Stress effects in the hippocampus: synaptic plasticity and memory

It is now well-documented that exposures to uncontrollable (inescapable and unpredictable) stress in adulthood can have profound effects on brain and behavior. Converging lines of evidence from human and animal studies indicate that stress interferes with subsequent performances on a variety of hippocampal-dependent memory tasks. Animal studies further revealed that stress impedes ensuing induction of long-term potentiation (LTP) in the hippocampus. Because the hippocampus is important for key aspects of memory formation and because LTP has qualities congruent to an information storage mechanism, it is hypothesized that stress-induced modifications in hippocampal plasticity contribute to memory impairments associated with stress. Recent studies provide evidence that the amygdala, a structure important in stress- and emotion-related behaviors, plays a necessary role in the emergence of stress-associated changes in hippocampal LTP and memory. Early life stress also alters hippocampal plasticity and memory in a manner largely consistent with effects of adult stress exposure. This review focuses on endocrine-system-level mechanisms of stress effects in the hippocampus, and how stress, by altering the property of hippocampal plasticity, can subsequently influence hippocampal memory.     

Lexical effects in phonemic processing: facilitatory or inhibitory

This article addresses the questions of how and when lexical information influences phoneme identification in a series of phoneme-monitoring experiments in which conflicting predictions of autonomous and interactive models were evaluated. Strong facilitatory lexical effects (reflected by large differences in detection latencies to targets in words and matched nonwords) were found only when targets came after the uniqueness point of the target-bearing word. Furthermore, no evidence was obtained for lexically mediated inhibition on phoneme identification as predicted by the interactive activation model TRACE. These results taken together point to strong limitations in the way in which lexical information can affect the perception of unambiguous speech.     

Timing of facilitatory and inhibitory effects of visual attention

Three experiments were conducted to investigate influences on the precue-to-target delay at which response facilitation is first replaced by inhibition of return (IOR). In Experiment 1, different ranges of delays were used; the interpolated delay at which faster RTs for matching precue and target locations changed to slower RTs was inversely related to the length of the range of precue-to-target delays within a block of trials. These findings were replicated in Experiment 2, which additionally showed that task difficulty provided an insufficient explanation for the delay in the changeover time. These data allowed the conclusion that a shorter range of precue-to-target delays results in later onset of IOR than does a longer range of delays. The data from Experiment 3 suggested that a single character on the target screen confounds the interpretation of possible facilitation and/or inhibition due to the allocation of attention. These results were related to other reported findings and to theories of attention allocation.     

Neural functions of calcineurin in synaptic plasticity and memory

Major brain functions depend on neuronal processes that favor the plasticity of neuronal circuits while at the same time maintaining their stability. The mechanisms that regulate brain plasticity are complex and engage multiple cascades of molecular components that modulate synaptic efficacy. Protein kinases (PKs) and phosphatases (PPs) are among the most important of these components that act as positive and negative regulators of neuronal signaling and plasticity, respectively. In these cascades, the PP protein phosphatase 2B or calcineurin (CaN) is of particular interest because it is the only Ca(2+)-activated PP in the brain and a major regulator of key proteins essential for synaptic transmission and neuronal excitability. This review describes the primary properties of CaN and illustrates its functions and modes of action by focusing on several representative targets, in particular glutamate receptors, striatal enriched protein phosphatase (STEP), and neuromodulin (GAP43), and their functional significance for synaptic plasticity and memory.     

Semantic priming and retrieval from lexical memory: Evidence for facilitatory and inhibitory processes

Immediately prior to each visually presented target letter string to which the subject made a speeded word-nonword classification response, a visually presented prime to which no overt response was required was shown for 360, 600, or 2,000 msec. For word (W) target trials, the priming event was either a semantically neutral warning signal (Condition NX), a word semantically related to the target word (Condition R), or a word semantically unrelated to the target word (Condition U); for nonword (N) target trials, the priming event was either the neutral warning signal (Condition NX) or a word prime (Condition WP). For the W target trials, reaction times (RTs) were slower in Condition U than in Condition NX and equally so for all three prime durations; RTs were faster in Condition R than in Condition NX and to a greater degree for the 600- and 2,000-msec prime durations than for the 360-msec prime duration. For the N targets, RTs were faster in Condition WP than in Condition NX and equally so for all prime durations. These results were interpreted within the framework of a two-factor theory of attention proposed by Posner and Snyder (1975a).     

