Extending the duration of ACTH-induced memory reactivation in an amnesic paradigm

The effectiveness of ACTH treatment in reversing hypothermia-induced retrograde amnesia was investigated in a passive avoidance paradigm. Subcutaneous injections of ACTH 30 min prior to a retention test attenuated the amnesia typically evidenced 24 hr after whole body cooling. Experiment 2 found no evidence for the reversal of amnesia 24 hr after ACTH treatment; however, when ACTH was combined with brief exposure to the “fear” cues previously associated with training substantial memory recovery was sustained over 24 hr. Although fear cue exposure without prior ACTH treatment also attenuated amnesia, the memory recovery was significantly less than that following the combined ACTH/cue exposure. Neither ACTH nor ACTH/cue exposure following sham-training appeared to have any consequence on performance. A final experiment replicated these findings and further suggested that the memory recovery induced by the combined ACTH/cue exposure persisted over 7, but not 14 days. It was suggested that although the combined hormone/behavioral reactivation treatment may extend the duration of ACTH-induced recovery from amnesia, a reactivated memory, like other memories, appears susceptible to ordinary sources of retention loss.     

大鼠场景性恐惧记忆再激活过程中海马HDAC2的表达变化

目的:探讨组蛋白去乙酰化酶2(histone deacetylase 2,HDAC2)在场景性恐惧记忆再激活过程中的表达变化。方法:对大鼠进行不可逃避的电击刺激与中性刺激(训练环境)联结匹配训练,建立大鼠场景性恐惧条件化模型,之后采用免疫组织化学、Western Blot和RT-PCR方法检测实验组(恐惧记忆唤起后30 min、2 h、6 h、24 h组和不进行恐惧记忆唤起的no-recall组)和对照组(与实验组相同的处理方式但没有足底电击的刺激)大鼠海马中HDAC2的表达变化。结果:免疫组织化学、Western Blot和RT-PCR方法检测结果均显示场景性恐惧记忆唤起后30 min与24 h,HDAC2在大鼠海马中的表达水平明显高于对照组,差异具有统计学意义。其它时间点及no-recall组HDAC2的表达与对照组相比,没有统计学意义。结论:场景性恐惧记忆唤起后30 min与24 h,HDAC2在大鼠海马中表达水平显著升高,此变化可能与恐惧记忆产生的相关行为(恐惧记忆的消退行为、焦虑行为等)有一定的联系。     

Characterization of the role of medial prefrontal cortex dopamine receptors in cocaine-induced locomotor activity

Medial prefrontal cortex (mPFC) dopamine (DA) modulates the motor-stimulant response to cocaine. The present study examined the specific mPFC DA receptor subtypes that mediate this behavioral response. Intra-mPFC injection of the DA D2-like receptor agonist quinpirole blocked cocaine-induced motor activity, an effect that was prevented by coadministration of the D2 receptor antagonist sulpiride. Intra-mPFC injection of the selective D4 receptor agonist PD 168,077 or the selective D1 receptor agonist SKF 81297 did not alter the motor-stimulant response to cocaine. Finally, it was found that an intermediate dose of quinpirole, which only attenuated cocaine-induced motor activity, was not altered by SKF 81297 coadministration, suggesting a lack of synergy between mPFC D1 and D2 receptors. These results suggest that D2 receptor mechanisms in the mPFC are at least partly responsible for mediating the acute motor-stimulant effects of cocaine.     

Characteristics of retrograde amnesia following reactivation of memory in mice

Amnesia for approach-avoidance learning was induced in mice by injecting the protein synthesis inhibitor anisomycin (ANI) immediately, 1, or 2 hours, but not 3 hours after training. A robust amnesia could be demonstrated if ANI was administered 3 hours after training, immediately following a 60 second exposure to the training apparatus or to a structurally similar environment. The temporal gradient of effectiveness of amnesia production by ANI was significantly steeper following reactivation treatment than it was following initial training. In addition, while amnesia produced by the conventional procedure remained stable for 6 days, the amnesia induced following reactivation treatment spontaneously recovered 4 days after training. These findings are discussed in terms of their relevance to interpretations of retrograde amnesia studies.     

