Cyclophosphamide impairs hippocampus-dependent learning and memory in adult mice: Possible involvement of hippocampal neurogenesis in chemotherapy-induced memory deficits

Cyclophosphamide (CYP) is an anti-neoplastic agent as well as an immunosuppressive agent. In order to elucidate the alteration in adult hippocampal function following acute CYP treatment, hippocampus-related behavioral dysfunction and changes in adult hippocampal neurogenesis in CYP-treated (intraperitoneally, 40 mg/kg) mice (8–10-week-old ICR) were analyzed using hippocampus-dependent learning and memory tasks (passive avoidance and object recognition memory test) and immunohistochemical markers of neurogenesis (Ki-67 and doublecortin (DCX)). Compared to the vehicle-treated controls, mice trained at 12 h after CYP injection showed significant memory deficits in passive avoidance and the object recognition memory test. The number of Ki-67- and DCX-positive cells began to decrease significantly at 12 h post-injection, reaching the lowest level at 24 h after CYP injection; however, this reverted gradually to the vehicle-treated control level between 2 and 10 days. We suggest that the administration of a chemotherapeutic agent in adult mice interrupts hippocampal functions, including learning and memory, possibly through the suppression of hippocampal neurogenesis.     

Memory for reward location is enhanced even though acetylcholine efflux within the amygdala is impaired in rats with damage to the diencephalon produced by thiamine deficiency

Sleep facilitates declarative memory processing. However, we know little about whether sleep plays a role in the processing of a fundamental feature of declarative memory, relational memory – the flexible representation of items not directly learned prior to sleep. Thirty-one healthy participants first learned at 12 pm two sets of face–object photograph pairs (direct associative memory), in which the objects in each pair were common to both lists, but paired with two different faces. Participants either were given approximately 90 min to have a NREM-only daytime nap (n = 14) or an equivalent waking period (n = 17). At 4:30 pm, participants who napped demonstrated significantly better retention of direct associative memory, as well as better performance on a surprise task assessing their relational memory, in which participants had to associate the two faces previously paired with the same object during learning. Particularly noteworthy, relational memory performance was correlated with the amount of NREM sleep during the nap, with only slow-wave sleep predicting relational memory performance. Sleep stage data did not correlate with direct associative memory retention. These results suggest an active role for sleep in facilitating multiple processes that are not limited to the mere strengthening of rote memories, but also the binding of items that were not directly learned together, reorganizing them for flexible use at a later time.     

Blockade of nucleus basalis magnocellularis or activation of insular cortex histamine receptors disrupts formation but not retrieval of aversive taste memory

Recent research, using several experimental models, demonstrated that the histaminergic system is clearly involved in memory formation. This evidence suggested that during different associative learning tasks, histamine receptor subtypes have opposite functions, related to the regulation of cortical cholinergic activity. Given that cortical cholinergic activity and nucleus basalis magnocellularis (NBM) integrity are needed during taste memory formation, the aim of this study was to determine the role of histamine receptors during conditioned taste aversion (CTA). We evaluated the effects of bilateral infusions of 0.5 μl of pyrilamine (100 mM), an H₁ receptor antagonist, into the NBM, or of R-α-methylhistamine (RAMH) (10 mM), an H₃ receptor agonist, into the insular cortex of male Sprague-Dawley rats 20 min before acquisition and/or retrieval of conditioned taste aversion. The results showed that blockade of H₁ receptors in NBM or activation of H₃ receptors in the insular cortex impairs formation but not retrieval of aversive taste memory. These results demonstrated differential roles for histamine receptors in two important areas for taste memory formation and suggest that these effects could be related with the cortical cholinergic activity modulation during CTA acquisition.     

SLV330, a cannabinoid CB1 receptor antagonist,ameliorates deficits in the T-maze,object recognition and Social Recognition Tasks in rodents

Cannabinoid CB₁ receptor (CB₁R) signaling has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the CB₁R antagonist SLV330 (doses ranging from 0.3 to 10 mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of SLV330 were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept®, approved for symptomatic treatment of Alzheimer’s disease) and nicotine were used as reference compounds.SLV330 markedly improved aging and scopolamine-induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1 mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl-d-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3 mg/kg. In the ORT, we have found that combined administration of subthreshold doses of SLV330 (1 mg/kg, p.o.) and the AChEI donepezil (0.1 mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of SLV330 and donepezil on cognitive impairment. Finally, SLV330 was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3 mg/kg (p.o.).In conclusion, the CB₁R antagonist SLV330 was found to clearly improve memory in several preclinical models for cognitive impairment.     

