Temporary inactivation reveals an essential role of the dorsal hippocampus in consolidation of object recognition memory

The role of the hippocampus in novel object recognition (NOR) memory remains controversial. Here we report the finding that the dorsal hippocampus is essential for consolidation of NOR memory up to 3h after training. Temporary inactivation of the dorsal hippocampus with a bilateral intrahippocampal infusion of muscimol immediately or 3h, but not 6h post-training impaired 24-h NOR retention in male rats. These results strongly indicate that the dorsal hippocampus is required for early and delayed NOR consolidation.     

Impairment of spatial memory consolidation in APP(751SL) mice results in cue-guided response

APP(751SL) mice of 5-6- and 7-8-month-old and their wild-type littermates were submitted to one-session learning in a water-maze with three levels of training (4, 12 or 22 trials). Training consisted in finding a submerged platform with a fixed location and marked by a cue. During testing two platforms were presented: one consistent with the spatial location allowing place-response (PR) and the other signaled by the cue enabling cued-response (CR). When testing occurred 24h after training, wild-type and 5-6-month-old APP(751SL) mice exhibited a shift in response strategy as a function of training level, by executing CR when trained with 4 trials and PR when trained with 12 trials, but 7-8-month-old APP(751SL) mice executed only CR. However, they displayed PR when tested 1h after 12- and 22-trial, suggesting a consolidation deficit. Zif268 imaging showed plasticity impairment of the hippocampal-dependent memory system but not of the dorsolateral caudate nucleus. Moreover, in these APP(751SL) mice, the deficit selectively affecting hippocampal function cannot be directly related to the onset of beta-amyloid deposits.     

Pharmacological correction of ketamine-impaired spatial memory of rats

Department of Pharmacology, Volgograd Medical Institute. (Presented, by Academician of the Academy of Medical Sciences of the USSR A. V. Val'dman.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 110, No. 12, pp. 618–620, December, 1990.     

Local dopamine production in the dorsal striatum restores goal-directed behavior in dopamine-deficient mice

To determine whether dopamine signaling in the dorsal striatum is sufficient for performance of goal-directed behaviors, local dopamine production was restored in the dorsal striatum of dopamine-deficient (DD) mice through viral-mediated gene therapy. Virally rescued DD (vrDD) mice were tested for learning of an appetitive T-maze task designed to measure goal-directed behavior. The results indicate that in contrast with the performance of DD mice that have dysregulated dopamine signaling, vrDD mice were able to perform the T-maze task and reverse their behavior as well as sham-operated control mice. The authors conclude that finely tuned dopaminergic signaling within the dorsal striatum is sufficient for performance of goal-directed behavior.     

Effects of estrogen and progesterone on spatial memory consolidation in aged females

Interpretation of data illustrating that estrogen, with or without progestin, is detrimental to memory in post-menopausal women is complicated by the fact that little is known about the effects of progestins on memory. The present study examined if estrogen, alone or with progesterone, affects spatial memory consolidation in ovariectomized aged female mice. Mice received eight training trials in a spatial Morris water maze followed immediately by injection of water-soluble 17beta-estradiol (E(2); 0.2 mg/kg) or vehicle. Mice were re-tested 24 h later. All mice learned to find the platform on Day 1. On Day 2, the performance of control, but not E(2) mice, deteriorated, suggesting that E(2) enhanced memory for the platform location. In a second experiment, mice were injected with E(2) and 10 or 20 mg/kg water-soluble progesterone. The 10 mg/kg dose of progesterone did not affect estrogen's ability to enhance spatial memory consolidation, but 20 mg/kg blocked this effect. These data indicate that estrogen can improve spatial memory consolidation in aged females and that this effect can be attenuated by progesterone.     

