The acetylcholinesterase reversible inhibitor N-octyl-1,2,3, 4-tetrahydro-9-aminoacridine (THA-C8) is a new synthesized derivative of tacrine (THA) characterized by an alkyl chain in the molecular structure which ameliorates the penetrability of the compound into the central nervous system. THA-C8 (0.1-5 mg/kg) significantly reduced spontaneous locomotor activity in CD1 mice at a dose of 3 mg/kg. Moreover, THA-C8 (0.2-2 mg/kg) significantly improved shuttle-box avoidance acquisition at doses (0.25, 0.3, 1 mg/kg) not affecting locomotion and that are much lower than the doses reported to be effective for THA in animal models. From the data reported it seems that the new compound could be interesting for therapeutic purposes.
Small G proteins including Rac are mediators of changes in neuronal morphology associated with synaptic plasticity. Previous studies in our laboratory showed that Rac is highly expressed in the adult mouse hippocampus, a brain area that exhibits robust synaptic plasticity and is crucial for the acquisition of memories. In this study, we investigated whether Rac was involved in NMDA receptor-dependent associative fear learning in the area CA1 of adult mouse hippocampus. We found that Rac translocation and activation was increased in the hippocampus following associative fear conditioning in mice, and that these increases are blocked by intraperitoneal injection of the NMDA receptor channel blocker MK801 at the acquisition stage. Our data indicate that NMDA receptor-dependent associative fear learning alters Rac localization and function in the mouse hippocampus.
Male Swiss mice were tested 24 h after training in a one-trial step-through inhibitory avoidance task. Low subeffective doses of d-(+)-glucose (10 mg/kg, ip), but not its stereoisomer l-(-)-glucose (30 mg/kg,ip), administered immediately after training, and AF-DX 116 (0.3 mg/kg,ip), a presynaptic muscarinic receptor antagonist, given 10 min after training, interact to improve retention. Insulin (8 IU/kg, ip) impaired retention when injected immediately after training, and the effects were reversed, in a dose-related manner, by AF-DX 116 (0.3, 1.0, or 3.0 mg/kg, ip) administered 10 min following insulin. Since AF-DX 116 possibly blocks autoreceptors mediating the inhibition of acetylcholine release from cholinergic nerve terminals, the present data support the view that changes in the central nervous system glucose availability, subsequent to modification of circulating glucose levels, influence the activity of central cholinergic mechanisms involved in memory storage of an inhibitory avoidance response in mice.
High synaptic concentrations of dopamine and/or norepinephrine can impair the working memory function of the prefrontal cortex and impede attention and learning. Methylphenidate, a dopamine and norepinephrine transporter blocker known to facilitate these cognitive processes at low doses, was hypothesized to interfere with memory storage at doses that may raise concentrations of these neurotransmitters to systemically disruptive levels. In the present experiments, a dose of 10.0mg/kg of this drug was administered to female and male Long-Evans rats using a novel oral administration procedure designed to model the normal mode of delivery to humans. It was found to interfere with single-trial memory acquisition in a delayed object recognition test, a spontaneous learning task that involves no appetitive or aversive motivator. The time that the rats spent in overt exploration of the to-be-remembered objects during the acquisition trial was not affected, suggesting that the drug may have impaired processes of memory formation independently of interference with attention.
In some situations, memory is enhanced by stressful experience, while in others, it is impaired. The specific components of the stress-response that may result in these differing effects remain unclear, and the current study sought to address this knowledge gap. Forty healthy participants (20 women, 20 men) were exposed to emotionally arousing and neutral pictures. Twenty-four hours later, 20 participants underwent a social stressor (speech and math tests), and 20 underwent a control reading task, both followed by a delayed free recall task. Cortisol responders to the stress condition (5 men and 1 woman) showed reduced memory retrieval for both neutral and emotionally arousing pictures. Men and women in the stress condition who did not produce a cortisol response showed increased retrieval of unpleasant pictures compared to controls. The results provide further evidence that cortisol is a primary effector in the stress-induced memory retrieval deficit. At the same time, stress can enhance memory retrieval performance, especially for emotional stimuli, when the cortisol response is absent.
Dehydroepiandrosterone sulfate (DHEAS), is an excitatory neurosteroid synthesized within the CNS that modulates brain function. Effects associated with augmented DHEAS include learning and memory enhancement. Inhibitors of the steroid sulfatase enzyme increase brain DHEAS levels and can also facilitate learning and memory. This study investigated the effect of steroid sulfatase inhibition on learning and memory in rats with selective cholinergic lesion of the septo-hippocampal tract using passive avoidance and delayed matching to position T-maze (DMP) paradigms. The selective cholinergic immunotoxin 192 IgG-saporin (SAP) was infused into the medial septum of animals and then tested using a step-through passive avoidance paradigm or DMP paradigm. Peripheral administration of the steroid sulfatase inhibitor, DU-14, increased step-through latency following footshock in rats with SAP lesion compared to both vehicle treated control and lesioned animals (p<0.05). However, in the DMP task, steroid sulfatase inhibition impaired acquisition in lesioned rats while having no effect on intact animals. These results suggest that steroid sulfatase inhibition facilitates memory associated with contextual fear, but impairs acquisition of spatial memory tasks in rats with selective lesion of the septo-hippocampal tract.
In the present research the interaction between the endogenous ligand for the cannabinoid CB1 receptor anandamide (arachidonylethanolamide) and morphine in memory consolidation was investigated. Four sets of experiments were carried out with CD1 mice tested in a one-trial inhibitory avoidance task. The drugs were administered intraperitoneally after training of the animals in the apparatus. In the first set of experiments morphine (0.3 or 0.5, but not 0.15mg/kg) or anandamide (3 or 6 but not 1.5mg/kg) dose-dependently impaired memory consolidation. In the second set of experiments the administration of an otherwise ineffective dose of anandamide (1.5mg/kg) enhanced the memory impairment exerted by morphine (0.3 and 0.5mg/kg) when the drugs were injected immediately after training. In the third set of experiments the combined treatments of anandamide (1.5mg/kg) and morphine (0.5mg/kg) 2h after training were ineffective showing that the effects observed on performance following immediate posttraining administration of anandamide and morphine combinations were reflecting direct influences on memory consolidation. In the fourth set of experiments otherwise ineffective doses of the D1 DA receptor agonist SKF 38393 or the D2 DA receptor agonist LY 171555 antagonized the memory impairment produced by anandamide and morphine in combination, suggesting a possible involvement of dopaminergic mechanisms.