Muscimol,AP5, or scopolamine infused into perirhinal cortex impairs two-choice visual discrimination learning in rats

The perirhinal cortex (PRh) has been strongly implicated in object recognition memory and visual stimulus representation. Studies of object recognition have revealed evidence for the involvement of several neurotransmitter subsystems, including those involving NMDA (N-methyl-d-aspartic acid) and muscarinic cholinergic receptors. In the present study, we assessed the possible involvement of PRh and related receptor subsystems in two-choice visual discrimination learning by Lister Hooded rats tested in touchscreen-equipped operant boxes. In Experiment 1, daily pre-training inactivation of PRh with the GABA_A receptor agonist muscimol (0.5 μg/hemisphere) significantly impaired acquisition of the two-choice visual discrimination. In Experiment 2, daily pre-training blockade of either NMDA or muscarinic receptors in PRh with AP5 (5.9 μg/hemisphere) or scopolamine (10 μg/hemisphere), respectively, impaired task acquisition. These results parallel the findings from object recognition studies and suggest a generality of neurotransmitter receptor involvement underlying the role of PRh in both object recognition memory and visual discrimination learning. The involvement of PRh in both types of tasks may be related to its role in complex visual stimulus representation.     

Memantine ameliorates scopolamine-induced amnesia in chicks trained on taste-avoidance learning

In day-old chicks trained on the one-trial taste-avoidance task, activation of NMDA receptors by glutamate is particularly important in the initial stages of memory consolidation. In addition, acetylcholine receptor activation has been shown to be a necessary component of memory formation for this task because injection of scopolamine produces amnesia. Memantine, a non-competitive NMDA receptor antagonist, improves memory formation under certain impairing circumstances, despite inhibiting the activation of NMDA receptors. The present experiments tested the hypothesis that memantine can ameliorate scopolamine-induced amnesia in day-old chicks (Gallus gallus domesticus) trained on the one-trial taste-avoidance task. Three experiments assessed the effects of scopolamine, memantine, and glutamate in this task. The results of Experiment 1 demonstrated that 50.0 mM scopolamine produces significant amnesia. In Experiment 2, 1.0 mM memantine reversed the scopolamine-induced amnesia, while other doses were ineffective. In Experiment 3, injection of 50.0 mM glutamate in combination with scopolamine reversed the memantine amelioration. These results indicate a relationship between glutamate and acetylcholine in memory formation in the day-old chick.     

Effects of acute stress and GluN2B-containing NMDA receptor antagonism on object and object–place recognition memory

The mechanisms underlying the complex effects of acute stress on memory are incompletely understood. Previous work suggests that the activation of N-methyl-d-aspartate (NMDA) receptors specifically containing GluN2B subunits may underlie the disruptions in spatial memory retrieval caused by acute stress (Wong et al., 2007 PNAS 104:11471). The present experiments were designed to assess whether a similar mechanism is involved in recognition memory. Recognition memory retrieval was assessed in Sprague–Dawley rats using an object recognition test and an object–place recognition test, both of which rely on patterns of spontaneous exploration. Exposure to acute stress for 30 min immediately before the test phase of either test disrupted memory retrieval. Administration of the GluN2B-selective antagonist Ro25-6981 (6 mg/kg; i.p.) enhanced memory in the object recognition test regardless of whether animals were exposed to acute stress. In the object–place test, Ro25-6981 had no effect on memory retrieval in the absence of stress but promoted memory following acute stress. These data highlight the specific contributions made by GluN2B-containing NMDA receptors to recognition memory for different types of stimuli.     

Self-body recognition depends on implicit and explicit self-esteem

The present contribution bridges research on body image, self-esteem, and body recognition. Recent work in neuroscience indicates a superiority in the processing of self relative to others’ body parts. The present contribution shows that this ability is not universal but it is qualified by individual differences in implicit and explicit self-esteem. In fact, two studies (n₁ = 41 and n₂ = 35) using two different paradigms in body recognition and direct and indirect measures of self-esteem reveal that this advantage in recognizing one's own body parts is associated with one's level of self-esteem. Moreover, it appears that measures of implicit and explicit self-esteem provide different contributions to self-body recognition abilities and that these contributions depend on how self-body recognition is assessed. Implications of these results are discussed notably in the perspective of research on body image.     