Pharmacological evidence of inhibitory and disinhibitory neuronal circuits in dorsal cochlear nucleus

The dorsal cochlear nucleus (DCN) is rich in both glycine and GABA inhibitory neurotransmitter systems, and the response properties of its principal cells (pyramidal and giant cells) are strongly shaped by inhibitory inputs. For example, DCN principal cells often display highly nonmonotonic (so-called type IV) input-output functions in response to best-frequency (BF) tones. In this study, the inhibitory inputs onto the principal cell types and onto response types of known inhibitory interneurons were compared before and during iontophoretic application of the glycine- and GABA(A)-receptor antagonists, strychnine and bicuculline. Strychnine eliminates the central (on-BF) inhibitory area in type IV units, resulting in monotonic BF rate-level curves. Unexpectedly, bicuculline primarily enhances inhibition in principal-cell types; for example, type IV units are inhibited at lower sound levels in the presence of bicuculline. Principal cell types with weaker inhibitory inputs (type IV-T and type III units) are more strongly inhibited in the presence of bicuculline and usually are converted into type IV units. This enhancement of on-BF inhibition by bicuculline suggests a disinhibitory process involving GABA(A) action on a non-GABA(A)ergic inhibitory pathway. This latter pathway is probably glycinergic and involves type II units (deep-layer vertical cells) and/or complex-spiking units (superficial cartwheel cells) because both of these unit types are disinhibited by bicuculline. One intrinsic GABA(A) source could be the superficial stellate cells in DCN because bicuculline partly blocks the inhibition evoked by somatosensory-stimulated activation of the superficial granule-cell circuitry in DCN. Taken together, the results suggest that glycinergic circuits mediate directly the inhibition of DCN principal cells, but that GABA(A)ergic circuits modulate the strength of the inhibition.     

On the participation of hippocampal PKC in acquisition, consolidation and reconsolidation of spatial memory

Memory consolidation involves a sequence of temporally defined and highly regulated changes in the activation state of several signaling pathways that leads to the lasting storage of an initially labile trace. Despite appearances, consolidation does not make memories permanent. It is now known that upon retrieval well-consolidated memories can become again vulnerable to the action of amnesic agents and in order to persist must undergo a protein synthesis–dependent process named reconsolidation. Experiments with genetically modified animals suggest that some PKC isoforms are important for spatial memory and earlier studies indicate that several PKC substrates are activated following spatial learning. Nevertheless, none of the reports published so far analyzed pharmacologically the role played by PKC during spatial memory processing. Using the conventional PKC and PKCμ inhibitor 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrollo[3,4-c]carbazole (Gö6976) we found that the activity of these kinases is required in the CA1 region of the rat dorsal hippocampus for acquisition and consolidation of spatial memory in the Morris water maze learning task. Our results also show that when infused into dorsal CA1 after non-reinforced retrieval, Gö6976 produces a long-lasting amnesia that is independent of the strength of the memory trace, suggesting that post-retrieval activation of hippocampal PKC is essential for persistence of spatial memory.     

Sleep and memory consolidation: The role of electrophysiological neuroimaging

Summary Memory consolidation involves a complex series of molecular, cellular and network-level processes that take place on time scales from millisecond to months. Evidence from a wide range of experimental observations supports the hypothesis that parts of these processes occur during sleep when the brain is not engaged in processing and encoding incoming information. Indeed, sleep seems to be favorable for brain plasticity. Experience-dependent cortical plasticity observed during sleep has been hypothesized to be part of the global process of memory consolidation. Thus, studying task-dependent, regionally specific reactivation of neuronal assemblies during posttraining sleep may make important contributions to elucidating the role of sleep in memory trace processing. A new methodology – low-resolution brain electromagnetic tomography (LORETA) – offers the possibility of localizing electrical activity produced by cortical neuronal generators under normal (undisturbed) sleeping conditions. The high time resolution of brain electrical data can be exploited to produce neuroimages for specific EEG spectral frequency bands (e.g. delta, theta, or spindle bands). This makes it possible to investigate, dependent on the type of memory, when – in which sleep stages (S2 sleep, SWS, REM sleep) – and where – in which cortical brain regions (primary sensory cortex, higher association cortex) – experience-dependent reactivation occurs.     