Short-term memory, exploration and locomotor activity in aged rats

Behavioral profiles of young (3-6 months) and aged (24-27 months) rats were compared in three respects: (1) short-term memory, (2) exploration and (3) locomotor activity. Compared to young rats, aged rats were impaired in the 8-arm radial maze acquisition, but not in the delayed reinforced alternation acquisition. They had lower scores of spontaneous alternation, of exploration of a novel object and of a novel environment. Their exploratory activity was lower in a simple environment but similar in a complex environment. Their spontaneous locomotor activity was lower during the dark part of the cycle (8 p.m.-8 a.m.) but not different during the light part of the cycle (8 a.m.-8 p.m.). These results suggest that with respect to short-term memory and exploration, differences between aged and young rats may be influenced by a "complexity" factor and may be secondary to differences in motivation and reactions to novelty.     

Effect of object consistency in a spatial contextual cueing paradigm

Previous studies demonstrated that attention can be quickly guided to a target location in a visual search task when the spatial configurations of search items and/or the object identities were repeated in the previous trials. This phenomenon is termed contextual cueing. Recently, it was reported that spatial configuration learning and object identity learning occurred independently, when novel contours were used as search items. The present study examined whether this learning occurred independently even when the search items were meaningful. The results showed that the contextual cueing effect was observed even if the relationships between the spatial locations and object identities were jumbled (Experiment 1). However, it disappeared when the search items were changed into geometric patterns (Experiment 2). These results suggest that the spatial configuration can be learned independent of the object identities; however, the use of the learned configuration is restricted by the learning situations.     

Early adolescents show enhanced acute cocaine-induced locomotor activity in comparison to late adolescent and adult rats

Initiation of drug use during adolescence is associated with an increased probability to develop a drug addiction. The present study examined dose-response effects of cocaine (0, 5, 10, or 20 mg/kg, i.p.) on locomotor activity in early adolescent (postnatal day (PND) 35), late adolescent (PND 45), and young adults (PND 60) by measuring total distance moved (TDM) and frequency of start-stops. In response to 20 mg/kg cocaine, early adolescents showed the greatest cocaine-induced increase in TDM in comparison to late adolescent and adult rats. At this same dose, early adolescents showed the greatest cocaine-induced attenuation of start-stops relative to older rats. Results suggest that early adolescents engage in more cocaine-induced locomotor activity and less stationary behavior indicating that early adolescents are more sensitive to locomotor activating effects of high dose cocaine than older rats.     

Ageing-related changes of neural activity associated with spatial contextual memory

Neuropsychological studies provide evidence for an ageing-related decline of memory for contextual information related to remembered items. Using event-related fMRI we investigated the neural correlates of ageing-related changes during encoding and retrieval of spatial contextual memory. Eighteen young and 17 older subjects were included in the analysis (mean age 24 and 60 years, respectively). Although young and older subjects recognised the same amount of items during retrieval, spatial context memory for remembered items was superior in younger subjects. In both groups, left parahippocampal activity during encoding predicted contextual memory performance during retrieval. During encoding, an interaction between age and success of spatial context encoding was found in the left fusiform gyrus. During retrieval, the left hippocampal formation showed higher activity for successful than for unsuccessful spatial context retrieval as well as an interaction between age and spatial context judgement. Both findings are likely to underlie the contextual memory deficit observed in older subjects.     

Perturbations of locomotor activity rhythms following suprachiasmatic bungarotoxin infusion

The actions of intracranial injections of alpha bungarotoxin (BTX) on locomotor activity rhythms were examined in male rats. The hypothalamic suprachiasmatic region is known to be a locus of high affinity BTX binding although the potential roles of this receptor system are unknown. Rats were stereotaxically implanted with cannulae aimed just dorsal to the SCN (or cortex for control injections). Free-running locomotor activity rhythms in darkness were constantly monitored. Seventy-eight percent (78%) of the animals injected with BTX in the SCN region had phase shifts that were outside the 99% confidence limits of control animals. Infusion of either saline (into the SCN) or BTX into cortex were without effects. Doses of BTX varied from 125 fmol to 600 pmol. At the highest dose a substantial fraction of the animals showed both period changes and loss of rhythmicity as well as phase shifts. Although nearly all of the animals injected with BTX experienced phase shifts the direction of the shifts were not consistently correlated with the circadian time of injection. However, the sensitivity of the animals varied systematically with the smallest shifts resulting after injection at CT12 and CT16. These results argue that BTX does not influence the SCN pacemaker as an entraining signal but does potently perturb the circadian system.     

