Enhanced passive avoidance learning and appetitive T-maze learning with post-trial rewarding hypothalamic stimulation

Experiments were carried out to investigate the effects of post-trial reinforcing stimulation of the lateral hypothalamus on learning in rats. The reinforcing stimulation was always presented for a duration of 20–30 sec (0.2 sec on/0.8 sec off), and was administered either immediately, 30 sec delayed or 300 sec delayed after exposure to the learning situation. In Experiment 1 post-trial stimulation led to improved passive avoidance learning of an alcove-avoidance task when presented 30 sec compared to immediately after the footshock. In Experiment 2 reversal learning of a one-way shuttle-box avoidance task was facilitated by 30 sec delayed, but not 300 sec delayed post-trial reinforcing stimulation. In Experiment 3 appetitive left-right discrimination was investigated using a T-maze task. Thirty sec delayed post-trial reinforcing stimulation presented contingent on errors facilitated learning of this task. Together, the 3 studies provide further support for the hypothesis that reinforcers directly influence labile memory processes (such as short-term memory) and thereby improve learning.     

The role of neurotensin in passive avoidance learning in the rat central nucleus of amygdala

Tridecapeptide neurotensin (NT) acts as a neurotransmitter and/or neuromodulator and plays a role in learning and reinforcement. The central nucleus of amygdala (CeA), which is relatively rich in NT and neurotensin-1 receptors (NTS1), participates in the regulation of memory and learning mechanisms. The aim of this study was to examine the possible effect of NT and NTS1 antagonist (ANT) on passive avoidance learning after their microinjection into the CeA of male wistar rats. NT significantly increased the latency time. Effect of NT was blocked by ANT pretreatment. ANT in itself had no effect. Our results show that in the rat CeA NT facilitates passive avoidance learning via NTS1.     

外源性N-甲基-D-天冬氨酸对成年大鼠被动回避学习记忆的影响

目的 探讨脑内植入外源性N-甲基-D-天冬氨酸(NMDA)对成年大鼠被动回避学习记忆的影响. 方法 在大鼠脑内植入不同浓度的NMDA缓释膜片后,比较各组大鼠被动同避学习记忆(避暗实验)的能力以及额前腹内侧皮质(vMPFC)及扣带同前皮质(ACC)区域NMDA受体活性的区别. 结果 避暗实验中各组大鼠潜伏期和错误次数间差异无统计学意义(P=0.846,P=0.792).各组大鼠vMPFC及ACC区域的NMDA受体活性之间差异无统计学意义(P=0.546),但随着所植入的缓释膜片中NMDA浓度增加.这些区域NMDA受体活性有降低的趋势. 结论 外源性植入NMDA对成年大鼠被动回避学习记忆无明显影响,但本实验为进一步研究NMDA改变受损脑组织的神经可塑性奠定了一定的基础.     

A comparison of protocols for passive and discriminative avoidance learning tasks in the domestic chick

A one-trial learning task, where chicks learn that a bead of a particular shape and/or colour has a bitter taste (because it has been coated in 100% methyl anthranilate, MeA) and subsequently avoids it on test, has been widely used by research groups across the world. However, there are some differences in the results reported by different research laboratories. One important difference is found when chicks are trained with a diluted bitter taste on the bead (10 or 20% MeA); memory is not consolidated and fades, lasting for different times. At Monash and La Trobe Universities, memory lasts for 30 min but at the Open University (OU), memory lasts for 4-6h before fading. Differences in protocol that may explain this apparent discrepancy are whether the chicks have seen the bead before (novelty) and whether the colour or the shape of the bead is an important feature. In this review, we discuss these and other factors that may contribute to the differences in the characteristics of memory processing at Monash and at the OU, such as chick strain, hatchery or laboratory incubated chicks, age at training. It is clear that there is a difference between passive avoidance and discriminative avoidance protocols and this may explain the differences in duration of the memory with weakly reinforced learning. Is the OU task a more salient experience because of the novelty of the bead and therefore a 'stronger' learning experience? The different protocols may allow different questions to be addressed.     