Learning and memory dissociation in rats with lesions to the subthalamic nucleus or to the dorsal striatum

The striatum and the subthalamic nucleus (STN) are the two main cortical inputs to the basal ganglia. Both structures are involved in motor and cognitive functions, particularly executive functions, known to rely mainly on fronto-basal ganglia circuits. The present work investigated the respective role of the dorsal part of the striatum (dST) and the STN by studying their involvement in learning and memory processes in two separate experiments. In a first experiment, rats with lesions to the STN or to the dST were trained in a light-tone discrimination task. When the learning criterion was reached, rats were then trained to the reversed discrimination. In a second experiment, surgery was done when the learning criterion had been reached. Three weeks after surgery, animals were then subjected to two relearning sessions and then to either a reversal learning or a working memory task. When surgery was done before learning, dysfunction of the dorsal striatum induced slight difficulties in acquisition, whereas dysfunction of the STN induced no difficulties during the initial learning but induced a more rapid inhibition of responses to the first lever press following the presentation of the tone during the reversed discrimination. In the second experiment, dST-lesioned rats showed long-term memory deficit in contrast to STN-lesioned rats which showed no difficulties during relearning but deficits in working memory. These results indicate a clear dissociation in cognitive functions in which STN and dorsal striatum are involved, suggesting that the fronto-striatal circuit and the fronto-STN circuit support, at least in part, different cognitive functions.     

The locus coeruleus: its possible role in memory consolidation.

Three experiments were done looking at the effects on memory of discrete electrolytic lesions in the locus coeruleus of mice. In Experiment 1 mice received electrolytic lesions of the locus coeruleus immediately following training on the 1 trial inhibitory avoidance step-through task. Retention of this response, measured 48 hr later was normal, suggesting that locus coeruleus lesions per se do not interfere with the performance of this rather simple response. In Experiments 2 and 3 mice were treated exactly as in Experiment 1 except that a transcorneal ECS was administered 40 hr or 7 days after initial training and locus coeruleus lesions. Mice with locus coeruleus lesions were amnesic following a 40 hr delayed ECS treatment when tested either 8 hr or 24 hr after ECS. Mice with locus coeruleus lesions were not amnesic following a 7 day delayed ECS. These data are interpreted to suggest that the locus coeruleus is normally involved in the temporal delineation of the susceptibility period of newly formed memory. A malfunction of the locus coeruleus can result in a profound extension of the normal susceptibility period of newly formed memory to ECS produced amnesia.     

Estradiol-induced enhancement of object memory consolidation involves NMDA receptors and protein kinase A in the dorsal hippocampus of female C57BL/6 mice

This study examined the role of dorsal hippocampal NMDA receptors and PKA activation in 17 beta-estradiol (E2)-induced enhancement of object memory consolidation. Mice explored two identical objects during training, after which they immediately received intraperitoneal injections of 0.2 mg/kg E2, and bilateral dorsal hippocampal infusions of Vehicle, the NMDA receptor antagonist APV (2.5 microg/side), or the cAMP inhibitor Rp-cAMPS (18.0 microg/side). Retention was tested 48 hours later. The enhanced object memory and increased ERK phosphorylation observed with E2 alone was reduced by APV and Rp-cAMPS, suggesting that estrogenic enhancement of object memory involves NMDA receptors and PKA activation within the dorsal hippocampus.     

Functions of dopamine in the dorsal and ventral striatum

Manipulations of dopamine levels in the dorsal and ventral striatum are shown to affect the activation of behaviour in distinct, yet parallel ways, which depend upon the nature of the neocortical and limbic input to these structures. Whereas dopamine in the dorsal striatum contributes to the sensorimotor co-ordination of consummatory behaviour and the development of a ‘response set’ in motor preparatory processes for skilled responses, dopamine in the ventral striatum influences the impact of reward-related stimuli on appetitive aspects of behaviour. The circumstances under which the striatal dopamine projections are normally active to effect these functions are defined by studies which attempt to correlate firing in single units or neurochemical indices of dopamine activity with environmental conditions, internal states and behaviour.     