PKG-mediated MAPK signaling is necessary for long-term operant memory in Aplysia

Signaling pathways necessary for memory formation, such as the mitogen-activated protein kinase (MAPK) pathway, appear highly conserved across species and paradigms. Learning that food is inedible (LFI) represents a robust form of associative, operant learning that induces short- (STM) and long-term memory (LTM) in Aplysia. We investigated the role of MAPK signaling in LFI memory in vivo. Inhibition of MAPK activation in animals prior to training blocked STM and LTM. Discontinuing MAPK signaling immediately after training inhibited LTM with no impact on STM. Therefore, MAPK signaling appears necessary early in memory formation for STM and LTM, with prolonged MAPK activity required for LTM. We found that LFI training significantly increased phospho-MAPK levels in the buccal ganglia. Increased MAPK activation was apparent immediately after training with greater than basal levels persisting for 2 h. We examined the mechanisms underlying training-induced MAPK activation and found that PKG activity was necessary for the prolonged phase of MAPK activation, but not for the early MAPK phase required for STM. Furthermore, we found that neither the immediate nor the prolonged phase of MAPK activation was dependent upon nitric oxide (NO) signaling, although expression of memory was dependent on NO as previously reported. These studies emphasize the role of MAPK and PKG in negatively reinforced operant memory and demonstrate a role for PKG-dependent MAPK signaling in invertebrate associative memory.     

A fresh look at an ancient receptor family: emerging roles for low density lipoprotein receptors in synaptic plasticity and memory formation

The well-known family of low-density lipoprotein receptors represents a collection of ancient membrane receptors that have been remarkably conserved throughout evolution. These multifunctional receptors, known to regulate cholesterol transport, are becoming increasingly interesting to the neuroscience community due to their ability to transduce a diversity of extracellular signals across the membrane in the adult CNS. Their roles in modulating synaptic plasticity and necessity in hippocampus-specific learning and memory have recently come to light. In addition, genetic, biochemical and behavioral studies have implicated these signaling systems in a number of human neurodegenerative and neuropsychiatric disorders involving loss of cognitive ability, such as Alzheimer's disease, schizophrenia and autism. This review describes the known functions of these receptors and discusses their potential role in processes of synaptic regulation and memory formation.     

Genetic approaches to the study of synaptic plasticity and memory storage

Long-term memory is believed to depend on long-lasting changes in the strength of synaptic transmission known as synaptic plasticity. Understanding the molecular mechanisms of long-term synaptic plasticity is one of the principle goals of neuroscience. Among the most powerful tools being brought to bear on this question are genetically modified mice with changes in the expression or biological activity of genes thought to contribute to these processes. This article reviews how strains of mice with alterations in the cyclic adenosine monophosphate/protein kinase A/cyclic adenosine monophosphate-response element-binding protein signaling pathway have advanced our understanding of the biological basis of learning and memory.     

Gene targeting of presynaptic proteins in synaptic plasticity and memory: across the great divide

The past few decades have seen an explosion in our understanding of the molecular basis of learning and memory. The majority of these studies in mammals focused on post-synaptic signal transduction cascades involved in post-synaptic long-lasting plasticity. Until recently, relatively little work examined the role of presynaptic proteins in learning and memory in complex systems. The synaptic cleft figuratively represents a "great divide" between our knowledge of post- versus presynaptic involvement in learning and memory. While great strides have been made in our understanding of presynaptic proteins, we know very little of how presynaptically expressed forms of short- and long-term plasticity participate in information processing and storage. The paucity of cognitive behavioral research in the area of presynaptic proteins, however, is in stark contrast to the plethora of information concerning presynaptic protein involvement in neurotransmitter release, in modulation of release, and in both short- and long-term forms of presynaptic plasticity. It is now of great interest to begin to link the extensive literature on presynaptic proteins and presynaptic plasticity to cognitive behavior. In the future there is great promise with these approaches for identifying new targets in the treatment of cognitive disorders. This review article briefly surveys current knowledge on the role of presynaptic proteins in learning and memory in mammals and suggests future directions in learning and memory research on the presynaptic rim of the "great divide."     

