Hippocampus-dependent Memory Consolidation Research Articles

Inducible and Cell-Type Restricted Manipulation in the Entorhinal Cortex

The entorhinal cortex functions as the gateway to the hippocampal formation. However, its role in formation and consolidation of hippocampus-dependent memory remains relatively unexplored. In this issue of Neuron, Yasuda and Mayford report an elegant cell-type restricted inducible transgenic mouse overexpressing a mutant form of CaM kinase II selectively in superficial layers of medial entorhinal cortex and its upstream regions. These animals display a selective spatial memory deficit during the immediate posttraining period as well as during acquisition in the Morris water maze. Similar to the hippocampus, this time-limited involvement of entorhinal cortex in spatial memory processing suggests a crucial role for hippocampal-entorhinal circuitry in spatial memory formation.

The negative cell cycle regulator, Tob (transducer of ErbB-2), is involved in motor skill learning

Tob (transducer of ErbB-2) is a negative cell cycle regulator with anti-proliferative activity in peripheral tissues. Our previous study identified Tob as a protein involved in hippocampus-dependent memory consolidation (M.L. Jin, X.M. Wang, Y.Y. Tu, X.H. Zhang, X. Gao, N. Guo, Z.Q. Xie, G.P. Zhao, N.H. Jing, B.M. Li, Y.Yu, The negative cell cycle regulator, Tob (Transducer of ErbB-2), is a multifunctional protein involved in hippocampus-dependent learning and memory, Neuroscience 131 (2005) 647–659). Here, we provide evidence that Tob in the central nervous system is engaged in acquisition of motor skill. Tob has a relatively high expression in the cerebellum. Tob expression is up-regulated in the cerebellum after rats receive training on a rotarod-running task. Rats infused with Tob antisense oligonucleotides into the 4th ventricle exhibit a severe deficit in running on a rotating rod or walking across a horizontally elevated beam.

Sleep, hormones and memory

Nocturnal sleep in humans is characterised by a unique pattern of endocrine activity. Secretory activity of the hypothalamo-pituitary-adrenal (HPA) system is maximally suppressed during the early part of sleep, which is dominated by slow wave sleep (SWS). Concurrently, release of growth hormone (GH) and prolactin reach a maximum. During the late part of sleep when rapid eye movement (REM) sleep is predominant, HPA secretory activity distinctly increases while the release of GH reaches a minimum and also prolactin concentrations decrease. Release of thyroid stimulating hormone (TSH) usually peaks in the evening and is suppressed during sleep. The regulatory effects of sleep and circadian rhythm on HPA secretory activity are synergistic so that sleep amplifies the effects of circadian oscillators. In contrasts, the effects of sleep and circadian rhythm on the release of TSH are antagonistic. The effects of sleep on the release of GH and prolactin appear to be rather independent from circadian rhythm. What are the functions of this sleep specific regulation of endocrine activity? Considering the essential role sleep plays for the consolidation of memories, in an ongoing series of studies we are testing whether the endocrine regulation during sleep serves to enhance the memory function of sleep. The first studies focussed on the role of pituitary-adrenal activity. SWS-rich early sleep has been demonstrated to benefit particularly the hippocampus dependent declarative memory system (storing facts and episodes). In contrast, REM sleep-rich late sleep appears to improve in particular procedural memory for skills, not depending on the hippocampus. Enhancing plasma glucocorticoid concentrations during SWS-rich early sleep completely blocked hippocampus dependent declarative memory consolidation, but did not affect hippocampus independent procedural memory. Also, procedural memory consolidation was not impaired when the rise in plasma cortisol concentration during late REM-sleep rich sleep was prevented by administration of metyrapone. The data underscore the importance of pituitary-adrenal inhibition during early SWS-rich sleep for efficient consolidation of declarative memories.