Block of glucocorticoid synthesis during re-activation inhibits extinction of an established fear memory

BackgroundThe pharmacology of traumatic memory extinction has not been fully characterized despite its potential as a therapeutic target for established, acquired anxiety disorders, including post-traumatic stress disorder (PTSD). Here we examine the role of endogenous glucocorticoids in traumatic memory extinction.MethodsMale C57BL/6J mice were injected with corticosterone (10 mg/kg, i.p.) or metyrapone (50 mg/kg, s.c.) during re-activation of a contextual fear memory, and compared to vehicle groups (N = 10–12 per group). To ensure that metyrapone was blocking corticosterone synthesis, we measured corticosterone levels following re-activation of a fear memory in metyrapone- and vehicle-treated animals.ResultsCorticosterone administration following extinction trials caused a long-lasting inhibition of the original fear memory trace. In contrast, blockade of corticosteroid synthesis with metyrapone prior to extinction trials enhanced retrieval and prevented extinction of context-dependent fear responses in mice. Further behavioral analysis suggested that the metyrapone enhancement of retrieval and prevention of extinction were not due to non-specific alterations in locomotor or anxiety-like behavior. In addition, the inhibition of extinction by metyrapone was rescued by exogenous administration of corticosterone following extinction trials. Finally, we confirmed that the rise in corticosterone during re-activation of a contextual fear memory was blocked by metyrapone.ConclusionsWe demonstrate that extinction of a classical contextual fear memory is dependent on endogenous glucocorticoid synthesis during re-activation of a fear memory. Our data suggest that decreased glucocorticoids during fear memory re-activation may contribute to the inability to extinguish a fear memory, thus contributing to one of the core symptoms of PTSD.     

Vasopressin/oxytocin-related peptides influence long-term memory of a passive avoidance task in the cuttlefish,Sepia officinalis

The vasopressin (VP)/oxytocin (OT)-related peptides constitute a large superfamily found in a wide range of both vertebrate and invertebrate species. While intensive literature reports that these neuropeptides influence behavior, especially learning and memory, in numerous species from diverse vertebrate groups, their roles in behavioral regulation have never been studied in invertebrates. Here, we investigated the role of two VP/OT superfamily peptides, octopressin (OP) and cephalotocin (CT), on long-term memory (LTM) formation of a passive avoidance task in a cephalopod mollusc, the cuttlefish, Sepia officinalis. Subadult cuttlefish were intravenously injected, in a dose range of 3–60 μg/kg, 1 h after the training phase (consolidation design); retention performance was tested 24 h post-training. We found that administration of OP at low dose (3 μg/kg) enhanced LTM, whereas a dose of 60 μg/kg attenuated it. No effect of OP on LTM was observed for the 15 μg/kg dose. Conversely, an enhancement of retention performance was observed at all doses of CT tested. This study is the first to demonstrate the behavioral effects of VP/OT superfamily peptides in an invertebrate species. The valuable role of VP/OT-like peptides on memory processes offers new evolutionary perspectives on peptidergic transmission and neuromodulation.     

Involvement of dorsal hippocampal α-adrenergic receptors in the effect of scopolamine on memory retrieval in inhibitory avoidance task

The present study evaluated the possible role of α-adrenergic receptors of the dorsal hippocampus on scopolamine-induced amnesia and scopolamine state-dependent memory in adult male Wistar rats. The animals were bilaterally implanted with chronic cannulae in the CA1 regions of the dorsal hippocampus, trained in a step-through type inhibitory avoidance task, and tested 24 h after training to measure step-through latency. Results indicate that post-training or pre-test intra-CA1 administration of scopolamine (1 and 2 μg/rat) dose-dependently reduced the step-through latency, showing an amnestic response. Amnesia produced by post-training scopolamine (2 μg/rat) was reversed by pre-test administration of the scopolamine that is due to a state-dependent effect. Interestingly, pre-test intra-CA1 microinjection of α1-adrenergic agonist, phenylephrine (1 and 2 μg/rat) or α2-adrenergic agonist, clonidine improved post-training scopolamine (2 μg/rat)-induced retrieval impairment. Furthermore, pre-test intra-CA1 microinjection of phenylephrine (0.25, 0.5 and 1 μg/rat) or clonidine (0.25, 0.5 and 1 μg/rat) with an ineffective dose of scopolamine (0.25 μg/rat), synergistically improved memory performance impaired by post-training scopolamine. On the other hand, pre-test injection of α1-receptors antagonist prazosin (1 and 2 μg/rat) or α2-receptors antagonist yohimbine (1 and 2 μg/rat) prevented the restoration of memory by pre-test scopolamine. It is important to note that pre-test intra-CA1 administration of the same doses of prazosin or yohimbine, alone did not affect memory retrieval. These results suggest that α1- and α2-adrenergic receptors of the dorsal hippocampal CA1 regions may play an important role in scopolamine-induced amnesia and scopolamine state-dependent memory.     