Role of the somatostatin system in contextual fear memory and hippocampal synaptic plasticity

Somatostatin has been implicated in various cognitive and emotional functions, but its precise role is still poorly understood. Here, we have made use of mice with somatostatin deficiency, based upon genetic invalidation or pharmacologically induced depletion, and Pavlovian fear conditioning in order to address the contribution of the somatostatin system to associative fear memory. The results demonstrate an impairment of foreground and background contextual but not tone fear conditioning in mice with targeted ablation of the somatostatin gene. These deficits were associated with a decrease in long-term potentiation in the CA1 area of the hippocampus. Both the behavioral and the electrophysiological phenotypes were mimicked in wild-type mice through application of the somatostatin-depleting substance cysteamine prior to fear training, whereas no further deficits were observed upon application in the somatostatin null mutants. These results suggest that the somatostatin system plays a critical role in the acquisition of contextual fear memory, but not tone fear learning, and further highlights the role of hippocampal synaptic plasticity for information processing concerning contextual information.     

Hebb repetition effects in visual memory: The roles of verbal rehearsal and distinctiveness

A version of the Hebb repetition task was used with faces to explore the generality of the effect in a nonverbal domain. In the baseline condition, a series of upright faces was presented, and participants were asked to reconstruct the original order. Performance in this condition was compared to another in which the same stimuli were accompanied by concurrent verbal rehearsal to examine whether Hebb learning is dependent on verbal processing. Baseline performance was also compared to a condition in which the same faces were presented inverted. This comparison was used to determine the importance in Hebb learning of being able to visually distinguish between the list items. The results produced classic serial position curves that were equivalent over conditions with Hebb repetition effects being in evidence only for upright faces and verbal suppression as having no effect. These findings are interpreted as posing a challenge to current models derived from verbal-domain data.     

Tactile Ranschburg effects: facilitation and inhibitory repetition effects analogous to verbal memory

The present paper examines the effect of within-sequence item repetitions in tactile order memory. Employing an immediate serial recall procedure, participants reconstructed a six-item sequence tapped upon their fingers by moving those fingers in the order of original stimulation. In Experiment 1a, within-sequence repetition of an item separated by two-intervening items resulted in a significant reduction in recall accuracy for that repeated item (i.e., the Ranschburg effect). In Experiment 1b, within-sequence repetition of an adjacent item resulted in significant recall facilitation for that repeated item. These effects mirror those reported for verbal stimuli (e.g., Henson, 1998a Henson, R. N. A. (1998a). Item repetition in short-term memory: Ranschburg repeated. Journal of Experimental Psychology: Learning, Memory, and Cognition, 24(5), 1162–1181. doi:doi.org/10.1037/0278-7393.24.5.1162[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]. Item repetition in short-term memory: Ranschburg repeated. Journal of Experimental Psychology: Learning, Memory, and Cognition, 24(5), 1162–1181. doi:doi.org/10.1037/0278-7393.24.5.1162). These data are the first to demonstrate the Ranschburg effect with non-verbal stimuli and suggest further cross-modal similarities in order memory.     

The role of constraints in expert memory

A great deal of research has been devoted to developing process models of expert memory. However, K. J. Vicente and J. H. Wang (1998) proposed (a) that process theories do not provide an adequate account of expert recall in domains in which memory recall is a contrived task and (b) that a product theory, the constraint attunement hypothesis (CAH), has received a significant amount of empirical support. We compared 1 process theory (the template theory; TT; F. Gobet & H. A. Simon, 1996c) with the CAH in chess. Chess players (N=36) differing widely in skill levels were required to recall briefly presented chess positions that were randomized in various ways. Consistent with TT, but inconsistent with the CAH, there was a significant skill effect in a condition in which both the location and distribution of the pieces were randomized. These and other results suggest that process models such as TT can provide a viable account of expert memory in chess.     