A role for adult neurogenesis in spatial long-term memory

Adult hippocampal neurogenesis has been linked to learning but details of the relationship between neuronal production and memory formation remain unknown. Using low dose irradiation to inhibit adult hippocampal neurogenesis we show that new neurons aged 4–28 days old at the time of training are required for long-term memory in a spatial version of the water maze. This effect of irradiation was specific since long-term memory for a visibly cued platform remained intact. Furthermore, irradiation just before or after water maze training had no effect on learning or long-term memory. Relationships between learning and new neuron survival, as well as proliferation, were investigated but found non-significant. These results suggest a new role for adult neurogenesis in the formation and/or consolidation of long-term, hippocampus-dependent, spatial memories.     

Influence of three-day morphine-treatment upon impairment of memory consolidation induced by cannabinoid infused into the dorsal hippocampus in rats

In the present study, the effects of morphine treatment upon reduction of memory consolidation by post-training administration of the non-selective cannabinoid CB(1)/CB(2) receptor agonist, WIN55,212-2, into the dorsal hippocampus (intra-CA1) have been investigated in rats. Step-through inhibitory avoidance apparatus was used to test memory retrieval, which was made of two white and dark compartments. In training day, electric shocks were delivered to the grid floor of the dark compartment. On the test day, the animal was placed in the white compartment and allowed to enter the dark compartment. The latency with which the animal crossed into the dark compartment was recorded as memory retrieval. Morphine was injected subcutaneously (S.C.), once daily for three days, followed by a five day morphine-free period before training. Bilateral post-training intra-CA1 infusions of WIN55,212-2 (0.25 and 0.5 μg/rat) shortened the step-through latency, which suggested impaired memory consolidation. The deleterious effect of WIN55,212-2 (0.5 μg/rat) was prevented in rats previously injected with morphine (10 mg/kg/day × 3 days, S.C.). Prevention of the WIN55,212-2-induced amnesic-like effect was counteracted by the mu-receptor antagonist, naloxone, and the dopamine D(2) receptor antagonist, sulpiride, but not by the D(1) receptor antagonist, SCH 23390, when administered prior to each morphine injection. The results have suggested that subchronic morphine treatment may cause mu-opioid and D(2) receptor sensitization, which in turn prevents impairment of memory consolidation induced by WIN55,212-2.     

Impaired spatial memory in APP-overexpressing mice on a homocysteinemia-inducing diet

Consumption of a diet that significantly elevates homocysteine (homocysteinemia) induces cell death in the CA3 hippocampal subfield in amyloid precursor protein (APP) over-expressing transgenic mice but not in wild-type controls. We assessed behavioral and other neuropathological effects of a homocysteinemia-inducing diet in aged APP-overexpressing mice. Starting at 16-18 months of age, mice were fed either a treatment diet lacking folate, choline, and methionine, and supplemented with homocysteine, or a control diet containing normal amounts of folate, choline and methionine but no homocysteine. After 5 months on the experimental diets, performance on a delayed non-matching-to-position working-memory task was unimpaired. In contrast, spatial reference memory in the water maze was impaired in transgenic mice on the treatment diet. Transgenic mice had higher homocysteine levels than wild-type mice even when fed the control diet, suggesting an effect of genotype on homocysteine metabolism. Methyl-donor deficiency did not alter amyloid deposition in the transgenic mice. These results suggest that disrupted homocysteine metabolism may induce Abeta-associated memory impairments and neurodegeneration in APP overexpressing mice.     