Double-stranded RNA-mediated suppression of Period2 expression in the suprachiasmatic nucleus disrupts circadian locomotor activity in rats

Circadian behavioral rhythms in mammals are controlled by a central clock located in the suprachiasmatic nucleus (SCN). PER2, the protein product of the clock gene, Period 2 (Per2), is expressed rhythmically in the SCN [Beaule C, Houle LM, Amir S (2003) Expression profiles of PER2 immunoreactivity within the shell and core regions of the rat suprachiasmatic nucleus: Lack of effect of photic entrainment and disruption by constant light. J Mol Neurosci 21:133-148] and has been implicated in the control of circadian behavioral rhythms based on the evidence that genetic mutations in Per2 abolish free running locomotor activity rhythms in mice [Zheng B, Larkin DW, Albrecht U, Sun ZS, Sage M, Eichele G, Lee CC, Bradley A (1999) The mPer2 gene encodes a functional component of the mammalian circadian clock. Nature 400:169-173; Bae K, Jin X, Maywood ES, Hastings MH, Reppert SM, Weaver DR (2001) Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron 30:525-536]. Such mutations eradicate PER2 expression in the SCN and disrupt the SCN molecular clockwork, however, they also affect PER2 in the rest of the brain and body leaving open the possibility that the changes in behavioral rhythms might be influenced, at least in part, by disruptions in PER2 functioning outside the SCN. We used RNA interference-mediated transient knockdown of Per2 to study the effect of selective suppression of PER2 expression in the SCN, per se, on behavioral circadian rhythms. We found that transient suppression of PER2 in the SCN disrupted free running locomotor activity rhythms for up to 10 days in rats. Infusions of control dsRNA into the SCN or infusions of dsRNA to Per2 immediately dorsal to the SCN had no effect. These results constitute evidence for a direct link between PER2 expression in the SCN and the expression of behavioral circadian rhythms in mammals.     

Maternal and sex-related influences on locomotor activity in rats following weaning

The effect of the presence of the mother beyond the normal time of weaning on the locomotor activity of litters is evaluated in the present work. Weaned rats, either females or males, showed a significantly higher activity in the open-field arena than the non-weaned ones. A sex-related difference was also detected. Weaned and nonweaned females showed higher activity than the weaned and nonweaned males, respectively. The androgen-induced lowering of female activity is affected by the presence of the mother. This is substained by the fact that weaned androgenized females exhibited higher levels of activity than nonweaned androgenized females. Our observations suggest that the presence of the mother after the normal time of weaning disturbs the emotional maturation of litters.     

The role of inducible nitric oxide synthase in cocaine-induced locomotor sensitization.

Experimentally naive male Sprague-Dawley rats (weighing 85-110 g) were used to examine the role of inducible nitric oxide synthase (iNOS) in cocaine-induced locomotor sensitization. Repeated administration of cocaine (15 mg/kg, ip) for 7 consecutive days produced locomotor sensitization. Pretreatment with iNOS inhibitors, L-N(6)-(1-iminoethyl) lysine (NIL) or (-)-epigallocatechin gallate (EGCG; 10 mg/kg, ip), 30 min before cocaine (15 mg/kg, ip) administration totally blocked the development of cocaine-induced locomotor sensitization. Dopamine (DA) receptor binding in the nucleus accumbens (NAC) showed a significant decrease in the density of D(2) receptor and the affinity of D(1) receptor after cocaine treatment. Pretreatment with EGCG or NIL abolished the cocaine-induced changes in these parameters. These results suggest that iNOS may participate in the process of development of locomotor sensitization through the modulation of DA receptors in the NAC.     

Sex differences in locomotor activity following beta-endorphin in the ventrolateral periaqueductal gray

Both morphine and selective opioid receptor agonists produce typical biphasic effects upon activity in male rats with initial reductions in activity followed by subsequent increases in activity. Sex differences have been observed in a number of opioid-mediated responses, including the observation that microinjection of the opioid peptide, beta-endorphin into the ventrolateral periaqueductal gray (vlPAG) produces more pronounced analgesia in male rats relative to female rats. The present study evaluated whether beta-endorphin (5.2-26 microg) in the vlPAG produced biphasic activity effects in male and female rats. Both male and female rats displayed initial reductions in total, ambulatory, and stereotypic activity following beta-endorphin in the vlPAG. Whereas male rats displayed subsequent (90-120 min) increases in total and ambulatory activity following beta-endorphin in the vlpAG, female rats tested during the estrous stage of their estrous cycle failed to display any changes. These sex differences in the opioid modulation in the pattern of activity measures in the vlPAG are discussed in terms of the roles of sex hormones in opioid peptide processing within the vlPAG.     