The relationship between US (footshock) intensity and the two conditioned freezing responses (to acoustic CS and to "context") was investigated in fear conditioning. Administered footshock intensity was 0.00, 0.15, 0.30, 0.60, 0.90, and 1.20 mA to six different groups of 70-day-old male Albino Wistar rats. To measure contextual freezing, the animals were again placed inside the conditioning apparatus without acoustic CS and US presentation. To measure acoustic CS freezing, the animals were placed in a totally different apparatus and only the acoustic CS was presented. The 0.15 mA footshock intensity was not sufficient to condition the animals, in fact no freezing was exhibited as in the non-shocked control group. The 0.30 mA footshock intensity was sufficient only to condition the animals to the acoustic CS, whereas the 0.60 mA was sufficient to condition the animals both to acoustic CS and to context. Footshock intensities (0.90 and 1.20 mA) did not elicit any significant increase in conditioned freezing for either acoustic CS or context but at the highest one the generalization phenomenon appeared (freezing in the different context before presentation of acoustic CS). Acoustic CS freezing to all over-threshold intensities was longer than that to context. In conclusion, freezing responses to acoustic CS and context after increasing footshock intensities follow distinct patterns, and intermediate footshock intensities (0.60 and 0.90 mA) appear to be the most useful for eliciting conditioned freezing responses to acoustic CS and to context without inducing a generalized fear status contamination.
The Morris water maze task is a widely used tool to assess hippocampus-dependent learning and memory in rodents. Performance depends upon several factors including not only the traits of the experimental animals, but also apparatus and protocol characteristics. The present study aimed at investigating the effect of maze diameter on acquisition and probe trial performance in three commonly used strains: C57Bl/6, BALB/c, and 129/SvEvBrd mice. Three maze diameters (150, 120, and 75 cm) were used under identical protocol and testing conditions. Downscaling maze dimensions, hence reducing difficulty and stress levels, did not allow BALB/c mice, commonly known as poor learners, to acquire this visual-spatial learning task. C57Bl/6 mice performed satisfactory in all three maze settings, with superior probe trial performance in the 120-cm-diameter setting. Further downscaling of maze dimensions might even render this task too simple for this strain. If the 129S5/SvEvBrd background strain is preferred, testing of visual-spatial learning abilities should be performed in a small sized MWM pool, as this strain performed only adequately in the smallest maze setting. Attention is drawn to the importance of supplying a detailed description 129 substrain nomenclature in future studies. Generalization of observations from one strain to another and from data obtained with a specific strain and maze diameter to other maze dimensions should be dealt with very carefully. The present study emphasizes the importance of a well-substantiated choice of background strain and water maze characteristics when researchers plan to investigate visual-spatial learning and memory in a chemically/lesion-induced or targeted mutagenesis model.
Retrieving a consolidated memory--by exposing an animal to the learned stimulus but not to the associated reinforcement--leads to two opposing processes: one that weakens the old memory as a result of extinction learning, and another that strengthens the old, already-consolidated memory as a result of some less well-understood form of learning. This latter process of memory strengthening is often referred to as "reconsolidation", since protein synthesis can inhibit this form of memory formation. Although the behavioral phenomena of the two antagonizing forms of learning are well documented, the mechanisms behind the corresponding processes of memory formation are still quite controversial. Referring to results of extinction/reconsolidation experiments in honeybees, we argue that two opposing learning processes--with their respective consolidation phases and memories--are initiated by retrieval trials: extinction learning and reminder learning, the latter leading to the phenomenon of spontaneous recovery from extinction, a process that can be blocked with protein synthesis inhibition.
Rat fetuses proximal to birth process alcohol-derived cues when the drug is directly delivered into the amniotic fluid. Prior evidence indicates that chemosensory sensation is detected during gestational Day 17 (GD17). In the present study Wistar-derived pregnant females received 0, 1, or 2 g/kg/day of alcohol (intragastric intubation) during GDs 17-20. Prenatal treatment failed to affect different maternal-fetal and perinatal physical parameters, e.g., placenta weight, umbilical cord length, offspring's body weights, weights and/or size of the olfactory bulbs, cerebral hemispheres, and cerebellum. Alcohol chemosensory responsiveness assessed in a perinatal motor activity test, indicated that pups pretreated with the 1 and 2 g/kg alcohol dose exhibit significant decrements in their activity rate when alcohol odor is presented in the test chamber. Alcohol concentrations in maternal and fetal blood and in the amniotic fluid were also recorded through head-space chromatography 1 h after females received the last intubation procedure (GD20) with the 1 or 2 g/kg alcohol doses. Dose-dependent alcohol concentrations across the different sites of assessment were recorded. As indicated by previous studies, even the alcohol level in the amniotic fluid attained with the 1 g/kg alcohol dose is above threshold values in terms of allowing fetal chemosensory stimulation with alcohol-derived cues. The results suggest that maternal ethanol intoxication during the last days of pregnancy leads to fetal exposure to alcohol's sensory attributes and that this experience subsequently modifies responsiveness to these cues.
An understanding of synaptic plasticity in the mammalian brain has been one of R. F. Thompson's major pursuits throughout his illustrious career. A current series of experiments of significant interest to R. F. Thompson is an examination of the interactions between sex hormones, synaptic plasticity, aging, and stress. This research is contained within a broader project whose aim is to investigate animal models that evaluate estrogen interactions with Alzheimer's disease. This paper reviews the recent results that have led to a better understanding of how the sex hormone estrogen influences synaptic plasticity in an important structure within the mammalian brain responsible for learning and memory: the hippocampus. In this review, a number of experiments have been highlighted that investigate the molecular mechanisms that underlie estrogen's effect on two specific forms of synaptic plasticity commonly studied in neurophysiology and the behavioral neurosciences: long-term potentiation and long-term depression.