Reversible lesion of the rat’s orbitofrontal cortex interferes with hippocampus-dependent spatial memory

In this study, tetrodotoxin (TTX) inactivation was employed to evaluate the involvement of the rat’s orbitofrontal cortex (OFC) in hippocampus-dependent spatial memory using Morris water maze (MWM) and place avoidance learning (PAL) tasks. In Experiment 1, rats trained in MWM task with two blocks of four trials per day for 3 consecutive days received bilateral injections of either TTX or saline into the OFC 60 min before each daily training session. The acquisition of spatial memory was evaluated 24 h after the last training day and it was shown an impairment by the TTX. In Experiment 2, bilateral intra-OFC injections of TTX or saline were made immediately after two blocks of four trials. Testing 24 h later, it was revealed that TTX also impairs spatial memory consolidation. In Experiments 3 and 4, rats were trained in a single 30-min session to avoid a 60° segment of the stable circular (80-cm diameter) arena, entering which was punished by a mild shock (PAL task) and retention was tested 24 h later in a 30-min extinction session. Bilateral injections of TTX or saline were made into the OFC 60 min before training or immediately after training. Again, TTX impaired the place avoidance retention when it was injected into the OFC either before (acquisition phase) or after (consolidation phase) training. These findings indicate that functional integrity of the OFC is necessary for both the acquisition and the consolidation of hippocampus-dependent spatial memory in rats.

Genetic neuroscience of mammalian learning and memory.

Our primary research interest is to understand the molecular and cellular mechanisms on neuronal circuitry underlying the acquisition, consolidation and retrieval of hippocampus-dependent memory in rodents. We study these problems by producing genetically engineered (i.e. spatially targeted and/or temporally restricted) mice and analysing these mice by multifaceted methods including molecular and cellular biology, in vitro and in vivo physiology and behavioural studies. We attempt to identify deficits at each of the multiple levels of complexity in specific brain areas or cell types and deduce those deficits that underlie specific learning or memory. We will review our recent studies on the acquisition, consolidation and recall of memories that have been conducted with mouse strains in which genetic manipulations were targeted to specific types of cells in the hippocampus or forebrain of young adult mice.

Post-training cyclooxygenase-2 (COX-2) inhibition impairs memory consolidation.

Evidence indicates that prostanoids, such as prostaglandins, play a regulatory role in several forms of neural plasticity, including long-term potentiation, a cellular model for certain forms of learning and memory. In these experiments, the significance of the COX isoforms cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in post-training memory processes was assessed. Adult male Long-Evans rats underwent an eight-trial (30-sec intertrial interval) training session on a hippocampus-dependent (hidden platform) or dorsal striatal-dependent (visible platform) tasks in a water maze. After the completion of training, rats received an intraperitoneal injection of the nonselective COX inhibitor indomethacin, the COX-1-specific inhibitor piroxicam, the COX-2-specific inhibitor N-[2-cyclohexyloxy-4-nitrophenyl]-methanesulfonamide (NS-398), vehicle (45% 2-hydroxypropyl-beta-cyclodextrin in distilled water), or saline. On a two-trial retention test session 24 h later, latency to mount the escape platform was used as a measure of memory. In the hidden platform task, the retention test escape latencies of rats administered indomethacin (5 and 10 mg/kg) or NS-398 (2 and 5 mg/kg) were significantly higher than those of vehicle-treated rats, indicating an impairment in retention. Injections of indomethacin or NS-398 that were delayed 2 h post-training had no effect on retention. Post-training indomethacin or NS-398 had no influence on retention of the visible platform version of the water maze at any of the doses administered. Furthermore, selective inhibition of COX-1 via post-training piroxicam administration had no effect on retention of either task. These findings indicate that COX-2 is a required biochemical component mediating the consolidation of hippocampal-dependent memory.

The immune system and memory consolidation: a role for the cytokine IL-1β

Interleukin-1 beta (IL-1β), known to play a role in orchestrating the physiological and behavioral adjustments that occur during sickness, has also been shown to significantly influence memory consolidation. To support this assertion we present neurobiological evidence that the substrates for IL-1β to influence memory processing and neural plasticity exist. We then present behavioral evidence that central IL-1β administration and agents that induce central IL-1β activity impair the consolidation of memories that depend on the hippocampal formation but have no effect on the consolidation of hippocampal-independent memories. Further, we demonstrate that the impairments in hippocampal-dependent memory consolidation produced by agents that induce IL-1β activity are blocked by antagonizing the actions of IL-1β. Finally, we discuss these data in terms of their implications for a physiological role of IL-1β in memory consolidation processes and a potential role of IL-1β in producing memory impairments associated with stress, aging, Alzheimer's disease, and AIDS related dementia complex.