The action of pituitary adenylate cyclase activating polypeptide (PACAP) on passive avoidance learning. The role of transmitters

In the present study, the action of PACAP 38 on one-way passive avoidance learning was investigated. PACAP-38 was administered into the lateral brain ventricle and the latency of the passive avoidance response was measured 24 h later. In order to study the possible roles of various neurotransmitters in mediating the action of PACAP on the consolidation of passive avoidance learning, the animals were pre-treated with receptor blockers in doses that per se proved to be ineffective. PACAP facilitated the learning, the consolidation of learning and the retrieval of the passive avoidance response. The following receptor blockers attenuated the action of PACAP on this consolidation: haloperidol, phenoxybenzamine, propranolol and methysergide. An antagonist of PACAP 38, PACAP 6-38, and also nitro-L-arginine (the latter blocks the enzyme nitric oxide synthase) thereby inhibiting the formation of NO from L-arginine, completely blocked the action of PACAP 38 on consolidation. The following receptor blockers were ineffective: naloxone, bicuculline and atropine. The presented data suggest that PACAP 38 is able to improve the learning and memory processes in a passive avoidance paradigm. In this action, the PACAP 38 receptor and NO are important mediators. Dopaminergic, alpha- and beta-adrenergic mediation and serotonin receptors modified the action of PACAP 38, but they are probably not of great importance.     

Effect of reversible inactivation of reuniens nucleus on memory processing in passive avoidance task

The reuniens nucleus (RE) is the largest nucleus of the midline thalamic nuclei (MLN). RE has strongly connections with the amygdala and hippocampus, the structures that are involved in the learning and memory processes. In our previous report we have shown the role of RE in the spatial learning and memory using Morris water maze (MWM) task. Since RE is connected to multiple limbic structures, its involvement in the emotional learning and memory is a possibility. The present study was designed to elucidate the role of RE in acquisition, consolidation, and retrieval on the passive avoidance (PA) task which depends on a distributed network including the thalamus, amygdala, medial prefrontal cortex (mPFC) and hippocampus. For this purpose, rats were chronically implanted with a cannula aimed at the RE through which 0.5 μl tetracaine (2%) or saline were injected. Rats were trained in a PA task and their retention test was performed 24 h later. The injection of saline or tetracaine was applied 5 min before or 5, 90, and 360 min after the acquisition trial and 5 min before the retention tests. Our findings showed that inactivation of RE before training did not affect acquisition, but affected memory retention 24 h later in PA task. Moreover, inactivation of RE only 5 min after training impaired consolidation but not after 90 or 360 min. Also, inactivation of the RE, 5 min before the retrieval test impaired memory retrieval in PA task. In conclusion, it seems that RE is involved in memory processes in rats.     

Sepsis facilitates brain serotonin activity and impairs learning ability in rats

Sepsis often provokes various neurological disorders. Because many neurologic symptoms are caused by changes in neurotransmissions, we investigated the relationship between behavioral alterations and changes in activities of the monoaminergic systems in rats. Sepsis was induced by cecal ligation and puncture. A step-through passive avoidance test was used for the behavioral evaluation. Passive avoidance retention in animals subjected to learning immediately before the septic or sham operation was examined after 24 or 48 h. Retention performance in animals subjected to learning 24 h after the operation was also examined after a further 24 h. Plasma concentrations of amino acids were determined 24 h after the operation. The activities of the brain monoaminergic systems were evaluated by ratios of metabolites to monoamines. Marked damage was found in the septic rats in the blood analysis 24 h after the operation. The plasma concentrations of tyrosine and arginine in the septic rats were decreased to 69% and 70% of those in the sham-operated animals, respectively. Retention performance was impaired in the septic rats when they were subjected to learning 24 h after the operation, but it was not impaired when animals were subjected to learning before the septic operation. The brain concentration of serotonin was increased in the cerebral cortex, striatum, and hippocampus 48 h after the septic operation, but not after 24 h. The concentration of 5-hydroxyindoleacetic acid, a metabolite of serotonin, was increased in the above three regions both 24 and 48 h after the operation, but not in the hypothalamus. Facilitation of the serotonergic activity in the telencephalon and hippocampus is suggested to be involved in the impairment of learning ability in sepsis.     

