Enhancement of long-term memory retention by Colostrinin in one-day-old chicks trained on a weak passive avoidance learning paradigm

Colostrinin (CLN) is a biologically active proline-rich polypeptide which has therapeutic potential for the alleviation of memory deficits in age-related dementias in a number of human conditions, particularly Alzheimer's disease. To examine the efficacy of CLN in other species, day-old domestic chicks were used as a model system to study its effects on retention of memory for a single one-trial learning paradigm--avoidance of a bitter-tasting substance (methylanthranilate, MeA). Birds were presented with a bead coated with either a dilute (10%) solution of MeA or a bead coated with 100% MeA. Those trained on 100% MeA avoided pecking at a similar but dry bead 24 h later, thereby demonstrating long-term memory whereas chicks trained on the 10% solution pecked the bead at 24 h, indicating lack of long term memory for the task. However, when CLN was injected (i.c.) into a region known to be important in memory formation, the mesopallium intermediomediale (IMM), prior to training with 10% MeA, chicks exhibited strong memory retention at 24 h, similar to those trained on 100% MeA. Control chicks trained on 10% MeA but injected i.c. with a 10% saline solution did not show improvement in memory retention. Intraperitoneal (i.p.) injections of CLN were as effective as the i.c. route. These data extend the known efficacy of CLN from mammals demonstrating its widespread efficacy as a cognitive enhancer.     

Selective and protracted effect of nifedipine on fear memory extinction correlates with induced stress response

Memory extinction, defined as a decrease of a conditioned response as a function of a non-reinforced conditioned stimulus presentation, has high biological and clinical relevance. Extinction is not a passive reversing or erasing of the plasticity associated with acquisition, but a novel, active learning process. Nifedipine blocks L-type voltage gated calcium channels (LVGCC) and has been shown previously to selectively interfere with the extinction, but not the acquisition, of fear memory. We studied here the effect of retrograde and anterograde shifts of nifedipine application, with respect to an extinction training, on the extinction of fear conditioning. Subcutaneous injection of 30 mg/kg nifedipine, at least up to 4 h before the extinction session, significantly impaired extinction, as did intraperitoneal injection of 15 mg/kg nifedipine, at least up to 2 h before extinction training. However, the injection of nifedipine also induced a strong and protracted stress response. The pharmacokinetics of nifedipine suggest that it was mainly this stress response that triggered the specific inhibition of extinction, not the blockade of LVGCC in the brain. Our results support recent findings that stress selectively interferes with the extinction, but not the acquisition, of fear memory. They also indicate that a pharmacological approach is not sufficient to study the role of brain LVGCC in learning and memory. Further research using specific genetically modified animals is necessary to delineate the role of LVGCC in fear memory extinction.     

Inhibition of endogenous carbon monoxide production induces transient retention losses in the day-old chick when trained using a single trial passive avoidance learning task

Carbon monoxide (CO) is most often thought of as an exogenous toxin rather than as a possible endogenous nootrope. However, a limited number of studies have suggested that CO is necessary in memory processing for at least some tasks. While nitric oxide (NO) and CO are known activators of guanylyl cyclase (GC), only the effect of NO on GC has been extensively investigated as a mechanism underlying memory processing. The aim of the present study was to determine if inhibition of CO production would have an effect on memory processing. Using chicks trained on a single trial passive avoidance task, inhibition of CO production using zinc (II) deuteroporphyrin IX 2,4-bis ethylene glycol (ZnBG; 5 microM) resulted in two transient retention losses occurring at around 40 and 130 min post-training. The timing of these transient retention losses was similar to those observed following inhibition of GC, using the same species and task in a previous study. This supports the notion that CO is necessary in memory processing for this task and may act through a GC-dependent mechanism. As ZnBG also directly inhibits GC or nitric oxide synthase (NOS) at high concentrations, a second experiment was carried-out to confirm the specificity of ZnBG for heme oxygenase (HO) at the concentration used. The action of ZnBG was challenged with the HO agonist hemin (100 microM) and the transient deficits were abolished. This confirmed that the action of ZnBG on memory was through a CO-related mechanism rather than directly on GC or NOS. In this way the specificity of ZnBG (5 microM) for HO could be confirmed. The results support a role for endogenous CO in memory processing, possibly through activation of GC. In addition, the transient retention losses observed following administration of ZnBG suggest that CO may be necessary for memory retrieval and not formation as previously thought.     