Effects of Age on the Generalization and Incubation of Memory in the F344 Rat

Freezing (immobility) in the presence of aversive stimuli is a species-specific behavior that is used as an operational measure of fear. Conditioning of this response to discrete sensory stimuli and environmental context cues has been used as a tool to study the neuropsychology of memory dynamics and their development over the lifespan. Three age groups of F344 rats (3, 9, and 27 month) received tone-foot shock pairing (or tone only) in a distinctive chamber on two consecutive days. Separate subgroups of rats from each age group were then tested, at retention intervals of 1, 20, 40, or 60 days, for context-mediated fear in the environment in which they were trained, for generalization of the fear response to a novel chamber, and for fear of the tone. Beginning at day 20, the 27-month-old rats exhibited less freezing behavior than did younger rats when tested in the conditioning context. This age difference was a result of freezing behavior becoming progressively stronger with time in the two younger age groups, a phenomenon that has been referred to as memory incubation. Incubation of the contextual fear response was not detected in the old rats. In a novel context, all age groups exhibited significantly more freezing than did control animals. There was also pronounced incubation of this generalized freezing response, and the extent of incubation declined significantly with age. In the novel context, the freezing response to the tone was robust in all age groups and increased over time, in constant proportion to the degree of freezing elicited by the novel context itself, prior to tone onset. The fact that old animals are known to be relatively selectively impaired in forms of memory that depend on a functional hippocampus suggests a possible explanation for the reduced incubation effects seen in old rats; however, whether the increased expression of fear over time is mediated by a hippocampal-dependent memory consolidation process or whether it reflects a generalized increase in the gain of the circuitry mediating the fear response itself, remains to be determined.

Arousal-Mediated Memory Consolidation: Role of the Medial Temporal Lobe in Humans

Although the influence of emotional arousal on declarative memory has been documented behaviorally, the mechanisms underlying arousal-memory interactions and their representation in the human brain remain uncertain. One route through which arousal achieves its effects on memory performance is by regulating consolidation processes. Animal research has revealed that the amygdala strengthens hippocampal-dependent memory consolidation in a limited time window following participation in an arousing task. To examine whether this integrative function of amygdalo-hippocampal structures extends to the human brain, we tested unilateral-temporallobectomy patients on an adaptation of a classic paradigm in which levels of physiological arousal at encoding modulate retention over time. Subjects rated emotionally arousing (taboo) and neutral words on an arousal scale while their skin conductance responses (SCRs) were monitored. Recall for the words was assessed immediately and after a 1-hr delay. Both temporal-lobectomy patients and control subjects generated enhanced SCRs and arousal ratings for the arousing words at the time of encoding. However, only control subjects exhibited an increase in memory for the arousing words over time. This group difference in the effect of arousal on the rate of forgetting suggests that the role of medial temporal lobe structures in memory consolidation for arousing events is conserved across species.

Antisense oligodeoxynucleotide-mediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training.

Extensive evidence suggests that long term memory (LTM) formation is dependent on the activation of neuronal second messenger systems and requires protein synthesis. The cAMP response element binding protein (CREB) is a constitutively expressed regulatory transcription factor that couples changes in second messenger levels to changes in cellular transcription. Several recent studies suggest that CREB and related transcription factors regulate gene expression necessary for neuronal plasticity and LTM. However, the role of CREB, within defined mammalian brain structures, in mediating the cellular events underlying LTM formation has not been investigated. We examined whether CREB-mediated transcription within the dorsal hippocampus is critical to LTM consolidation of water maze spatial training, which is known to depend on dorsal hippocampal function. Pretraining infusions of antisense oligodeoxynucleotides (ODN) directed against CREB mRNA were used to disrupt hippocampal CREB protein levels in adult rats. Control groups received pretraining infusions of ODN of the same base composition but in a randomized order (scrambled ODN) or buffer. Task acquisition and memory up to 4 h (i.e., short term memory) were similar in CREB antisense ODN and control groups. In contrast, CREB antisense ODN-infused rats exhibited significantly impaired memory 48 h later (i.e., LTM). Moreover, administration of antisense ODN 1 day after training did not affect subsequent retention performance. These findings provide the first evidence that CREB-mediated transcription is integral to hippocampal-dependent memory consolidation processes.