ACTH release during passive avoidance behavior

ACTH was measured by radioimmunoassay during learning and retention of a passive avoidance response. Electric footshock, used during the learning trial, appeared to be a weaker stimulus for ACTH release than was the retention test. Moreover high latency scores during retention were associated with high plasma ACTH levels, whereas shorter latencies were associated with lower levels. The results indicate that psychological mechanisms organizing behavioral coping are important in the response of the pituitary-adrenocortical system to stimuli which are related to a previous adversive experience.     

Implication of amygdaloid muscarinic cholinergic mechanisms in passive avoidance learning in the developing rat

Young rats, 12–20 days of age, received bilateral microinjections of atropine sulfate (1, 5 and 20 μg) into the basolateral part of the amygdala, and were trained to learn a cool-draft-stimulus passive avoidance task 17 min later. Twelve-day rats did not perform differently from their controls. In contrast, rats 13–20 days of age exhibited significant age- and dose-related acquisition deficits. Sensitivity to atropine was high until day 17, and decreased progressively thereafter. These results demonstrate that muscarinic cholinergic synaptic elements located in the basolateral part of the amygdala are involved in passive avoidance learning in the young rat and begin to function on postnatal day 13. They also suggest that the number of functioning muscarinic receptor sites increase reliably after day 17.     

Tyr-MIF-1 affects passive avoidance behavior but not motor activity in rats

The effects of the brain peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) were tested with several behavioral tests after peripheral injection in rats. In a passive avoidance test, Tyr-MIF-1 (1 mg/kg SC) resulted in significantly faster entry into the second compartment of a two-chamber shuttle box than was found with MIF-1 or diluent. Tyr-MIF-1 also resulted in flinch and escape responses that occurred at reliably lower amperage than the control. No significant effects were obtained on measures of ambulation, rearing, or defecation. The results demonstrate that Tyr-MIF-1 can affect behavior and that this action can differ from that of the same dose of MIF-1.     

Prenatal oxazepam affects passive avoidance performance of preweaning mice

CD-1 outbred mice were exposed to oxazepam on fetal days 12–16 by maternal administration (per os of 15 mg/kg twice daily at 8 a.m. and 8 p.m.) and fostered at birth to untreated dams, while control mice received vehicle solution. Mice were then tested on postnatal day 14 and 15 in a passive avoidance apparatus for their ability to withhold a step-down response from a vibrating platform. The step-down response was punished with a mild footshock. Each animal was subjected to a maximum of 15 trials. Mice prenatally treated with oxazepam showed an impairment in the acquisition of the task as indicated by shorter latencies to step-down throughout the 15 trials in both sessions (days 14 and 15). As control nonreinforced animals prenatally treated with oxazepam did not show a similar alteration in latency to step-down, these data suggest that prenatal exposure to oxazepam influences behavioral performance of preweaning mice in an aversively motivated task.     

Adenosine–amino acid interactions in the chick brain: a role in passive avoidance learning

The present work describes interactions between adenosine and the amino acids glutamate and GABA in slices of intermediate medial hyperstriatum ventrale (IMHV), an area of the chick brain known to be involved in learning and memory events associated with a one-trial passive avoidance task. In slices derived from the IMHV of untrained chicks, the A₁ receptor agonist N⁶-cyclohexyladenosine (CHA; 10 μM) specifically inhibited glutamate release. Conversely, cyclopentyltheophylline (CPT; 100 μM an A₁ antagonist) increased glutamate release from the slices and blocked the CHA-induced inhibition of glutamate. The A₂ receptor agonist 2-p-(2-carboxylethyl)-phenylamino-5′-N-ethylcarboxamido adenosine hydrochloride (CGS 21680) selectively increased glutamate release when applied at 5 μM while it selectively inhibited GABA release at a lower concentration (10 nM). The addition of NMDA to the medium, resulted in increased adenosine release equivalent to that found following stimulation with 50 mM KCl. Both the NMDA and the KCl-induced increases were eliminated by addition of -2-amino-5 phosphopentanoic acid ( -AP5), an NMDA-receptor antagonist. Slices prepared from the IMHV of chicks following successful training on the task showed enhanced adenosine release 30 min, 1, 3 and 6.5 h after training compared to chicks trained to peck a water-coated bead. The results show that changes in adenosine release from the IMHV accompany memory formation in the chick. We suggest that adenosine–amino acid transmitter interactions potentially via the activation of NMDA receptors, a necessary step in long-term memory formation for the task, may modulate the formation of memory for the one-trial passive avoidance task.     

