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.     

Enhancement of glutamate release by L-fucose changes effects of glutamate receptor antagonists on long-term potentiation in the rat hippocampus

In previous studies L-fucose has been shown to facilitate long-term memory formation and to enhance and prolong long-term potentiation (LTP). To search for possible presynaptic or postsynaptic mechanisms that are affected by L-fucose, we examined the effect of L-fucose on (1) inhibition of LTP induction via glutamate receptors by antagonists, (2) paired-pulse facilitation, and (3) presynaptic transmitter release. Coapplication of 0.2 mM L-fucose with the competitive N-methyl-D-aspartate (NMDA) receptor antagonist, D-2-amino-5-phosphonovalerate (AP5), or coapplication of 0.2 mM L-fucose in the presence of an inhibitor for class I/II metabotropic glutamate receptors, (S)-alpha-methyl-4-carboxyphenylglycine (MCPG), reversed LTP blockade in the CA1-region of hippocampal slices. In contrast, L-fucose had no effect on the LTP blockade by the noncompetitive NMDA ion-channel blocker (5R,10S)-(+)-5-Methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine hydrogen maleate (MK-801). Paired-pulse facilitation, which is a primarily presynaptic phenomenon of short-term plasticity, was decreased in the presence of 0.2 mM L-fucose. Furthermore, L-fucose enhanced the K(+)-stimulated release of [(3)H]-D-aspartate from preloaded hippocampal slices in a concentration-dependent manner. These observations demonstrate an influence of L-fucose on transmitter release that in turn can increase transmitter availability at postsynaptic glutamate receptors. This effect of L-fucose may contribute to the LTP facilitation seen in vitro and in vivo as well as to improvement in memory formation.     

Protein kinase Mzeta is essential for the induction and maintenance of dopamine-induced long-term potentiation in apical CA1 dendrites

Dopaminergic D1/D5-receptor-mediated processes are important for certain forms of memory as well as for a cellular model of memory, hippocampal long-term potentiation (LTP) in the CA1 region of the hippocampus. D1/D5-receptor function is required for the induction of the protein synthesis-dependent maintenance of CA1-LTP (L-LTP) through activation of the cAMP/PKA-pathway. In earlier studies we had reported a synergistic interaction of D1/D5-receptor function and N-methyl-D-aspartate (NMDA)-receptors for L-LTP. Furthermore, we have found the requirement of the atypical protein kinase C isoform, protein kinase Mζ (PKMζ) for conventional electrically induced L-LTP, in which PKMζ has been identified as a LTP-specific plasticity-related protein (PRP) in apical CA1-dendrites. Here, we investigated whether the dopaminergic pathway activates PKMζ. We found that application of dopamine (DA) evokes a protein synthesis-dependent LTP that requires synergistic NMDA-receptor activation and protein synthesis in apical CA1-dendrites. We identified PKMζ as a DA-induced PRP, which exerted its action at activated synaptic inputs by processes of synaptic tagging.     

The effects of acute 17beta-estradiol treatment on gene expression in the young female mouse hippocampus

Previous studies have demonstrated that treatment with 17beta-estradiol (E(2)) improves both spatial and nonspatial memory in young female mice. Still unclear, however, are the molecular mechanisms underlying the beneficial effects of E(2) on memory. We have previously demonstrated that a single post-training intraperitoneal (i.p.) injection of 0.2 mg/kg E(2) can enhance hippocampal-dependent spatial and object memory consolidation (e.g., Gresack & Frick, 2006b). Therefore, in the present study, we performed a microarray analysis on the dorsal hippocampi of 4-month-old female mice injected i.p. with vehicle or 0.2 mg/kg E(2). Genes were considered differentially expressed following E(2) treatment if they showed a greater than 2-fold change in RNA expression levels compared to controls. Overall, out of a total of approximately 25,000 genes represented on the array, 204 genes showed altered mRNA expression levels upon E(2) treatment, with 111 up-regulated and 93 down-regulated. Of these, 17 of the up-regulated and 6 of the down-regulated genes are known to be involved in learning and memory. mRNA expression changes in 5 of the genes were confirmed by real-time quantitative PCR analysis, and protein changes in these same genes were confirmed by Western blot analysis: Hsp70, a heat shock protein known to be estrogen responsive; Igfbp2, an IGF-I binding protein; Actn4, an actin binding protein involved in protein trafficking; Tubb2a, the major component of microtubules; and Snap25, a synaptosome-specific protein required for neurotransmitter release. The types of genes altered indicate that E(2) may induce changes in the structural mechanics of cells within the dorsal hippocampus that could be conducive to promoting memory consolidation.     

