mPFC and iCA1 during encoding and retrieval is unclear, it may be supported by the integration of goals and spatial cues or strategy switching.     

Aging,memory load,and resource allocation during reading

To test the notion that aging brings an inability to self-initiate processing, the authors investigated the effects of memory load on online sentence understanding. Younger and older adults read a series of short passages with or without a simultaneous updating task, which would be expected to deplete resources by consuming memory capacity. Regression analyses of word-by-word reading times onto text variables within each condition were used to decompose reading times into resources allocated to the array of word-level and textbase-level processes needed for comprehension. Among neither the young nor the old were word-level processes disrupted by a simultaneous memory load. However, older readers showed relatively greater levels of resource allocation to conceptual integration than the younger adults when under load, regardless of working-memory span or task priority. These results suggest that the ability to self-initiate the allocation of processing resources during reading is preserved among older readers.     

The effects of refreshing and elaboration on working memory performance,and their contributions to long-term memory formation

Refreshing and elaboration are cognitive processes assumed to underlie verbal working-memory maintenance and assumed to support long-term memory formation. Whereas refreshing refers to the attentional focussing on representations, elaboration refers to linking representations in working memory into existing semantic networks. We measured the impact of instructed refreshing and elaboration on working and long-term memory separately, and investigated to what extent both processes are distinct in their contributions to working as well as long-term memory. Compared with a no-processing baseline, immediate memory was improved by repeating the items, but not by refreshing them. There was no credible effect of elaboration on working memory, except when items were repeated at the same time. Long-term memory benefited from elaboration, but not from refreshing the words. The results replicate the long-term memory benefit for elaboration, but do not support its beneficial role for working memory. Further, refreshing preserves immediate memory, but does not improve it beyond the level achieved without any processing.