NK(3) receptor agonism promotes episodic-like memory in mice

The mammalian tachykinins are a family of closely related peptides including substance P, neurokinin A, neurokinin B and, recently, also hemokinin-1. They are present in the peripheral and central nervous systems, and bind to three known neurokinin (NK) receptors, the NK(1)-, NK(2)- and NK(3) receptors. In both rodents and humans, NK(3) receptors are expressed in brain structures which have been associated with learning and memory. Evidence for a role of NK(3) receptors in learning and memory has been found in NK(3) receptor knockout mice. Here, we investigated the influence of the NK(3) receptor agonist, senktide (0.1, 0.2 and 0.4 mg/kg), on the performance of C57BL/6 mice in a recently developed episodic-like memory task. Since a promnestic effect of senktide was expected, we employed an experimental protocol that provided sub-optimal learning conditions for episodic-like memory. The results indicate that senktide promotes episodic-like memory in mice in a dose-dependent manner, providing, for the first time, evidence for an involvement of NK(3) receptors in episodic-like memory.     

Cognitive aspects of congenital learned helplessness and its reversal by the monoamine oxidase (MAO)-B inhibitor deprenyl

Cognitive processes are assumed to change with learned helplessness, an animal model of depression, but little is known about such deficits. Here we investigated the role of cognitive and related functions in selectively bred helpless (cLH, n = 10), non-helpless (cNLH, n = 12) and wild type (WT, n = 8) Sprague Dawley rats. The animals were exposed to an open field for 10 min on each of two test days. On the third day, an object exploration paradigm was carried out. The animals were later tested for helplessness. Both cLH and cNLH rats were more active than WTs on the first day in the open field. Over trials, cNLH and WT rats lowered their activity less than cLH rats. This resistance-to-habituation co-varied with a resistance to develop helplessness. In cLH rats, higher ‘anxiety’ or less time spent in the center of the open field co-varied with severe helplessness. In WTs, a greater reactivity to novel objects and to a spatially relocated object predicted lower levels of helplessness. In cLH rats (n = 4–5 per group), chronic treatment with a high dose of the monoamine oxidase (MAO)-B inhibitor deprenyl (10 mg/kg; i.p.), an anti-Parkinson, nootropic and antidepressant drug, attenuated helplessness. Remarkably, helplessness reversal required the experience of repeated test trials, reminiscent of a learning process. Chronic deprenyl (10 mg/kg; i.p.) did not alter locomotion/exploration or ‘anxiety’ in the open field. In conclusion, helplessness may be related to altered mechanisms of reinforcement learning and working memory, and to abnormalities in MAO-A and/or MAO-B functioning.     

Rugby versus Soccer in South Africa: Content familiarity contributes to cross-cultural differences in cognitive test scores

In this study, cross-cultural differences in cognitive test scores are hypothesized to depend on a test's cultural complexity (Cultural Complexity Hypothesis: CCH), here conceptualized as its content familiarity, rather than on its cognitive complexity (Spearman's Hypothesis: SH). The content familiarity of tests assessing short-term memory, attention, working memory, and figural and verbal fluid reasoning, was manipulated by constructing test versions with an item content derived from either Afrikaans or Tswana culture in South Africa. Both test versions were administered to children of both cultures. The sample consisted of 161 urban Afrikaans, 181 urban, and 159 rural Tswana children (M_age = 9.37 years). Children generally performed best on the test version that was designed for their own group, particularly on the cognitively and culturally complex working memory and figural fluid reasoning tests. This relation between content familiarity and cognitive test performance supports CCH and disconfirms SH.     

Origins of adolescents’ autobiographical memories

Adolescents (N = 46; M = 12.46 years) who had previously participated in a longitudinal study of autobiographical memory development narrated their early childhood memories, interpreted life events, and completed a family history questionnaire and language assessment. Three distinct components of adolescent memory emerged: (1) age of earliest memory and insight into life events; (2) volume of early memories; and (3) density of specific memories from early childhood. Children's language, self-awareness, and theory of mind during early childhood (19–51 months) all contributed to their memories as adolescents. However, adolescents’ early reminiscing environment was the best single predictor of the age and volume of their early memories and their insight into life events. In contrast, adolescents’ delayed self-recognition and reminiscing in early childhood predicted the density of their early memories. These findings provide partial support for theories of autobiographical memory development.     