Odor-specific habituation arises from interaction of afferent synaptic adaptation and intrinsic synaptic potentiation in olfactory cortex

Segmentation of target odorants from background odorants is a fundamental computational requirement for the olfactory system and is thought to be behaviorally mediated by olfactory habituation memory. Data from our laboratory have shown that odor-specific adaptation in piriform neurons, mediated at least partially by synaptic adaptation between the olfactory bulb outputs and piriform cortex pyramidal cells, is highly odor specific, while that observed at the synaptic level is specific only to certain odor features. Behavioral data show that odor habituation memory at short time constants corresponding to synaptic adaptation is also highly odor specific and is blocked by the same pharmacological agents as synaptic adaptation. Using previously developed computational models of the olfactory system we show here how synaptic adaptation and potentiation interact to create the observed specificity of response adaptation. The model analyzes the mechanisms underlying the odor specificity of habituation, the dependence on functioning cholinergic modulation, and makes predictions about connectivity to and within the piriform neural network. Predictions made by the model for the role of cholinergic modulation are supported by behavioral results.Filtering sensory input is critical for information processing tasks such as background segmentation, and shifting processing power away from redundant, stable, or repetitive stimuli toward dynamic, novel stimuli. A critical aspect of this filtering however, is stimulus specificity. Under most circumstances it may be most beneficial to selectively filter the redundant stimulus, while maintaining responsiveness to different, though perhaps highly similar stimuli.In the olfactory system, short-term habituation to stable or repeated odorants involves a metabotropic glutamate receptor (mGluR)-dependent depression of afferent synapses to the piriform cortex (Best and Wilson 2004). Blockade of group III mGluR receptors prevents cortical adaptation odors (Best and Wilson 2004), and reduces short-term habituation of odor-evoked reflexes (Best et al. 2005) and odor investigation (Yadon and Wilson 2005; Bell et al. 2008; McNamara et al. 2008). This short-term habituation is highly odor specific, with minimal cross-adaptation of piriform cortical single-unit responses or cross-habituation of behavioral responses to similar odors, including between mixtures and their components (Wilson 2000; Cleland et al. 2002). Interestingly, there is an experience-dependent component to short-term habituation odor specificity. The odor specificity is most pronounced for familiar odors, with very brief (<20 sec) exposure to odors producing more generalization, and longer exposures (>50 sec) sufficient to permit strong odor specificity in cortex adaptation (Wilson 2003).The homosynaptic nature of afferent synaptic depression underlying cortical adaptation (Wilson 1998; Best and Wilson 2004) may contribute to this odor specificity. However, the experience dependence suggests that there may be an additional process involved. In fact, theoretical views of piriform cortical function suggest that the cortex learns previous patterns of input via potentiation of intracortical association fiber synapses (Hasselmo et al. 1990; Barkai et al. 1994; Haberly 2001; Linster et al. 2003). This autoassociative process essentially creates a template of previous network activity, against which new input patterns can be compared, allowing enhanced discrimination between similar patterns, as well as completion of degraded patterns (Barkai et al. 1994; Barnes et al. 2008). In support of this hypothesis, previous work has demonstrated that disruption of normal synaptic potentiation in association fiber synapses through blockade of cholinergic muscarinic receptors (Patil et al. 1998; Linster et al. 2003), reduces odor specificity of cortical adaptation (Wilson 2001b), prevents the effects of odor experience on subsequent behavioral cross-habituation (Fletcher and Wilson 2002), and disrupts odor discrimination (Linster et al. 2001).The present series of studies further explored the role of combined afferent synaptic depression and intracortical association fiber synaptic potentiation on the specificity of cortical adaptation and odor habituation. Using a computational model of the olfactory system (Linster et al. 2007), the results suggest that activity-dependent association fiber plasticity is necessary to account for the specificity of odor habituation. Furthermore, in behavioral experiments blockade of cholinergic muscarinic receptors during habituation enhances generalization of odor habituation, consistent with the modeling and with previous electrophysiological results.     

Progesterone regulation of synaptic transmission and plasticity in rodent hippocampus

Ovarian hormones influence memory formation by eliciting changes in neural activity. The effects of various concentrations of progesterone (P4) on synaptic transmission and plasticity associated with long-term potentiation (LTP) and long-term depression (LTD) were studied using in vitro hippocampal slices. Extracellular studies show that the highest concentration of P4 tested (10(-6) M) decreased the baseline synaptic transmission and magnitude of LTP, but did not affect LTD. Intracellular studies suggest the P4 effect to be mediated, at least in part, by GABA(A) activity. These results establish a general effect of P4 on synaptic transmission, multiple forms of synaptic plasticity, and a possible mechanism of P4 action in hippocampus.     