Specificity in the reactivation of infant memory

In three experiments the specificity of an effective reactivation stimulus, or reminder, was examined. Two weeks after learning to produce movement in a crib mobile by footkicking, 3-month-old human infants showed no retention of the response-reinforcer contingency. A reactivation procedure 24 hours prior to the long-term retention test was effective if the reminder was a brief noncontingent exposure to the original 5-component training mobile or a mobile containing one novel substitution. When more than one novel component were substituted into the original mobile, the reminder was ineffective. This was predicted by the discrimination function 24 hours following training. A reminder containing only a single familiar (predictive) component and four novel ones was also moderately effective. In subsequent studies, we explored different interpretations of the reminder specificity effect. We hypothesize that reminder specificity is of particular adaptive value for developing organisms in providing a buffer against memory retrieval in inappropriate contexts.     

N-methyl-D-aspartate and dopamine receptor involvement in the modulation of locomotor activity and memory processes

In this study we report on the effects of N-methyl-d-aspartate (NMDA)- and dopamine (DA)-receptor manipulation on the modulation of one-trial inhibitory avoidance response and the encoding of spatial information, as assessed with a non-associative task. Further, a comparison with the well-known effects of the manipulation of these two receptor systems on locomotor activity is outlined. It is well assessed that NMDA-receptor blockage induces a stimulatory action on locomotor activity similar to that exerted by DA agonists. There is evidence showing that the nucleus accumbens is involved in the response induced by both NMDA antagonists and DA agonists. We show results indicating a functional interaction between these two neural systems in modulating locomotor activity, with D2 DA-receptor antagonists (sulpiride and haloperidol) being more effective than the D1 antagonist (SCH 23390) in blocking MK-801-induced locomotion. A different profile is shown in the effects of NMDA antagonists and DA agonists in the modulation of memory processes. In one-trial inhibitory avoidance response, NMDA antagonists (MK-801 and CPP) impair the response on test day, while DA agonists exert a facilitatory effect; furthermore, sub-effective doses of both D1 (SKF 23390) and D2 (quinpirole) are able to attenuate the impairing effect in a way similar to that induced by NMDA antagonists. The effects of NMDA- and DA-acting drugs on the response to spatial novelty, as assessed with a task designed to study the ability of animals to react to discrete spatial changes, are in good accord with the effects observed on passive avoidance. The results show that NMDA as well as DA antagonists, at low doses, selectively impair the reactivity of mice to spatial changes. In a last series of experiments, the possible role of NMDA receptors located in the nucleus accumbens was investigated regarding reactivity to spatial novelty. The experiments gave apparently contrasting results: while showing an impairing effect of focal administrations of NMDA antagonists in the nucleus accumbens on reactivity to spatial novelty, no effect of ibotenic acid lesions of the same structure was observed.     

Inhibition of adult hippocampal neurogenesis disrupts contextual learning but spares spatial working memory,long-term conditional rule retention and spatial reversal