Inhibition of monoADP-ribosylation prevents long-term memory consolidation of a single-trial passive avoidance task in the day-old chick

The cytosolic posttranslational protein-modifying mechanism of monoADP-ribosylation has been implicated in long-term potentiation, a synaptic model of memory formation. The current study investigated the effect of inhibiting mono(ADP-ribosyl) transferase on memory for the passive avoidance task in day-old chicks (white Leghorn-black Australorp). Various doses of novobiocin or menadione sodium bisulfite were administered intracranially at different times before or after training. Control chicks were administered saline at matched times. Novobiocin (650 microM) or menadione sodium bisulfite (250 microM) administered between 5.0 min pretraining and 2.5 min posttraining was found to cause a persistent loss of retention from 120 min posttraining. These data provide the first demonstration that monoADP-ribosylation is required for the maintenance of long-term memory. Furthermore, the temporal characteristics of the memory loss caused by monoADP-ribosylation inhibition appears to exclude this mechanism as a downstream effect of the well-established nitric oxide activity previously shown to occur within 40 min of passive avoidance training.     

Long-term memory formation in the chick requires mobilization of ryanodine-sensitive intracellular calcium stores

Training chicks (Gallus domesticus) on a one-trial passive avoidance task results in transient and time-dependent enhanced increases in N-methyl-d-aspartate- or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-stimulated intracellular calcium concentration in synaptoneurosomes isolated from a specific forebrain region, the intermediate medial hyperstriatum ventrale. This increase could result from either calcium entry from the extracellular medium or from mobilization of intracellular calcium stores. We have therefore examined the effects of dantrolene, an inhibitor of calcium release from the intracellular ryanodine-sensitive store, on these processes. Dantrolene, 50 nmol per hemisphere injected intracerebrally 30 min pre- or 30 min posttraining, blocked longer term memory for the passive avoidance task, whereas memory for the task was unaffected when dantrolene was injected at earlier or later times. Preincubation of synaptoneurosomes, isolated from the intermediate hyperstriatum ventrale 10 min after training, with 100 nM dantrolene abolished the enhanced training-induced increase in intracellular calcium concentration elicited by 0.5 mM N-methyl-d-aspartate. By contrast, the training-induced enhancement of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-stimulated increase in intracellular calcium concentration in synaptoneurosomes prepared 6 h posttraining was unaffected by preincubation with dantrolene, which was not amnestic at this time. Calcium release from ryanodine-sensitive intracellular stores may thus be a necessary stage in the early phase of the molecular cascade leading to the synaptic modulation required for long-term memory storage.     

Sequence-Specific Impairment of Memory Formation by NCAM Antisense Oligonucleotides

The functional role of NCAM gene expression in memory formation was studied in the one-trial passive avoidance task in day-old chicks by pretraining injections of one of three different 18-mer end-protected oligonucleotides corresponding to positions 190-, 207-, and 332- of the NCAM Ig1 domain. Twenty-four-hour-old chicks were trained by pecking at a bitter-tasting bead and tested for avoidance 30 min, 3, 8, or 24 hr later. Memory retention was significantly reduced only in the group of animals injected with the NCAM antisense corresponding to position 207- (AS-ODN-207), and only if given twice, both immediately after hatching and 12 hr before training. This antisense was without effect on the general behavior of the chicks, training or acquisition, and did not produce observable neurotoxic damage. Under such conditions amnesia was evident by 3 hr after training and lasted until at least 24 hr after training. The two other tested oligonucleotides were without behavioral effect. To control for nonsequence-specific effects of AS-ODN-207, brains from injected and trained animals were processed for Western blotting and probed using anti-NCAM, anti-L1, and anti-actin antibodies. NCAM antisense corresponding to position 207- significantly reduced the level of NCAM, whereas the level of L1 and actin remained unchanged. These results confirm our earlier conclusion that NCAM is necessary for longer term memory retention.     