Time-course of 5-HT6 receptor mRNA expression during memory consolidation and amnesia

Growing evidence indicates that antagonists of the 5-hydroxytryptamine (serotonin) receptor₆ (5-HT₆) improve memory and reverse amnesia although the mechanisms involved are poorly understood. Hence, in this paper RT-PCR was used to evaluate changes in mRNA expression of 5-HT₆ receptor in trained and untrained rats treated with the 5-HT₆ receptor antagonist SB-399885 and amnesic drugs scopolamine or dizocilpine. Changes in mRNA expression of 5-HT₆ receptor were investigated at different times in prefrontal cortex, hippocampus and striatum. Data indicated that memory in the Pavlovian/instrumental autoshaping task was a progressive process associated to reduced mRNA expression of 5-HT₆ receptor in the three structures examined. SB-399885 improved long-term memory at 48 h, while the muscarinic receptor antagonist scopolamine or the non-competitive NMDA receptor antagonist dizocilpine impaired it at 24 h. Autoshaping training and treatment with SB-399885 increased 5-HT₆ receptor mRNA expression in (maximum increase) prefrontal cortex and striatum, 24 or 48 h. The scopolamine-induced amnesia suppressed 5-HT₆ receptor mRNA expression while the dizocilpine-induced amnesia did not modify 5-HT₆ receptor mRNA expression. SB-399885 and scopolamine or dizocilpine were able to reestablish memory and 5-HT₆ receptor mRNA expression. These data confirmed previous memory evidence and of more interest is the observation that training, SB-399885 and amnesic drugs modulated 5-HT₆ receptor mRNA expression in prefrontal cortex, hippocampus and striatum. Further investigation in different memory tasks, times and amnesia models together with more complex control groups might provide further clues.     

Posttraining infusion of cholinergic drugs into the ventral subiculum modulated memory in an inhibitory avoidance task: Interaction with the bed nucleus of the stria terminalis

The ventral subiculum (vSUB), a hippocampal efferent target implicated in learning and stress coping, receives cholinergic input and sends glutamatergic output to the bed nucleus of the stria terminalis (BNST). This study examined the roles of vSUB muscarinic activation and its interaction with BNST N-methyl-d-aspartate and noradrenergic receptors in formation of aversive memory. Male Wistar rats with cannulae implanted into the vSUB or BNST were trained on a step-through inhibitory avoidance task. Shortly after training, they received cholinergic drugs infused into the vSUB and/or glutamatergic or noradrenergic drugs infused into the BNST. Results of the 1-day retention tests showed that intra-vSUB infusion of oxotremorine (0.01 μg) or scopolamine (0.3 or 3.0 μg) enhanced or impaired retention, respectively. Both effects were dose- and time-dependent, and 0.001 μg oxotremorine attenuated the amnesia induced by 3.0 μg scopolamine. The oxotremorine-induced memory enhancement was blocked by intra-BNST infusion of dl-2-amino-5-phosphonovaleric acid or propranolol at a dose not affecting retention; the amnesia induced by scopolamine was blunted by intra-BNST infusion of glutamate or norepinephrine at a dose with a negligible effect on retention. These data suggest that in an inhibitory avoidance task muscarinic activation of the vSUB modulated memory formation by interacting with the BNST glutamatergic and noradrenergic functions.     

The role of working memory and visual processing in prototype category learning

To investigate whether working memory and visual processing have the same role or different roles in A/B and A/not A prototype category learning, the present study adopted an A/B or A/not A category learning task in control and dual conditions. The results of Experiment 1 showed that an additional dual visual working memory task rather than a dual verbal working memory task reduced accuracy of the A/B task, whereas no dual tasks influenced accuracy of the A/not A task. The results of Experiment 2 revealed that an additional dual visual processing task impaired accuracy of the A/B task, whereas the dual visual processing task did not influence accuracy of the A/not A task. These results indicate that visual working memory and visual processing play different roles in A/B and A/not A prototype category learning, and support that these two types of prototype category learning are mediated by different memory systems.     

Negative emotion elicited in high school students enhances consolidation of item memory,but not source memory

The study examined the effect of negative emotion on consolidation of both item and source memory. Participants learned words read by either a male or female. Then they watched either a negative or a neutral video clip. Memory tests were carried out either 25 min or 24 h after learning. The study yielded the following findings. First, negative emotion enhanced consolidation of item memory as measured by recognition memory in the 25-min delay, and enhanced consolidation of item memory as measured by free recall in both the 25-min and the 24-h delay. Second, negative emotion had little effect on consolidation of source memory, either in the 25-min or the 24-h delay. These findings provide evidence for the differential effects of negative emotion on item memory and source memory and have implications for using emotion as a strategy to intervene memory consolidation.