Neurogenesis in the adult dentate gyrus (DG) of the hippocampus has been implicated in neural plasticity and cognition but the specific functions contributed by adult-born neurons remain controversial. Here, we have explored the relationship between adult hippocampal neurogenesis and memory function using tasks which specifically require the participation of the DG. In two separate experiments several groups of rats were exposed to fractionated ionizing radiation (two sessions of 7 Gy each on consecutive days) applied either to the whole brain or focally, aiming at a region overlying the hippocampus. The immunocytochemical assays showed that the radiation significantly reduced the expression of doublecortin (DCX), a marker for immature neurons, in the dorsal DG. Ultrastructural examination of the DG region revealed disruption of progenitor cell niches several weeks after the radiation. In the first experiment, whole-brain and focal irradiation reduced DCX expression by 68% and 43%, respectively. Whole-brain and focally-irradiated rats were unimpaired compared with control rats in a matching-to-place (MTP) working memory task performed in the T-maze and in the long-term retention of the no-alternation rule. In the second experiment, focal irradiation reduced DCX expression by 36% but did not impair performance on (1) a standard non-matching-to-place (NMTP) task, (2) a more demanding NMTP task with increasingly longer within-trial delays, (3) a long-term retention test of the alternation rule and (4) a spatial reversal task. However, rats irradiated focally showed clear deficits in a “purely” contextual fear-conditioning task at short and long retention intervals. These data demonstrate that reduced adult hippocampal neurogenesis produces marked deficits in the rapid acquisition of emotionally relevant contextual information but spares spatial working memory function, the long-term retention of acquired spatial rules and the ability to flexibly modify learned spatial strategies.     

Deletion of the N-terminus of murine map2 by gene targeting disrupts hippocampal ca1 neuron architecture and alters contextual memory

Microtubule-associated protein-2 (MAP2) is a brain specific A-kinase anchoring protein that targets the cyclic AMP-dependent protein kinase holoenzyme (PKA) to microtubules. Phosphorylation of MAP2 by different protein kinases is crucial for neuronal growth. The N-terminus of MAP2 contains the binding site for regulatory subunit II of cAMP-dependent protein kinase (PKA-RIIbeta). Using homologous recombination, we created a mutant line of mice (delta1-158) that express truncated MAP2 lacking the N-terminal peptide and the PKA binding site. Deletion of the PKA binding site from the MAP2 gene resulted in decreased efficiency of MAP2 phosphorylation. Biochemical and immunohistochemical studies demonstrate major changes in the morphology of hippocampal neurons in delta1-158 mice. Behavioral tests indicate that delta1-158 mice were impaired (exhibited less conditioned freezing) relative to Wild-Type (WT) controls during a test of contextual, but not during auditory cue, fear conditioning when tested at 8 weeks or 8 months of age. The delta1-158 mice displayed a heightened sensitivity to shock at 8 weeks, but not at 8 months of age. We conclude that PKA binding to MAP2 and MAP2 phosphorylation is essential for the selective development of contextual memory.     

Nicotine enhances contextual fear memory reconsolidation in rats

There is increasing evidence that nicotine is involved in learning and memory. However, there remains no study that has explored the relationship between nicotine and memory reconsolidation. At present study, we tested the effects of nicotine on the reconsolidation of contextual fear memory in rats. Behavior procedure involved four training phases: habituation (Day 0), fear conditioning (Day 1), reactivation (Day 2) and test (Day 3). Rats were injected saline or nicotine (0.25, 0.5 and 1.0mg/kg) immediately after reactivation. Percent of time spent freezing was used to measure conditioned fear response. Results showed that compared with saline rats, rats with nicotine at 1.0mg/kg presented a significant increase of freezing response on Day 3. Nicotine at 1.0mg/kg was ineffective when injected 6h after reactivation. Further results showed that the enhancement of freezing response induced by nicotine at 1.0mg/kg was dependent on fear memory reconsolidation, and was not attributed to an enhancement of the nonspecific freezing response 24h after nicotine administration. The results suggest that nicotine administration immediately after reactivation enhances contextual fear memory reconsolidation. Our present finding extends previous research on the nicotinic effects on learning and memory.     

Potentiation of amphetamine-induced locomotor activity following NMDA-induced retrohippocampal neuronal loss in the rat

The present experiment assessed the locomotor response to a low dose (1 mg/kg) of systemic gemd-amphetamine in rats with cytotoxic lesions of the retrohippocampus (entorhinal and extra-subicular cortices), compared with vehicle-operated shams and unoperated controls. Under spontaneous and saline conditions, both the sham and the lesioned animals were more active than unoperated controls, and they did not differ from each other. Systemic gemd-amphetamine produced increased locomotion in all groups, but this effect was potentiated in animals with retrohippocampal lesions; two control groups did not differ from each other in their response to the drug. The present results are consistent with the suggestion that cell loss within the retrohippocampal region could affect the functional response of nucleus accumbens to amphetamine. The results are discussed in terms of the interaction between the retrohippocampus and nucleus accumbens in the control of mesolimbic dopamine release and the possible implications for schizophrenia.