The present article examined the requirement of hippocampal c-Fos for learning a socially transmitted food preference (STFP). We reported previously that expression of the c-Fos protein is increased in the dorsal and ventral hippocampus of rats trained on the STFP (Countryman, Orlowski, Brightwell, Oskowitz, & Colombo, 2005). Pretraining intrahippocampal antisense to the immediate early gene c-fos was administered to adult male Long-Evans rats to determine if c-fos expression is necessary for either short- or long-term memory for STFP. Guide cannulae were implanted bilaterally into the dorsal hippocampus. Antisense oligodeoxynucleotides (ODNs) were administered unilaterally either 6.5, 8.5, 10.5, or 12.5 h prior to STFP training while either sense ODNs or saline were infused into the opposite hemisphere. Immunocytochemistry was performed, and cells showing c-Fos immunoreactivity (ir) were counted from the antisense-treated hemisphere and compared to cell counts from the control hemisphere. The results indicated significant suppression of learning-induced c-Fos protein at the 8.5 and 10.5 infusion-train intervals. Additional rats were implanted with cannulae into the dorsal and ventral hippocampus, and antisense ODNs, sense ODNs, or saline were administered bilaterally 8.5h prior to training. Rats were tested immediately and 14 days after training. Rats in all groups showed a significant preference for the demonstrated food at the short-term memory test. At the long-term memory test, however, rats infused with c-fos antisense showed no preference for the demonstrated food whereas rats infused with either sense or saline maintained their preference. The present findings suggest that c-fos is necessary for consolidation of non-spatial hippocampal-dependent memory.
The central cholinergic system and muscarinic cholinergic receptor (mR) activation have long been associated with cognitive function. Although mR activation is no doubt involved in many aspects of cognitive functioning, the extensive evidence that memory is influenced by cholinergic treatments given after training either systemically or intra-cranially clearly indicates that cholinergic activation via mRs is a critical component in modulation of memory consolidation. Furthermore, the evidence indicates that activation of mRs in the basolateral amygdala (BLA) plays an essential role in enabling other neuromodulatory influences on memory consolidation. Memory can also be affected by posttraining activation of mRs in the hippocampus, striatum and cortex. Evidence of increases in hippocampal and cortical acetylcholine (ACh) levels following learning experiences support the view that endogenous ACh release is involved in long-term memory consolidation. Furthermore, the findings indicating that mR drug treatments influence plasticity in the hippocampus and in sensory cortices strongly suggest that mR activation is involved in the storage of information in these brain regions.
Chronic stress and estrogens alter many forebrain regions in female rats that affect cognition. In order to investigate how chronic stress and estrogens influence fear learning and memory, we ovariectomized (OVX) female Sprague-Dawley rats and repeatedly injected them (s.c.) with 17β-estradiol (E, 10 μg/250 g or sesame oil vehicle, VEH). Concurrently, rats were restrained for 6 h/d/21 d (STR) or left undisturbed (CON). Rats were then fear conditioned with 4 tone-footshock pairings and then after 1 h and 24 h delays, given 15 tone extinction trials. Regardless of E treatment, chronic stress (VEH, E) facilitated freezing to tone during acquisition and extinction following a 1h delay, but not during extinction after a 24 h delay. E did not influence freezing to tone during any phase of fear conditioning for either the control or chronically stressed rats, but did influence contextual conditioning that may have been carried predominately by the STR group. In the second experiment, we investigated "handling" influences on fear conditioning acquisition, given the disparate findings from the current study and previous work (Baran, Armstrong, Niren, & Conrad, 2010; Baran, Armstrong, Niren, Hanna, & Conrad, 2009). Female rats remained gonadally-intact since E did not influence tone fear conditioning. Indeed, brief daily handling (1-3 m/d/21 d) facilitated acquisition of fear conditioning in chronically stressed female rats, and either had no effect or slightly attenuated fear conditioning in controls. Thus, chronic stress impacts amygdala-mediated fear learning in both OVX- and gonadally-intact females as found previously in males, with handling significantly influencing these outcomes.
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.
The study of memory modulation in infant rats has typically focused on reminder/retrieval treatments involving reexposure to components of the internal or external training context. Rarely have studies employed pharmacological treatments to investigate the neurochemical substrates of memory storage in preweanling rats. The present study investigated the effect of 100 mg/kg of glucose, a common memory modulator in adult mammals, on memory for passive-avoidance conditioning in 18-day-old Sprague-Dawley rats. Subjects that were administered an immediate post-training injection of glucose performed significantly better, on a retention test 24 h following training, than those animals that received saline. The glucose group also performed comparably to a control group that was tested 10 min following training. These results are consistent with those of the memory modulation literature in adults and suggest that the rapid rate of forgetting in immature organisms may be the result of a deficiency in a general memory modulatory system.
Estradiol (17beta-E2) can have mnemonic-enhancing effects; however, its mechanisms for these effects are not well-understood. The present studies examined effects of 17beta-E2 and selective estrogen receptor modulators (SERMs) on emotional and spatial memory of female, Long-Evans rats. First, whether or not 17beta-E2 has dose-dependent effects on inhibitory avoidance memory was investigated. Only the highest concentration of 17beta-E2 examined (10 microg), which produces physiological concentrations of E2, was effective at enhancing inhibitory avoidance memory (Experiment 1). Further studies were designed to elucidate whether SERMs may produce mnemonic effects similar to those of 17beta-E2. Compounds utilized were, the ERalpha-selective SERMs, propyl pyrazole triol (PPT) or 17alpha-E2, the ERbeta-specific SERMs, diarylpropionitrile (DPN) or 7,12-dihydrocoumestan (coumestrol), or vehicle (oil). Post-training administration of 10 microg 17beta-E2 or coumestrol enhanced memory in the inhibitory avoidance task compared to vehicle (Experiment 2). Memory in the water maze was enhanced by post-training administration of 17beta-E2, coumestrol, or DPN, compared to vehicle (Experiment 3). Co-administration of 17alpha-E2&DPN enhanced inhibitory avoidance memory similar to that seen following 17beta-E2 or coumestrol (Experiment 4). Administration of E2 2 h post-training was not effective at enhancing memory in the inhibitory avoidance or water maze tasks (Experiment 5). Lordosis of rats was enhanced by 17beta-E2, 17alpha-E2, or PPT, compared to vehicle (Experiment 6). These data suggest that: E2's actions at ERbeta, rather than ERalpha, may enhance spatial memory, E2's actions at ERalpha can facilitate sexual behavior, and that E2's actions involving both ERalpha and ERbeta may be important for emotional memory.