Hemispheric dissociation of the involvement of NOS isoforms in memory for discriminated avoidance in the chick

Previous research has indicated a role for both the neuronal (nNOS) and endothelial (eNOS) nitric oxide isoforms in memory formation. In addition, two distinct periods of activity of nitric oxide activity, dissociated by hemispheric localization, are implicated following passive avoidance training in the chick. In the present study, we trained black Australorp-white Leghorn chicks on a color discrimination avoidance task. Diphenyleneiodonium chloride (1 microM) or N-propyl-l-arginine (50 microM) was administered into either the left or right hemisphere of the chick brain in an attempt to differentiate the effects of inhibiting eNOS or nNOS, respectively. The memory loss previously observed following administration of diphenyleneiodonium chloride between 10 and 20 min posttraining was found to be lateralized to the right hemisphere, although administration of this agent into the left hemisphere around the time of training was also amnestic. In contrast, N-propyl-l-arginine caused memory loss only when administered to the left hemisphere around the time of training. These findings suggest that activation of both eNOS and nNOS isoforms may be essential for long-term memory consolidation of this task. Further, these two periods of activity are defined temporally and by hemisphere localization, although confirmation with more selective inhibitors when they become available is advised.     

Perinatal leupeptin retards subsequent acquisition of a visual discrimination task in chicks

Recent discoveries that calcium sensitive proteases (calpains) may play an important role in memory led to investigation of the effects of leupeptin, a calpain inhibitor, on learning. Intracerebral injections of either 0.9% saline, 80 micrograms aprotinin, 306 micrograms glutamate, or 8 or 80 micrograms leupeptin were administered to 95 two-day-old chicks. On Day 10 posthatch, animals were then tested on a task requiring discriminations between pebbles and food pellets. Chicks receiving 8 or 80 micrograms leupeptin or 306 micrograms glutamate were found to be deficient in acquiring the task. Aprotinin, a control serine protease inhibitor, did not retard discrimination learning. None of the drugs tested altered body weight or gross visual skills. These results suggest that retardation produced by leupeptin is not due to nonspecific changes in protease activity, visual competency, or growth. The reported results confirm earlier reports of leupeptin-induced memory impairments in rats.     

Amnesia induced by 2-deoxygalactose in the day-old chick: lateralization of effects in two different one-trial learning tasks

2-Deoxy-D-galactose, an inhibitor of brain glycoprotein fucosylation, was injected intracranially (10 mumole dose in 10 microliters) into either the left or the right forebrain hemisphere of day-old chicks (Gallus domesticus). Bilateral injection of this dose of 2-deoxy-D-galactose is known to induce amnesia for several learning tasks including one-trial passive avoidance and sickness-induced learning. When a tritiated form of the drug was injected into one forebrain hemisphere only, a significantly large proportion of the dose remained in that hemisphere. Chicks were trained in two different one-trial learning tasks. The first was a passive avoidance task in which the chicks were allowed to peck at a green training stimulus (a small light-emitting diode, LED) coated in the bitter liquid, methylanthranilate, giving rise to a strong disgust response and consequent avoidance of the green stimulus. In the second paradigm the chicks were allowed to peck at a similarly colored dry stimulus but, 30 min later, were injected intraperitoneally with lithium chloride (0.1 ml of 1 M solution), causing a sickness-induced aversion for the green LED. 2-Deoxy-D-galactose caused amnesia for the passive avoidance task when injected before training into the right hemisphere but not the left. However, unilateral injection of the drug before training on the sickness-induced learning task did not cause amnesia. The results indicate that fucosylation of brain glycoproteins is required in the right hemisphere for learning the passive avoidance task but that memory for sickness-induced learning can be retained by either hemisphere.     

Cholinergic receptor antagonists impair formation of intermediate-term memory in the chick

Several experiments examined the effects of cholinergic receptor antagonists on formation of memory in the chick. Scopolamine produced amnesia in chicks trained on a one-trial peck avoidance task in a dose-dependent manner. Pretraining injection of scopolamine produced amnesia that developed between 15 and 30 min after training, suggesting that scopolamine interferes with intermediate-term memory (ITM), previously described to be active during this time (Patterson, Alvarado, Warner, Bennett, & Rosenzweig, 1986). Pretraining injection of scopolamine or ouabain, an inhibitor of ATPase activity shown previously to inhibit formation of ITM, produced identical time courses of amnesia development, supporting the hypothesis that scopolamine interferes with ITM. Pirenzepine, an inhibitor of M1 muscarinic receptors, was effective in producing amnesia, whereas gallamine, an M2 receptor inhibitor, did not produce amnesia. These results suggest that M1, but not M2, receptors are involved in memory formation in the chick.     