Impairment of spatial learning and hippocampal synaptic potentiation in c-kit mutant rats

The c-kit receptor tyrosine kinase encoded by the white-spotting (W) gene is highly expressed in rat hippocampal CA1–CA4 regions. We found an impaired spatial learning and memory in homozygous c-kit (Ws/Ws) mutant rats that have a 12-base deletion in the tyrosine kinase domain of the c-kit gene and a very low kinase activity. Electrophysiological studies in hippocampal slices revealed that the long-term potentiation (LTP) induced by the tetanic stimulation (100 Hz, 1 sec) in the mossy fiber (MF)–CA3 pathway, but not in the Schaffer collaterals/commissural–CA1 pathway, was significantly reduced in c-kit mutants compared with wild-type (+/+) rats. The paired-pulse facilitation (PPF) was measured before the tetanus and after the establishment of the LTP in each slice. The initial PPF in the MF–CA3 pathway positively correlated with the amplitude of the LTP in the wild-type rats but not in the c-kit mutant rats. Furthermore, they failed to show the normal characteristics observed in the MF–CA3 pathway of +/+ rats; that is, the negative correlation between the initial PPF and the changes in PPF measured after the LTP. These findings suggest an involvement of SCF/c-kit signaling in hippocampal synaptic potentiation and spatial learning and memory.     

mTOR signaling in the hippocampus is necessary for memory formation

It is widely accepted that the formation of long-term memory (LTM) requires mRNA translation, but little is known about the cellular mechanisms in the brain that regulate this process. Mammalian target of rapamycin (mTOR) is a key regulator of translational efficacy and capacity. Here, we show that LTM formation of one-trial inhibitory avoidance (IA) in rats, a hippocampus-dependent fear-motivated learning task, requires mTOR activation. IA training is specifically associated with a rapid increase in the phosphorylation state of mTOR and its substrate ribosomal S6 kinase (p70S6K). Bilateral intra-CA1 infusion of rapamycin, a selective mTOR inhibitor, 15 min before, but not immediately after training completely hinders IA LTM without affecting short-term memory (STM) retention. Therefore, our findings indicate that the regulation of hippocampal mRNA translation is a major control step in memory consolidation.     

Timing accuracy of mouse response registration on the IBM microcomputer family

Data and theoretical estimates reported by Segalowitz and Graves (1990) and Crosbie (1990) regarding delays of serial Microsoft mouse response registration are corrected and extended. Empirically measured mouse responses clearly confirm a theoretical minimum delay time of 22.5 msec for Microsoft-compatible serial mouse devices. Timing accuracy of key actions for the serial, bus, and PS/2 mouse devices are presented.     

Timing and torque involvement in the organisation of a rapid forearm flexion

The study was designed to determine whether the magnitude of force and the timing of force are response parameters involved in the organisation of a rapid forearm flexion to a target. The magnitude of torque and the timing of torque were manipulated independently through manipulations of the total moment of inertia and movement time, and the effect of these manipulations on premotor and motor reaction times was observed. Planned comparison analyses revealed that premotor and motor reaction times increased when a movement, which required the same magnitude of torque as in a fast movement, was performed slower. However, premotor and motor reaction times were not affected when movements were performed at the same speed, but differed with respect to the magnitude of torque required. These results indicate that a different timing requirement in the forthcoming movement is associated with a corresponding change in the amount of central processing time required. Therefore, the timing of torque appears to be a parameter of the movement that is organised in advance of movement execution. However, a change in the specification for the magnitude of torque does not affect the amount of time needed to organise the movement.     

Post-training administration of corticosterone enhances consolidation of contextual fear memory and hippocampal long-term potentiation in rats

This study was designed to examine the effect of corticosterone on consolidation of contextual fear memory and hippocampal long-term potentiation (LTP) in rats. In Experiment 1, dose–response effects of corticosterone on consolidation of contextual fear memory were determined. Immediately after training in contextual fear conditioning task, rats received different doses of corticosterone. Testing 24 h later, it revealed that corticosterone enhanced memory consolidation in an inverted U shape as evidenced in increased freezing behavior of corticosterone-treated animals. The most effective dose was 3 mg/kg. In Experiment 2, LTP was examined in rats whose memory consolidation has been enhanced with corticosterone. The rats were trained as the above and received corticosterone (3 mg/kg) immediately after training. Immediately or up to one day after retention test, rats were anesthetized with urethane for LTP experiments. For LTP induction, three episodes of high frequency stimuli, 30 s apart, were delivered to the perforant path, each consisting of 10 stimuli at 250 Hz. LTP was assessed by measuring the increase in the initial slope of the population excitatory post-synaptic potentials and the amplitude of the population spikes. Data indicated that animals whose memory has been enhanced by corticosterone, also displayed enhanced hippocampal LTP. The above findings suggest that glucocorticoids may enhance contextual fear memory consolidation via enhancing hippocampal LTP.     