Neuronal nicotinic acetylcholine receptors (nAChRs) are critical for higher order cognitive processes. Post-mortem studies suggest reductions in nAChRs (particularly the alpha(4)beta(2) subtype) with ageing and in Alzheimer's disease (AD). This study aimed to; (1) quantify nAChR distribution in vivo with 2-[18F]fluoro-A-85380 (2-FA) in 15 early AD patients compared to 14 age-matched, healthy controls (HC) and (2) correlate nAChR distribution with cognitive performance in both groups. All participants were non-smokers and underwent cognitive testing along with a dynamic PET scan after injection of 200 MBq of 2-FA. Brain regional 2-FA binding was assessed through a simplified estimation of Distribution Volume (DV(S)). The AD group differed significantly from HC on all cognitive measures employed, with impairments on measures of attention, working memory, language, executive function, visuospatial ability, verbal learning and verbal memory (p<.05). Contrary to post-mortem data this study found no evidence of in vivo nAChR loss in early AD despite significant cognitive impairment. Furthermore, no correlation between nAChR and cognitive performance was found for either group. The findings of the current study suggest preservation of nAChRs early in AD supporting previous studies. It is possible that while the clinical 2-FA PET method described here may be insensitive in detecting changes in early AD, such changes may be detected in more advanced stages of the illness.
The immunotoxin 192-saporin, infused intracerebroventricularly into rats, destroys cholinergic neurons in the basal forebrain nuclei. Doses required for complete cholinergic loss also kill some Purkinje cells. The immunotoxin OX7-saporin, when infused intraventricularly into rats, destroys Purkinje cells in a pattern similar to that produced by 192-saporin, without affecting cholinergic neurons. Thus, we used OX7-saporin to distinguish behavioral effects of 192-saporin due to cerebellar damage versus those due to cholinergic cell loss. Three doses of 192-saporin (1.6, 2.6, and 3.3 micrograms/rat) were chosen along with a dose of OX7-saporin (2.0 micrograms/rat) that produced Purkinje loss equivalent to the two highest doses of 192-saporin. Groups of Fischer-344 rats were trained in the multiple choice reaction time task and retested with more complex tasks after lesioning. They were also tested in the water maze, passive avoidance, acoustic startle, and open field. The OX7-saporin group exhibited changes in many tests suggesting hypermotility and sensory deficits. The 192-saporin groups differed from the OX7-saporin group when they displayed deficits in multiple choice reaction time tasks in which novel challenges were introduced, including sessions with a noise distractor, shortened and lengthened intertrial intervals, and use of nine instead of five sources of light stimulus. The 192-saporin groups showed no impairment in the other tasks. The cholinergic basal forebrain lesion may mask some of the effects of cerebellar damage up to a threshold after which effects of Purkinje cell loss predominate when 192-saporin is administered intraventricularly.
This experiment tests the hypothesis that the cholinergic nucleus basalis magnocellularis (NBM) is necessary for complex or configural association learning, but not elemental or simple association learning. Male Long-Evans rats with bilateral 192 IgG-saporin lesions of the NBM (n = 12) and sham-operated controls (n = 8) were tested in the transverse patterning problem, which provides a test of both simple and configural association learning. Rats were trained in phases to concurrently solve first one, then two, and finally three different visual discriminations; Problem 1 (A+ vs B- sign) and Problem 2 (B+ vs C-) could be solved using simple associations, whereas solving Problem 3 (C+ vs A-) required the ability to form configural associations. Consistent with our hypothesis, the NBM lesion group solved the simple discriminations in Problems 1 and 2 but showed impaired configural association learning in Problem 3. Additionally, when Problem 2 was introduced, previously high levels of performance on Problem 1 suffered more in the NBM lesion group than in the control group; this finding suggests an impairment in the ability of animals with NBM lesions to divide attention among multiple stimuli or to shift between strategies for solving different problems. Results support our argument that the NBM is critically involved in the acquisition of associative problems requiring a configural solution but not in problems that can be solved using only simple associations. The observed impairments in configural association learning and the apparent loss of cognitive flexibility or capacity are interpreted as reflecting specific attentional impairments resulting from NBM damage.
Knockout mice lacking the alpha-1b adrenergic receptor were tested in behavioral experiments. Reaction to novelty was first assessed in a simple test in which the time taken by the knockout mice and their littermate controls to enter a second compartment was compared. Then the mice were tested in an open field to which unknown objects were subsequently added. Special novelty was introduced by moving one of the familiar objects to another location in the open field. Spatial behavior and memory were further studied in a homing board test, and in the water maze. The alpha-1b knockout mice showed an enhanced reactivity to new situations. They were faster to enter the new environment, covered longer paths in the open field, and spent more time exploring the new objects. They reacted like controls to modification inducing spatial novelty. In the homing board test, both the knockout mice and the control mice seemed to use a combination of distant visual and proximal olfactory cues, showing place preference only if the two types of cues were redundant. In the water maze the alpha-1b knockout mice were unable to learn the task, which was confirmed in a probe trial without platform. They were perfectly able, however, to escape in a visible platform procedure. These results confirm previous findings showing that the noradrenergic pathway is important for the modulation of behaviors such as reaction to novelty and exploration, and suggest that this is mediated, at least partly, through the alpha-1b adrenergic receptors. The lack of alpha-1b adrenergic receptors in spatial orientation does not seem important in cue-rich tasks but may interfere with orientation in situations providing distant cues only.
Recent research has indicated that the pro-inflammatory cytokines, particularly interleukin-1beta (IL-1beta), can affect learning and memory. We injected male Sprague-Dawley rats with IL-1beta (1.0, 3.0, or 6.0 microg/kg, i.p.) or saline vehicle, 24h before a single 4-h session of leverpress escape/avoidance conditioning. No effect of IL-1beta at any dose was observed in the number of escape responses across the 4-h session. However, subjects treated with the two lower doses (1.0 and 3.0 microg/kg) of IL-1beta performed more avoidance responses during the final hour of the 4-h session than the other two groups. Subjects treated with the highest dose of IL-1beta (6.0 microg/kg) did not differ from controls. Results are discussed in terms of the possible mechanisms behind the IL-1beta-induced enhancement of learning, as well as the observed dose-response relationship.