Hebb repetition effects in visual memory: the roles of verbal rehearsal and distinctiveness

A version of the Hebb repetition task was used with faces to explore the generality of the effect in a nonverbal domain. In the baseline condition, a series of upright faces was presented, and participants were asked to reconstruct the original order. Performance in this condition was compared to another in which the same stimuli were accompanied by concurrent verbal rehearsal to examine whether Hebb learning is dependent on verbal processing. Baseline performance was also compared to a condition in which the same faces were presented inverted. This comparison was used to determine the importance in Hebb learning of being able to visually distinguish between the list items. The results produced classic serial position curves that were equivalent over conditions with Hebb repetition effects being in evidence only for upright faces and verbal suppression as having no effect. These findings are interpreted as posing a challenge to current models derived from verbal-domain data.     

Differential effects of prime-probe duration on positive and negative location priming: Evidence for opponent facilitatory and inhibitory influences in priming tasks

A series of four spatial localization experiments is reported that examined the effects of display duration and presentation mode on positive and negative priming using an attended-repetition and an ignored-repetition paradigm, respectively. Experiment 1 showed larger positive priming with response-dependent than with 150 ms display durations while negative priming remained unaffected. Experiments 2-4 were performed to further elucidate the effects of prime-probe durations. Data suggest largely independent effects of prime and probe duration on priming effects. Manipulation of prime duration affected facilitation due to repetition of the prime distractor location as well as inhibitory effects associated with ignored repetition. Furthermore, anticipated probe duration modulated the effectiveness of inhibition of return. Findings are discussed within a framework proposing two major components of priming effects—a stimulus-driven or automatic component, and a strategic component related to the participant's expectations towards the probe.     

Reorganization of learning-associated prefrontal synaptic plasticity between the recall of recent and remote fear extinction memory

We have previously shown that fear extinction is accompanied by an increase of synaptic efficacy in inputs from the ventral hippocampus (vHPC) and mediodorsal thalamus (MD) to the medial prefrontal cortex (mPFC) and that disrupting these changes to mPFC synaptic transmission compromises extinction processes. The aim of this study was to examine whether these extinction-related changes undergo further plasticity as the memory of extinction becomes more remote. Changes in synaptic efficacy in both vHPC-mPFC and MD-mPFC inputs were consequently analyzed when the memory was either 1 d or 7 d old. Increases of synaptic efficacy in the vHPC-mPFC pathway were observed when the memory was 1 d old, but not 7 d after initial extinction. In contrast, potentiation of synaptic efficacy in the MD-mPFC pathway increased over time. In rats that received low-frequency vHPC stimulation immediately after extinction, both vHPC-mPFC and MD-mPFC inputs failed to develop potentiation, and the recall of extinction (both recent and remote memories) was impaired. These findings suggest that post-extinction potentiation in vHPC-mPFC inputs may be necessary for both the recall of recent memory and post-extinction potentiation in the MD-mPFC inputs. This late potentiation process may be required for the recall of remote extinction memory.     

Modality-specific effects in inhibitory mechanisms: the interaction of peripheral and central components in working memory

Working memory is a complex system assumed to encompass both storage and processing components. At the same time, several authors have suggested the existence of separate peripheral modality-specific subsystems, in particular a verbal and a visuo-spatial mechanism. In the present research, we explored the hypothesis that modality-specific mechanisms may also operate in the central processing component. Inhibitory control has traditionally been considered as a typical function of the central executive, devoted to selecting, processing, and eliminating irrelevant information. We designed verbal and visuo-spatial tasks involving similar procedures and comparable levels of inhibitory control. Results indicate that accuracy profiles are similar in the two conditions; however, the patterns of data measuring inhibitory control, i.e., percentage of intrusion errors, are opposite in the case of verbal (intrusions decreased in more complex trials) and visuo-spatial (intrusions increased in more complex trials) material. These data are consistent with theoretical models of working memory suggesting that modality-specific effects emerge even in central processes and that both material-dependent and process-dependent features must be considered in working memory tasks.