Corticosterone time-dependently modulates beta-adrenergic effects on long-term potentiation in the hippocampal dentate gyrus

Previous experiments in the hippocampal CA1 area have shown that corticosterone can facilitate long-term potentiation (LTP) in a rapid non-genomic fashion, while the same hormone suppresses LTP that is induced several hours after hormone application. Here, we elaborated on this finding by examining whether corticosterone exerts opposite effects on LTP depending on the timing of hormone application in the dentate gyrus as well. Moreover, we tested rapid and delayed actions by corticosterone on β-adrenergic-dependent changes in LTP. Unlike the CA1 region, our in vitro field potential recordings show that rapid effects of corticosterone do not influence LTP induced by mild tetanization in the hippocampal dentate gyrus, unless GABA_A receptors are blocked. In contrast, the β-adrenergic agonist isoproterenol does initiate a slow-onset, limited amount of potentiation. When corticosterone was applied concurrently with isoproterenol, a further enhancement of synaptic strength was identified, especially during the early stage of potentiation. Yet, treatment with corticosterone several hours in advance of isoproterenol fully prevented any effect of isoproterenol on LTP. This emphasizes that corticosterone can regulate β-adrenergic modulation of synaptic plasticity in opposite directions, depending on the timing of hormone application.     

Timing is everything: Changes in presentation rate have opposite effects on auditory and visual implicit statistical learning

Implicit statistical learning (ISL) is exclusive to neither a particular sensory modality nor a single domain of processing. Even so, differences in perceptual processing may substantially affect learning across modalities. In three experiments, statistically equivalent auditory and visual familiarizations were presented under different timing conditions that either facilitated or disrupted temporal processing (fast or slow presentation rates). We find an interaction of rate and modality of presentation: At fast rates, auditory ISL was superior to visual. However, at slow presentation rates, the opposite pattern of results was found: Visual ISL was superior to auditory. Thus, we find that changes to presentation rate differentially affect ISL across sensory modalities. Additional experiments confirmed that this modality-specific effect was not due to cross-modal interference or attentional manipulations. These findings suggest that ISL is rooted in modality-specific, perceptually based processes.     

Timing is everything: changes in presentation rate have opposite effects on auditory and visual implicit statistical learning

Implicit statistical learning (ISL) is exclusive to neither a particular sensory modality nor a single domain of processing. Even so, differences in perceptual processing may substantially affect learning across modalities. In three experiments, statistically equivalent auditory and visual familiarizations were presented under different timing conditions that either facilitated or disrupted temporal processing (fast or slow presentation rates). We find an interaction of rate and modality of presentation: At fast rates, auditory ISL was superior to visual. However, at slow presentation rates, the opposite pattern of results was found: Visual ISL was superior to auditory. Thus, we find that changes to presentation rate differentially affect ISL across sensory modalities. Additional experiments confirmed that this modality-specific effect was not due to cross-modal interference or attentional manipulations. These findings suggest that ISL is rooted in modality-specific, perceptually based processes.     

Analysis of potentiation and overshadowing effects in the instrumental performance of pigeons

In each of two experiments, pigeons were trained on a multiple VI (variable interval) schedule with a 3-s delay of reinforcement. Different components were associated with different key colors. Experiment 1 (stage 2) confirmed a previous finding that the response rate is higher in a component having a signal (illumination of the houselight) filling the delay interval than in a component lacking the signal. This potentiation effect was replaced by an overshadowing effect (i.e., the rate was low in the signaled component) when in stage 1 of Experiment 1 the birds received concurrent experience of a component containing houselight presentations not correlated with reinforcement. In Experiment 2 it was found that this overshadowing effect was abolished when the signal used was the presentation of a pattern on the response key rather than illumination of the houselight. These results are interpreted in terms of an interaction between the rate-enhancing properties of the signal (perhaps a consequence of its conditioned reinforcing power) and the tendency of the signal in some conditions to evoke behavior that competes with the response being recorded.     

Timing moderates the effects of repeated suggestive interviewing on children's eyewitness memory

The relative role of the timing and repetition of misinformation on the accuracy of children's recall was examined in two experiments. Kindergarten children participated in a magic show and about 40 days later had a memory test. Between the magic show and the memory test, the children were suggestively interviewed either one time in a relatively ‘early’ interview (temporally closer to the magic show than the memory test) or a relatively ‘late’ interview (closer to the memory test than the magic show), or in both suggestive interviews. The timing of the suggestive interviewing was manipulated so that the interview was temporally distant from the event or memory test or temporally close to the event or memory test. Repeated interviewing heightened misinformation effects only when the children received the two interview sessions temporally close to the event and memory test. Copyright © 2004 John Wiley & Sons, Ltd.