Role of the basolateral amygdala in memory consolidation

Typically, emotionally charged events are better remembered than neutral ones. This paper reviews data indicating that the amygdala is responsible for this facilitation of memory by emotional arousal. Pharmacological and behavioral studies have shown that the release of adrenal stress hormones facilitates memory consolidation. The available evidence suggests that this effect depends on a central action of stress hormones involving the release of the neuromodulators noradrenaline (NA) and acetylcholine in the basolateral complex of the amygdala (BLA). Indeed, BLA lesions block the memory modulating effects of stress hormones. Moreover, microdialysis studies have revealed that BLA concentrations of NA and acetylcholine are transiently (2h) elevated following emotionally arousing learning episodes. Last, post-learning intra-BLA injections of beta-adrenergic or muscarinic receptor antagonists reduce retention. These results have led to the hypothesis that NA and acetylcholine increase the activity of BLA neurons in the hours after the learning episode. In turn, the BLA would facilitate synaptic plasticity in other brain structures, believed to constitute the storage sites for different types of memory. Consistent with this, post-learning treatments that reduce or enhance the excitability of BLA neurons respectively decrease or improve long-term retention on various emotionally charged learning tasks. However, a number of issues remain unresolved. Chief among them is how the BLA facilitates synaptic plasticity elsewhere in the brain. The present review concludes with a consideration of this issue based on recent advances in our understanding of the BLA. Among other possibilities, it is suggested that rhythmic BLA activity at the theta frequency during arousal as well as the uniform conduction times of BLA axons to distributed rhinal sites may promote plasticity in co-active structures of the temporal lobe.     

Posttraining administration of pentylenetetrazol dissociates gabapentin effects on memory consolidation from that on memory retrieval process in mice

Gabapentin (GBP), an anticonvulsant drug, 10 mg/kg, i.p., but not 100 mg/kg, i.p., enhanced retention of an inhibitory avoidance task when given 20 min after training, as indicated by retention performance 48 h later. The immediate post-training administration of pentylenetetrazol (PTZ, 45 mg/kg, i.p.) impaired retention performance. The amnesic effects of the convulsant drug PTZ were not influenced by GBP at any level of doses. However, GBP 100 mg/kg, but not 10 mg/kg, delayed the latency to first clonic body seizures and decreased the duration of convulsion induced by PTZ. The enhancing effect of GBP on retention was not prevented by the opiate receptor antagonist, naltrexone (0.01 mg/kg, i.p.), which completely prevented the impairment of retention caused by PTZ. Further, naltrexone did not modify the convulsions induced by PTZ. In mice pretreated with naltrexone and that received PTZ, the administration of GBP again, enhanced retention performance during the retention test. Since previous results indicate that the amnesic action of PTZ are due to an effect on memory retrieval, the present results provide additional pharmacological evidence suggesting that GBP influenced memory consolidation and not memory retrieval of an inhibitory avoidance task in mice.     

吗啡成瘾小鼠对正常小鼠学习记忆力能力的影响

目的:用BALB/C小鼠建立动物模型,观察吗啡成瘾戒断小鼠对其周围的正常小鼠学习记忆能力的影响。方法:将吗啡成瘾戒断小鼠与正常小鼠同笼饲养,然后用Morris水迷宫实验测定正常小鼠的学习记忆能力,应用RT-PCR的方法检测正常小鼠海马中PKCa、GABA分子表达的变化。结果:水迷宫实验证明,与生理盐水组相比,实验组小鼠的学习记忆能力明显降低(P<0.05),海马中PKCa和DABA的表达都明显升高(P<0.05)。     

No evidence for intra-individual correlations between sleep-mediated declarative memory consolidation and slow-wave sleep

Study ObjectivesMemory consolidation benefits from a retention period filled with sleep. Several theoretical accounts assume that slow-wave sleep (SWS) contributes functionally to processes underlying the stabilization of declarative memories during sleep. However, reports on correlations between memory retention and the amount of SWS are mixed and typically rely on between-subject correlations and small sample sizes. Here we tested for the first time whether the amount of SWS during sleep predicts the effect of sleep on memory consolidation on an intra-individual level in a large sample.MethodsOne hundred and fifty-nine healthy participants came to the lab twice and took a 90 min nap in both sessions. Sleep-mediated memory benefits were tested using the paired associates word-learning task in both sessions.ResultsIn contrast to the theoretical prediction, intra-individual differences in sleep-mediated memory benefits did not significantly correlate with differences in SWS or SWA between the two naps. Also between subjects, the amount of SWS did not correlate with memory retention across the nap. However, subjective ratings of sleep quality were significantly associated with the amount of SWS.ConclusionOur results question the notion that the amount of SWS per se is functionally related to processes of memory consolidation during sleep. While our results do not exclude an important role of SWS for memory, they suggest that “more SWS” does not necessarily imply better memory consolidation.