Central ghrelin increases anxiety in the Open Field test and impairs retention memory in a passive avoidance task in neonatal chicks

Ghrelin (Grh) is an endogenous ligand for the growth hormone secretagogue receptor. Although Ghr stimulates feeding in rats, it inhibits feeding in neonatal chicks. However, little is known about other central behavioral effects of Ghr. Therefore, we investigated the Ghr effects, injected intracerebroventricularly, on anxiety and memory retention of neonatal chicks in an Open Field test and in a one-trial passive avoidance task, respectively. In the Open Field test, the administration of Ghr in a dose-dependent manner increased the latency to ambulate but decreased ambulation activity, indicating an anxiogenic effect. Furthermore, chicks trained on a passive avoidance task and injected with a dose of 30 pmol of Ghr immediately after training showed an impairment of memory retention. However, there were no significant effects on the number of pecks during the pretraining, training, retention and discrimination. In addition, different doses of Ghr produced an inhibition in food intake at different times after injection. Our results indicate that Ghr induces anxiogenesis in chicks. Moreover, we have shown for the first time that Ghr can decrease memory retention in a non-mammalian species, suggesting that Ghr may play an important role in the processes of memory retention in birds.     

雏鸡左眼视剥夺不同时程后记忆形成过程与脑内Jun样蛋白表达差异的研究

本实验采用一次性味觉厌恶回避学习,研究２日龄雏鸡左眼视剥夺２４小时后的记忆形成过程,并与左眼视剥夺２小时后的记忆形成过程进行比较,同时利用免疫组化技术,观察并比较单眼视剥夺不同时程及单眼学习后Ｊｕｎ样蛋白在雏鸡脑内不同区域（ＨＶ和ＬＰＯ）的表达。结果表明：１．视剥夺左眼２４小时后对雏鸡的短时记忆、中时记忆和长时记忆均无明显影响,但中时记忆保持水平略低于双眼学习条件下的中时记忆保持水平。这与视剥夺２     

荷苞牡丹碱对雏鸡单眼视剥夺后记忆形成过程的改善作用

了雏鸡左眼视剥夺２小时后,进行一次性被动回避学习的记忆形成过程;以及ｒ一氨基丁酸（ｒ－ａｍｉｎｏ－ｂｕｔｙｒｉｃａｃｉｄＧＡＢＡ）的受体颉颌颃剂荷苞牡丹碱（ｂｉｃｕｃｕｌｌｉｎｅＢｉｃ）,对雏鸡左眼视剥夺后记忆形成过程的改善作用。实验结果表明：１．雏鸡左眼视剥夺２小时后,仅能形成较好的短时记忆,中时记忆和长时记忆难以形成;２．训练前１０分钟颅内注射荷苞牡丹碱,对雏鸡左眼视剥夺２小时后的记忆缺失有明显的改善作用,形成了较好的中时记忆和长时记忆。     

荷包牡丹碱对受低强度训练的小鸡的记忆形成的影响

在小鸡一次性被动回避行为中,低强度训练的动物其长时记忆保持不良,而训练前１０或２０分钟注射γ－氨基丁酸能颉颃剂荷包牡丹碱,可明显提高长时记忆的保持水平,这一作用可被激动剂蝇蕈碱反转。记忆保持曲线进一步显示,受低强度训练的动物其记忆仅能保持至训练后２０分钟,而注射荷包牡丹碱可使记忆至少延长至训练后１２０分钟。上述结果提示：小鸡的记忆形成受γ－氨基丁酸能系统的调节;γ－氨基丁酸能系统虽然直接参与中时记忆,但对长时记忆的形成似乎也是必需的。     

Lesions of the intermediate medial hyperstriatum ventrale impair sickness-conditioned learning in day-old chicks.

Lesion studies show that the intermediate medial hyperstriatum ventrale (IMHV), a forebrain visual association area in chicks, is involved in learning and memory for one-trial passive avoidance and imprinting. We examined the effects of IMHV lesions in a one-trial, nongustatory, sickness-conditioned learning task. This task is similar to passive avoidance and imprinting because all three tasks require the chick to remember visual cues in order to respond correctly. However, sickness-conditioned learning differs from imprinting and passive avoidance because it uses sickness as the aversive stimulus and there is a longer conditioned stimulus-unconditioned stimulus interval (30-min delay compared to seconds). Bilateral IMHV lesions given 24 h before training impaired the ability of the chicks to avoid a bead associated with sickness produced by lithium chloride injection, as did pretraining unilateral left or right IMHV lesions. Post-training IMHV lesions given 1 h after training did not impair avoidance of the test bead in the sickness-conditioned learning task. However, lesioned chicks showed generalized avoidance of all test beads. The pretraining lesion results are similar to those found in imprinting and passive avoidance learning; however, the effects of unilateral IMHV lesions differed. Post-training lesion effects are similar to those found in passive avoidance learning. We propose that both left and right IMHV are necessary for sickness-conditioned learning and that post-training IMHV lesions impair the ability of the chick to learn or remember the association between the color of the bead and the aversive consequences of LiCl injection.     