The present study evaluated the role of chronic docosahexaenoic acid (DHA) supplementation on active avoidance learning task performance in experimental hypertension. Male Wistar rats were randomly divided into five experimental groups as follows: control, sham, DHA treated, 1K-1C hypertensive, and 1K-1C hypertensive+DHA treated. Hypertension was induced in 1K-1C rats via placing a silver clip (0.20-mm ID) around the left renal artery following a right uninephrectomy. DHA (36 mg/kg/day) was given to the treatment groups for 60 days by gastric gavage. Arterial blood pressure was measured by using the tail-cuff method. Active avoidance responses were determined by an automated shuttle-box. In brain (cerebrum) and hippocampus tissues, thiobarbituric acid reactive substances (TBARS) and nitrite levels were measured by fluorometric methods. DHA supplementation decreased blood pressure in hypertensive rats. Data from active avoidance training indicated that performance of active avoidance learning tasks were significantly impaired in 1K-1C hypertensive rats, but was completely restored by DHA supplementation. Increased cerebrum TBARS levels in 1K-1C rats were abolished by DHA administration. Cerebrum nitrite levels were lower in the DHA, 1K-1C and 1K-1C+DHA treated groups compared to controls. Hippocampus nitrite levels were lower in DHA treated and 1K-1C hypertensive rats compared to controls and higher in 1K-1C+DHA treated rats compared to the 1K-1C group. Our data indicates that DHA supplementation improves the performance of active avoidance learning tasks which is impaired in experimental hypertension. These affirmative changes might be due to a DHA-induced decrease in lipid peroxidation which may in turn limit the consumption of nitric oxide (NO) which promotes active avoidance learning.
Although cholinergic mechanisms have been widely implicated in learning and memory processes, few studies have investigated the specific contribution of hippocampal cholinergic transmission during trace fear conditioning, a form of associative learning involving a temporal gap between two stimuli. Microinfusions of scopolamine, a muscarinic receptor antagonist, into the dorsal hippocampus (DH) produced dose-dependent impairment in the acquisition and expression of a conditioned response (CR) following trace fear conditioning with a tone conditioned stimulus (CS) and a footshock unconditioned stimulus (US) in rats. The same infusions, however, had no effect on delay conditioning, general activity, pain sensitivity or attentional modulation. Moreover, scopolamine infusions attenuated phosphorylation of extracellular signal-regulated kinase (ERK) in the amygdala, indicating that cholinergic signals in the DH are important for trace fear conditioning. Taken together, the current study provides evidence that cholinergic neurotransmission in the DH is essential for the cellular processing of CS-US association in the amygdala when the two stimuli are temporally disconnected.
Human episodic memory refers to the recollection of an unique past experience in terms of what happened, and where and when it happened. Factoring out the issue of conscious recollection, episodic memory, even at the behavioral level, has been difficult to demonstrate in non-human mammals. Although, it was previously shown that rodents can associate what and when or what and where information given on unique trials, it proved to be difficult to demonstrate memory for what, where, and when simultaneously in mammals, without using extensive training procedures, which might induce semantic rather than episodic memory recall. Towards the goal of an animal model of human episodic memory we designed an three-trial object exploration task in which different versions of the novelty-preference paradigm were combined to subsume (a) object recognition memory, (b) the memory for locations in which objects were explored, and (c) the temporal order memory for object presented at distinct time points. We found that mice spent more time exploring two "old familiar" objects relative to two "recent familiar" objects, reflecting memory for what and when and concomitantly directed more exploration at a spatially displaced "old familiar" object relative to a stationary "old familiar" object, reflecting memory for what and where. These results suggest that during a single test trial the mice were able to (a) recognize previously explored objects, (b) remember the location in which particular objects were previously encountered, and (c) to discriminate the relative recency in which different objects were presented. According to the currently discussed behavioral criteria for episodic-like memory in animals, our results suggest that mice are capable to form such higher order memories.
Previous research has shown that an acute, post-training injection of D-cycloserine (DCS) facilitates extinction of conditioned fear in rats; however, the effects of multiple exposures to DCS in this situation are not known. In Experiment 1, rats were conditioned (light-shock pairings) and 24 h later given six extinction (light-alone) trials followed by an injection of DCS (15 mg/kg) or saline. The next day, all rats were tested for light-elicited freezing. In Experiment 2, the effect of DCS on extinction was tested in the same manner, except that rats were pre-exposed to DCS (0, 1, or 5 injections) just prior to conditioning. In Experiment 3, rats received five pre-exposures of DCS but conditioning occurred either 2 or 28 days after the last pre-exposure. The results showed that DCS facilitated extinction of conditioned freezing to the light CS when no drug pre-exposure had occurred, but pre-exposure to DCS just prior to conditioning disrupted the facilitation of extinction effect. When 28 days were interposed between pre-exposure and conditioning, the facilitatory effects of DCS on extinction were restored. These findings suggest that DCS has significant clinical value but that behavioral desensitization may occur with multiple exposures; however, desensitization is not permanent and is reduced by the passage of time.
The prefrontal cortex is known to be involved in the acquisition of trace conditioning, a higher-cognitive form of Pavlovian conditioning in which a conditioned stimulus and an unconditioned stimulus are separated by a time gap. We have recently reported that medial prefrontal (mPFC) extracellular-signal regulated kinase (Erk) phosphorylation is involved in the long-term memory storage of trace fear conditioning. Because of the important role dopamine D1 receptors play in prefrontal function, such as working memory, and due to evidence that dopamine D1 receptor activity can modulate plasticity, we investigated their role in prefrontal Erk phosphorylation following trace fear conditioning. We found that inhibition of dopamine D1 receptors through intra-mPFC infusion of SCH-23390 (1 microg/0.5 microL) 15 min prior to trace fear conditioning resulted in a decrease in training-related Erk phosphorylation. Additionally, pre-training intra-mPFC infusion of SCH-23390 also resulted in the impairment of long-term retention of CS-US association. These findings implicate mPFC dopamine D1 receptor activity in the storage of long-term memory for higher-cognitive associative tasks.