Chronic moderate hyperammonemia impairs active and passive avoidance behavior and conditional discrimination learning in rats

The cerebral dysfunction associated with hepatic encephalopathy is generally considered to have hyperammonemia as one of its main causes. Hyperammonemia impairs the neuronal glutamate-nitric oxide-cyclic GMP pathway and the induction of NMDA receptor-dependent long-term potentiation in the hippocampus. We studied the performance of pre/neonatally and postnatally exposed rats to hyperammonemia on active avoidance, passive avoidance, and conditional discrimination tasks. Pre/neonatal hyperammonemia slowed learning of active avoidance behaviors and impaired memory for the passive avoidance task while postnatal hyperammonemia impaired learning on the conditional discrimination task. Hyperammonemia thus may produce cognitive disturbances that relate to the effects of ammonia on the neuronal glutamate-nitric oxide-cyclic GMP pathway.     

Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments

In this study we analyzed the effect on behavior of a chronic exposure to brain-derived neurotrophic factor (BDNF), by analysing a mouse line overexpressing BDNF under the αCaMKII promoter, which drives the transgene expression exclusively to principal neurons of the forebrain. BDNF transgenic mice and their WT littermates were examined with a battery of behavioral tests, in order to evaluate motor coordination, learning, short and long-term memory formation. Our results demonstrate that chronic BDNF overexpression in the central nervous system (CNS) causes learning deficits and short-term memory impairments, both in spatial and instrumental learning tasks. This observation suggests that a widespread increase in BDNF in forebrain networks may result in adverse effects on learning and memory formation.     

Pontine-wave generator activation-dependent memory processing of avoidance learning involves the dorsal hippocampus in the rat

The aim of this study was to test the hypothesis that the dorsal hippocampus plays a critical role in pontine-wave (P-wave) generator activation-dependent memory processing of two-way active avoidance (TWAA) learning. To achieve this objective, rats were given small bilateral lesions in the CA1, dentate gyrus (DG), or CA3 region of the dorsal hippocampus by microinjecting ibotenic acid. After recovery, lesioned and sham-lesioned rats were trained on a TWAA learning paradigm, allowed a 6-hr period of undisturbed sleep, and then were tested on the same TWAA paradigm. It was found that lesions in the CA3 region impaired retention of avoidance learning. Conversely, lesions in the CA1 and DG regions had no effect on TWAA learning retention. None of the groups showed any changes in the baseline sleep-wake cycle or in the acquisition of TWAA learning. All rats showed increased rapid eye movement (REM) sleep and increased REM sleep P-wave density during the subsequent 6-hr recording period. Impaired retention in the CA3 group occurred despite an increase in REM sleep and P-wave density, suggesting that during REM sleep, the P-wave generator interacts with the CA3 region of the dorsal hippocampus to aid in consolidation of TWAA learning. The results of the present study thus demonstrate that P-wave generator activation-dependent consolidation of memory requires an intact CA3 subfield of the dorsal hippocampus. The results also provide evidence that under mnemonic pressure, the dorsal hippocampus may not be involved directly in regulating the sleep-wake cycle.     

Ascorbic acid in the brain

Ascorbic acid is highly concentrated in the central nervous system. Measurement of the extracellular concentration of ascorbate in animals, mainly by the technique of voltammetry in vivo, has demonstrated fluctuation in release from neuropil, both spontaneously and in response to physical stimulation of the animal and to certain drugs. Although in the adrenal medulla ascorbate is co-released with catecholamines, release of ascorbate from brain cells is associated principally with the activity of glutamatergic neurones, mainly by glutamate-ascorbate heteroexchange across cell membranes of neurones or glia. This phenomenon is discussed in relation to a possible role of ascorbate as a neuromodulator or neuroprotective agent in the brain.     