Chicks Injected with Antisera to either S-100α or S-100β Protein Develop Amnesia for a Passive Avoidance Task

The cellular expression of S-100β protein is upregulated in Alzheimer's disease and in Down's syndrome, and this protein has been implicated in memory-related processes in laboratory animals. However, the possibility that the α subunit of S-100 is also involved in memory has not yet been examined. In the present study, day-old black Australorp white Leghorn cockerel chicks (Gallus domesticus) received injections of monoclonal antisera to S-100α (1:50) or S-100β (1:500) into each hemisphere immediately after training on a one-trial passive avoidance task. The chicks displayed significantly lower retention levels than control birds that had been injected with antisera to carbonic anhydrase, or with saline (p< .01). S-100α antisera had an amnestic effect when injected between 0 and 20 min after training, with memory deficits occurring from 30 min postlearning, at the point of transition between the A and the B phases of the Gibbs-Ng intermediate memory stage. By contrast, the S-100β antisera needed to be injected either 5 min before or immediately after training and produced amnesia 10 min earlier, at the start of the A phase of the intermediate memory stage. We conclude that the two subunits of the S-100 protein are required at different points in the sequence of events leading to the consolidation of passive avoidance memory.     

What I Was Doing Versus What I Did: Verb Aspect Influences Memory and Future Actions

ABSTRACT— This research examined whether describing past actions as ongoing using the imperfective aspect (rather than describing them as completed using the perfective aspect) promotes memory for action-relevant knowledge and reenactment of these actions in a future context. In Experiment 1 , participants who used the imperfective aspect to describe their strategy on a prior interpersonal task were more likely to use this strategy on a later task than were participants who used the perfective aspect to describe their prior strategy. Experiment 2 demonstrated that describing behaviors on a task using the imperfective rather than the perfective aspect increased willingness to resume that task by improving memory for task contents. The last two experiments showed that the effects of the imperfective aspect on memory decayed over time and that the imperfective aspect facilitated performance of a future behavior only when the described past behavior was relevant to the future behavior. Thus, the effects of aspect are moderated by memory decay and are behavior-specific.     

Midazolam amnesia and short-term/working memory processes

We examined whether midazolam impairs short-term/working memory processes. We hypothesize that prior dissociations in midazolam's effects on short-term/working memory tasks and episodic memory tasks arise because midazolam has a larger effect on episodic memory processes than on short-term/working memory processes. To examine these issues, .03 mg/kg of participant's bodyweight of midazolam was administered in a double-blind placebo-controlled within-participant design. Performance on the digit span and category generation/recall tasks was examined. The results of Experiment 1 demonstrated that: (1) midazolam impaired performance on the digit span task; (2) midazolam did not impair performance on the category generation task; (3) midazolam impaired performance on the category recall task; and (4) midazolam's effect on category recall was four times as large as its effect on digit span. The results of Experiment 2 demonstrated that midazolam did not impair digit span performance when the digit span task was administered at a later time. These results suggest that midazolam can impair short-term/working memory processes, but these effects are substantially smaller than midazolam's effect on episodic memory processes. Moreover, they demonstrate that conscious awareness of materials during study is not sufficient to produce episodic memory.     

Exposure to a rhythmic auditory stimulus facilitates memory formation for the passive avoidance task in the day-old chick.

Previous research regarding the beneficial effects of auditory stimuli on learning and memory in humans has been inconsistent. In the current study, day-old chicks were used to reduce the impact of individual differences on responses. Chicks were trained on a passive avoidance task and exposed to various auditory stimuli. Exposure to a complex rhythmic sequence for 1 min strongly facilitated chicks' long-term memory. The optimal time of presentation of the stimulus was between 10 min before and 20 min after training. Moreover, the enhancing effect was not generalized to the other auditory stimuli tested. It is suggested that this effect may be due to arousal because arousal hormones are critical to long-term memory formation. This study indicates that the temporal characteristics and type of stimulus may be important considerations when investigating the effects of auditory stimuli on cognitive functioning.     

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.