This Special Issue of Neurobiology of Learning and Memory dedicated to Dr. Richard Thompson to celebrate his 80th birthday and his numerous contributions to the field of learning and memory gave us the opportunity to revisit the hypothesis we proposed more than 25years ago regarding the biochemistry of learning and memory. This review summarizes our early 1980s hypothesis and then describes how it was tested and modified over the years following its introduction. We then discuss the current status of the hypothesis and provide some examples of how it has led to unexpected insights into the memory problems that accompany a broad range of neuropsychiatric disorders.
Rats were trained in a Y-shaped water maze to discriminate a light gray from a medium gray visual stimulus. The latter stimulus card cued the location of a nonvisible escape platform. The animals received either a sham operation or a large ablation in the posterior neocortex, and osmotic minipumps were implanted subcutaneously in the animal's back. The pumps chronically administered either saline or ORG 2766 at a rate of 0, 1, or 10 micrograms per 24 h for 14 days while the animals recovered in individual rat cages. Four weeks after surgery retention of the discrimination was tested and, for those reattaining criterion, transposition of the habit to a pairing of the medium gray card with a black stimulus card was assessed. Animals treated with 10 micrograms ORG 2766 reattained criterion on the original discrimination more rapidly than did animals treated with 0 or 1 microgram. Neither the lesion nor the drug resulted in consistent influences upon transposition. There was no evidence that the drug protected neurons within the dorsal lateral geniculate nuclei. Postinjury treatment with some doses of ORG 2766 can attenuate the severity of some dysfunctions that accompany neurotrauma by influencing the development of behavioral compensation.
Established traumatic memories have a selective vulnerability to pharmacologic interventions following their reactivation that can decrease subsequent memory recall. This vulnerable period following memory reactivation is termed reconsolidation. The pharmacology of traumatic memory reconsolidation has not been fully characterized despite its potential as a therapeutic target for established, acquired anxiety disorders including posttraumatic stress disorder (PTSD). The mammalian target of rapamycin (mTOR) kinase is a critical regulator of mRNA translation and is known to be involved in various forms of synaptic plasticity and memory consolidation. We have examined the role of mTOR in traumatic memory reconsolidation.
Male C57BL/6 mice were injected systemically with the mTOR inhibitor rapamycin (1-40mg/kg), at various time points relative to contextual fear conditioning training or fear memory retrieval, and compared to vehicle or anisomycin-treated groups (N=10-12 in each group).
Inhibition of mTOR via systemic administration of rapamycin blocks reconsolidation of an established fear memory in a lasting manner. This effect is specific to reconsolidation as a series of additional experiments make an effect on memory extinction unlikely.
Systemic rapamycin, in conjunction with therapeutic traumatic memory reactivation, can decrease the emotional strength of an established traumatic memory. This finding not only establishes mTOR regulation of protein translation in the reconsolidation phase of traumatic memory, but also implicates a novel, FDA-approved drug treatment for patients suffering from acquired anxiety disorders such as PTSD and specific phobia.
In two experiments we investigated the effects of elevated dopaminergic tone on instrumental learning and performance using dopamine transporter knockdown (DAT KD) mice. In Experiment 1, we showed that both DAT KD mice and wild-type controls were similarly sensitive to outcome devaluation induced by sensory specific satiety, indicating normal action-outcome learning in both groups. In Experiment 2, we used a Pavlovian-to-instrumental transfer procedure to assess the potentiation of instrumental responding by Pavlovian conditional stimuli (CS). Although during the Pavlovian training phase the DAT KD mice entered the food magazine more frequently in the absence of the CS, when tested later both groups showed outcome-selective PIT. These results suggest that the elevated dopaminergic tone reduced the selectivity of stimulus control over conditioned behavior, but did not affect instrumental learning.
Facilitation of memory extinction by manipulation of the endocannabinoid (eCB) system has been recently studied in several paradigms. Our previous results pointed to facilitation of contextual fear memory extinction by a low dose of a cannabinoid agonist, with a suggestion of short-term effects. The aim of the present study was to further investigate the effects of cannabinoid drugs in the short- and long-term extinction of conditioned fear using an extended extinction protocol. Male Wistar rats were placed in a conditioning chamber and after 3min received a footshock (1.5mA, 1s). On the next day, they received i.p. drug treatment (WIN55212-2 0.25mg/kg, AM404 10mg/kg, SR141716A 1mg/kg) and were re-exposed to the conditioning chamber for 30min (extinction training). No-Extinction groups received the same drug treatment, but were exposed for 3min to the conditioning chamber. A drug-free test of contextual memory (3min) was performed 7 days later. The cannabinoid agonist WI55212-2 and the inhibitor of eCB metabolism/uptake AM404 facilitated short-term extinction. In addition, long-term effects induced by treatments with WIN55212 and AM404 were completely divergent to those of SR141716A treatment. The present results confirm and extend previous findings showing that the eCB system modulates short-term fear memory extinction with long-lasting consequences.
Acetylcholine is involved in a variety of brain functions. In the visual cortex, the pattern of cholinergic innervation varies considerably across different mammalian species and across different cortical layers within the same species. The physiological effects of acetylcholine in the visual cortex display complex responses, which are likely due to cholinergic receptor subtype composition in cytoplasm membrane as well as interaction with other transmitter systems within the local neural circuitry. The functional role of acetylcholine in visual cortex is believed to improve the signal-to-noise ratio of cortical neurons during visual information processing. Available evidence suggests that acetylcholine is also involved in experience-dependent visual cortex plasticity. At the level of synaptic transmission, activation of muscarinic receptors has been shown to play a permissive role in visual cortex plasticity. Among the muscarinic receptor subtypes, the M(1) receptor seems to make a predominant contribution towards modifications of neural circuitry. The signal transduction cascade of the cholinergic pathway may act synergistically with that of the NMDA receptor pathway, whose activation is a prerequisite for cortical plasticity.