The corticosteroid synthesis inhibitors metyrapone and aminoglutethimide impair long-term memory for a passive avoidance task in day-old chicks

Long-term memory for a passive avoidance task in day-old chicks has proved to depend upon an action of the adrenal steroid corticosterone through specific receptors in a brain region, the intermediate medial hyperstriatum ventrale (IMHV), involved in learning the task. In this study, we questioned whether pretraining peripheral administration of drugs described to inhibit either basal levels of corticosterone – aminoglutethimide – or treatment-induced stimulated corticosterone secretion – metyrapone – might interfere with retention for the task at 24 h post-training. The results showed a dose-dependent effect of the inhibitors, with the highest doses tested for both drugs (10 and 50 mg/kg for metyrapone, and 50 mg/kg for aminoglutethimide) being amnestic for the task. Additional experiments, in which we studied possible effects of the inhibitors on concomitant aspects of learning (i.e., reactivity to novelty, and pecking pattern), show that the drugs did not affect general behavioural reactivity. The present results thus support the idea that training-induced corticosterone release plays a key role in the neurobiological processes that determine the establishment of a persistent memory for the aversively motivated avoidance response. In addition, they point to corticosteroid inhibitor drugs as potential tools for the study of the interactions between steroid hormones and cognition-enhancing compounds in this learning task.     

Lesioning of the rat basal forebrain leads to memory impairments in passive and active avoidance tasks

Effects of the bilateral electrolytic lesioning of the basal forebrain (BF), including the ventral globus pallidus, on passive or active avoidance tasks, were studied in male Wistar rats. A severe deficit in acquisition of passive avoidance response was produced by the lesioning in the posterior level of BF. The retention of the passive avoidance response was markedly disrupted with post-training lesioning. Time-dependent but only slight recovery from the memory impairments was observed in the passive avoidance task given 4,8 or 16 weeks after BF lesions. The acquisition of active avoidance response using a two-way shuttle ☐ was also disturbed by BF lesioning. Retention of active avoidance response was clearly impaired by post-training lesions of the BF. The BF lesioned rats gradually acquired the passive avoidance performance when trained repeatedly at 24- or 48-h intervals, by giving a foot shock in case of avoidance failure. Extinction of the acquired passive avoidance response rapidly occurred in the BF lesioned rats. Furthermore, neurotoxic lesions of BF with kainic acid produced a significant impairment in acquisition of passive avoidance response.These results suggest that bilateral BF lesions impair the acquisition and retention of passive or active avoidance response, and that these impaired rats may be useful as an experimental model for Alzheimer's disease and senile dementia.     

Ascorbic acid prevents water maze behavioral deficits caused by early postnatal methylmalonic acid administration in the rat

Methylmalonic acidemia consists of a group of inherited neurometabolic disorders biochemically characterized by accumulation of methylmalonic acid (MA) and clinically by progressive neurological deterioration whose pathophysiology is not yet fully established. In the present study we investigated the effect of chronic administration (from the 5th to the 28th day of life) of methylmalonic acid (MA) on the performance of adult rats in the Morris water maze task. MA doses ranged from 0.72 to 1.67 μmol/g of body weight as a function of animal age; control rats were treated with the same volume of saline. Chronic postnatal MA treatment had no effect on body weight and in the acquisition of adult rats in the water maze task. However, administration of MA provoked long lasting reversal learning impairment in this task. Motor activity, evaluated by the swim speed in the maze, was not altered by MA administration, indicating no deficit of locomotor activity in rats injected with the metabolite. We also determined the effect of ascorbic acid administered alone or combined with MA on the same behavioral parameters in order to test whether free radicals might be responsible for the behavioral changes observed in MA-treated animals. Ascorbic acid was able to prevent the behavioral alterations provoked by MA. Moreover, the in vitro exposure of hippocampal and striatal preparations to MA revealed that the acid significantly reduced total radical-trapping antioxidant potential (TRAP) and total antioxidant reactivity (TAR) in the striatum, but not in the hippocampus. Furthermore, MA increased the thiobarbituric acid–reactive substances (TBA–RS) measurement in both structures. These data indicate that oxidative stress might be involved in the neuropathology of methylmalonic acidemia and that early MA administration induces long-lasting behavioral deficits, which are possibly caused by oxygen reactive species generation.