This study assessed whether dopamine in the dorsomedial striatum is necessary for flexible adaptation to changes in stimulus-response contingencies. As KW-6002 (Istradefylline), an adenosine A(2A) antagonist, improves motor deficits resulting from striatal dopamine depletion, we also tested for potential ameliorative effects of KW-6002 on dopamine depletion-induced cognitive deficits. Male Lister hooded rats were presented with two bowls, discriminable by either a textured covering on the outer surface, their scent or the bowl contents (digging media) in which bait was buried. Once they had learned in which bowl food was buried, the stimulus-response contingencies were reversed. In both phases (acquisition and reversal), the criterion for learning was defined a priori as six consecutive correct trials. Following depletion of dopamine in the dorsomedial striatum, acquisition of the discriminations was intact but there was an increase in the number of trials to attain criterion performance in the reversal phases, indicating an impairment in reversal learning. KW-6002 (1mg/kg bidaily for 10 days) non-specifically increased the number of trials to criterion at all stages of the test and in both controls (sham-operated) and dopamine-depleted rats. Chronic KW-6002 treatment did not improve the reversal deficits in dopamine-depleted rats. These findings suggest that dopamine transmission in the dorsomedial striatum is critical for the flexible shifting of response patterns and the ameliorative effects of KW-6002 following depletion of dopamine in the striatum may be restricted to motor functions without relieving deficits in response-shifting flexibility.
Animal studies have established that drugs activating the serotonin 2A (5-HT2A) receptor can enhance learning and memory in a variety of classical and operant conditioning tasks. Unfortunately, long-term agonism typically results in receptor downregulation which can negate such nootropic effects. Conversely, chronic antagonism can act to increase receptor density, an adaptation which, in principle, should enhance cognition in a manner similar to acute agonism. In this study, we questioned whether chronic treatment with the 5-HT2A receptor antagonist SR 46349B, a drug known to increase 5-HT2A receptor density in vivo, would improve cognitive performance in normal mice. To address this question, we administered SR 46349B to mice for 4 days following initial training on a simple rule-based reward acquisition task. We subsequently tested their recall of this task and, finally, their ability to adapt to a reversal in reward contingency (reversal learning). For comparison, two additional groups were treated with the 5-HT2A/2C receptor agonist, DOI, which downregulates the 5-HT2A receptor. SR 46349B improved retention of the previously-learned task but did not affect reversal learning. Subjects treated with SR 46349B also completed trials faster and with greater motor efficiency than vehicle- or DOI-treated subjects. We hypothesize that long-term drug treatments resulting in 5-HT2A receptor up-regulation may be useful in enhancing recall of learned behaviors and thus may have potential for treating cognitive impairment associated with neurodegenerative disorders.
Two experiments were conducted to compare the effects of fornix/fimbria and caudate-putamen lesions in Long-Evans hooded rats (Rattus norvegicus) trained on two water maze tasks that differed in the type of spatial localization required for optimum solution. In Experiment 1, the lesioned rats and surgical controls were trained on the standard place task in the water maze (Morris, 1981) and given two postacquisition tests (a platform removal probe and platform relocation test). In Experiment 2, rats with similar lesions and control rats were trained on a modified cue navigation task. Fornix/fimbria lesions impaired a late stage of place task acquisition but did not impair acquisition of the cue task. Caudate-putamen lesions resulted in a severe place acquisition impairment and a transient cue acquisition impairment, both of which were characterized by an initial tendency to swim near the wall of the pool. Post-hoc analyses of the direction and angles of departure from the start points suggested that rats with fornix/fimbria lesions used non-allocentric spatial strategies to solve the place task. These rats also demonstrated a significantly weakened spatial bias for the former training quadrant on the platform removal probe and reduced flexibility in navigating to a novel platform location on the platform relocation test. In contrast, rats with caudate-putamen lesions showed a significant spatial bias for the former training quadrant but failed to cross the exact location within the quadrant where the platform was formerly positioned. The results suggest that the hippocampus mediates the allocentric spatial component of the water maze place task while the dorsomedial striatum may play an important role in the acquisition of the procedural aspects of both place and cue versions of the task.
Amyloid beta-protein (Abeta) in the brain of Alzheimer's disease (AD) plays a detrimental role in synaptic plasticity and cognitive function. The effects of Abeta on the early-phase long-term potentiation (E-LTP) have been reported widely. However, whether the late-phase long-term potentiation (L-LTP), which differs from E-LTP mechanistically, is also affected by Abeta is still an open question. The present study examined the effects of intracerebraventricular injection of Abeta fragments 25-35 and 31-35 on the L-LTP in the CA1 area of rat hippocampus in vivo, and further investigated its possible underlying mechanism. Our results showed that: (1) Abeta25-35 (6.25-25 nmol) did not affect the baseline field excitatory postsynaptic potentials, but dose-dependently suppressed multiple high-frequency stimuli-induced L-LTP; (2) Abeta31-35, a shorter Abeta fragment than Abeta25-35, also significantly suppressed L-LTP, with the same suppressive effects as Abeta25-35; (3) pretreatment with PMA (6 nmol/5 microl), a membrane permeable PKC agonist, effectively prevented Abeta31-35-induced deficits in the early and the late components of L-LTP; (4) co-application of Abeta31-35 and chelerythrine (12 nmol/5 microl), a PKC antagonist, caused no additive suppression of L-LTP. These results indicate that both Abeta25-35 and Abeta31-35 can impair hippocampal synaptic plasticity in vivo by suppressing the maintenance of L-LTP, and PKC probably mediates the Abeta-induced suppression of hippocampal L-LTP. In addition, the similar efficacy of Abeta31-35 and Abeta25-35 in L-LTP suppression supports the hypothesis we suggested previously that the sequence 31-35 in Abeta might be the shortest active sequence responsible for the neuronal toxicity induced by full length of Abeta molecules.
This study determined whether prior habituation to water immersion would ameliorate age-related deficits in learning and memory in a swim task. Aged (22 months) and young adult (3 months) rats were immersed in water (30 degrees C) for 15 min on each of 28 consecutive days before training in the swim task. Additional groups of age-matched animals served as handled controls. Training on a spatial discrimination version of the water task was conducted over 5 days with two trials per day (1-h intertrial interval). A probe trial was substituted for the last trial on the fifth day to assess the rats' use of spatial information. Three days later, rats received cue discrimination training to find a visible platform. In the spatial task, prior habituation to water immersion ameliorated deficits in acquisition within each day (i.e., at a 1-h intertrial interval) but not across days (at 24 h). The results obtained with the 24-h interval confirm the rapid forgetting characteristic of aged rats in many tasks. The stress-habituation procedures reduced age-related deficits seen on the probe trial and on cue discrimination training. These findings indicate that several aspects of age-related impairments in the swim task, often attributed to primary age-related deficits in learning and memory processes per se, may instead be secondary to age-related differences in stress responses to water immersion.
The fact that various neuropharmacological substances have anxiolytic as well as amnesic effects suggests that neuronal mechanisms of anxiety and learning/memory closely interact. Hence, we hypothesized that differences in anxiety-related behavior could be accompanied with differences in cognition or habituation. Two rat strains with different levels of anxiety, more anxious Fischer 344 rats by Charles River (FC) and less anxious Wistar rats by Winkelmann (WW), were tested in the Morris water maze task and an open field test for habituation learning. Additionally, we investigated the effect of different light intensities on the performance in the Morris water maze and the elevated plus maze. The results of the water maze task indicate that differences in anxiety-related behavior do not go along with differences in this performance of learning/memory. Moreover, the test was not affected by different light intensities. In contrast, illumination did affect performance in the elevated plus maze test, wherein dim light provoked an anxiolytic effect in both rat strains. The findings that neither different baseline levels of anxiety nor fear modulating light conditions were accompanied by changes in the performance of rats in the Morris water maze led us to the suggestion that there is no connection between anxiety and learning/memory in this task. Contrarily, anxiety might be associated with habituation learning in the open field test, shown by the superior habituation of the anxious FC rats in comparison to the less anxious WW rats. In sum, these results indicate that anxiety and learning/memory seem to be independently regulated behaviors, whereas habituation might be more closely correlated with anxiety. Nevertheless, a general statement about the relation between emotionality and learning/memory mechanisms would be premature and the link between behaviors remains to be clarified.
Young adult (3 months) and aged (22 months) Fischer 344 male rats were prepared with chronic tail artery catheters. Two days after surgery, rats were transferred to a test chamber and exposed to a single footshock (0, 0.25, 0.50, or 1.0 mA for 1 s). Blood samples were obtained from each rat under basal conditions and at timed intervals after exposure to footshock. Basal plasma levels of norepinephrine (NE) and epinephrine (EPI) were similar for 3- and 22-month-old rats. In contrast, plasma glucose (GLU) levels were significantly lower in aged rats compared to young adults. Increments in plasma levels of EPI were greater in aged rats compared to young adult controls following transfer of rats to the test chamber. In addition, aged rats had potentiated plasma EPI responses to footshock. Finally, aged rats had greater plasma levels of both catecholamines up to 5 min after a single training footshock compared to young adult controls. However, the increased responsiveness of EPI in aged rats was not accompanied by proportionate increases in plasma GLU levels, i.e., the EPI-GLU relationship was uncoupled in aged rats. These findings point to dramatic differences between young adult and aged rats in their plasma EPI responses to inhibitory avoidance training. Age-related increases in EPI secreted from the adrenal medulla, together with decreased blood GLU responses, may contribute in part to age-related deficits in memory modulatory processes.
The current study employed aged and young male Fischer 344 rats to examine the relationship between long-term depression (LTD), age, and memory. Memory performance was measured on two tasks that are sensitive to hippocampal function; inhibitory avoidance and spatial discrimination on the Morris water maze. The slope of the extracellular excitatory postsynaptic field potential was recorded from CA3-CA1 synapses in hippocampal slices. Low frequency stimulation (LFS) induced a modest LTD only in aged animals under standard recording conditions. The decrease in synaptic transmission examined only in aged animals correlated with memory scores on the spatial task and LTD was not observed in aged animals with the highest memory scores. LTD induction was facilitated by increasing the Ca(2+)/Mg(2+) ratio of the recording medium or employing a paired-pulse stimulation paradigm. Age differences disappeared when LFS was delivered under conditions of elevated Ca(2+)/Mg(2+) in the recording medium. Using multiple induction episodes under conditions which facilitate LTD-induction, no age-related difference was observed in the maximum level of LTD. The results indicate that the increased susceptibility to LTD induction is associated with impaired memory and results from a shift in the induction process. The possible relationship between LTD and memory function is discussed.
Evidence indicating a role for the nucleus accumbens in the development of latent inhibition of learning has accumulated. Two experiments were conducted using Wistar rats to investigate this role directly. Experiment 1 used a conditioned emotional response paradigm to assess the effects of discrete electrolytic lesions in the shell region of the nucleus accumbens. Latent inhibition was attenuated by this lesion. In order to determine the contribution made by damage to fibers en passage associated with electrolytic lesions, Experiment 2 assessed the effects of NMDA-induced lesions in the shell of the nucleus accumbens in the same task. Latent inhibition was again significantly attenuated. These findings support the proposition that an intact nucleus accumbens is necessary for the normal development of latent inhibition.
Previously, we showed that maternal deprivation (MD) (3h/day, postnatal-day 1-14) impaired the performance at adulthood in the object temporal order memory task (TMT) that principally implicates the medial prefrontal cortex (mPFC). Dopamine (DA) transmission in the PFC may play a critical role in the achievement of the TMT. Here, to investigate whether MD could results in dysfunction of the DA system in the mPFC, we assessed in this region the tissue contents and extracellular levels of DA and its metabolites, as the density of D1 receptor. Besides we examined whether an agonist of the DA receptor D1, the SKF38393, could have a beneficial effect on the performance of deprived (D) rats in the TMT. We observed that MD induced a significant reduction of the extracellular level of DOPAC in the mPFC and in the density of the D1 receptor in the anterior cingulate cortex, a sub-region of mPFC. On the other hand, we observed that an acute systemic injection of a D1 receptor agonist, SKF38393, was effective to correct the memory deficiency of D rats in the TMT, when administered before the retrieval phase. We showed that a stress suffered by rats during the perinatal period led to dysfunction of the adult DA system, possibly triggering greater vulnerability to cognitive and mood disorders. Interestingly, an acute administration of a D1 receptor agonist in adulthood was sufficient to improve the deficit in the temporal memory. A better understanding of this phenomenon would permit the development of treatments adapted to patients with a history of early traumatic experiences.