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Avoidance learning in autoimmune mice.

Previous studies have shown that autoimmune mice perform very poorly on active avoidance learning tasks. In the current studies, mice with lupus-like systemic autoimmunity were able to learn active, as well as passive, avoidance protocols with shock as reinforcement. Therefore, the behavioral deficits seen in active avoidance tasks are not a consequence of the use of electric shock. Rather, the current findings suggest that the inability of autoimmune mice to learn shock motivated responding is due to multiple performance factors, including shock level and properties of the testing apparatus.

Animals↗

Identification of the opioid receptors involved in passive-avoidance learning in the day-old chick during the second wave of neuronal activity.

Long-term memory formation for passive-avoidance learning in the day-old chick is known to have two distinct time windows of protein synthesis (F.M. Freeman, S.P.R. Rose, A.B. Scholey, 1995. Two time windows of anisomycin-induced amnesia for passive-avoidance training in the day-old chick. Neurobiol. Learn. Mem. 63, 291-295). The lobus parolfactorius (LPO) is thought to be an important site for the second wave of protein synthesis which occurs 4-5 h after training. Birds received bilateral intracranial injections of agonists and antagonists for the mu-, delta-, kappa-opioid receptors and the opioid receptor-like (ORL(1)) receptor directly into the LPO at 5 h post-training and were tested for recall 24 h later. Also, 100 microM beta-funaltrexamine (beta-FAN), a mu-opioid receptor antagonist, significantly impaired memory formation (P<0.01). The delta-opioid receptor was also involved in memory formation at this time-point since antagonism of this receptor by 1 mM ICI-174,864 caused amnesia (P<0.01) which was reversed by the agonist, DPLPE. The kappa-opioid receptor appeared not to be involved during the second phase of neuronal activity since neither stimulation by dynorphin nor inhibition by nor-BIN caused amnesia for the task. The ORL(1) receptor agonist orphanin FQ also had no effect suggesting that this receptor was not involved at this 5-h time-point. Cytosolic and mitochondrial protein synthesis has been shown to be important in passive-avoidance learning in the day-old chick. Both chloramphenicol (CAP) and anisomycin (ANI), inhibitors of mitochondrial and cytosolic protein synthesis, respectively, caused disruption when injected 5 h post-training into the LPO (P<0.05). Endomorphin-2 (Endo-2), a mu-opioid receptor agonist, reversed both the ANI- and CAP-sensitivity. However, DPLPE, a delta-opioid receptor agonist, only reversed the effect due to CAP. Possible mechanisms for these effects are discussed.

Age Factors↗

Subchronic treatment with prazosin improves passive avoidance learning in aged mice: possible relationships to alpha1-receptor up-regulation.

While many evidences indicate that deficits of central noradrenergic neurotransmission are involved in the age-related decline of cognitive functions in animals and man, very little is known about the specific role of central alpha1-adrenergic receptors. Therefore, this problem was specifically addressed in the present communication using the alpha1-adrenoceptor antagonist prazosin as pharmacological tool. While the acute administration of prazosin did not affect passive avoidance learning of young or aged mice, an improvement of learning capabilities was seen after subchronic treatment, but for the aged animals only. An U-shaped dose response curve was seen. 0.3 mg/kg prazosin was most effective. Very interestingly, only for this dose a significant up-regulation of the density of alpha1-adrenoceptors in the mouse brain was found in the aged animals only. The data suggest a possible causal relationship between effects of prazosin on passive avoidance learning and central alpha1-receptor density.

Adrenergic alpha-Antagonists↗

Ginkgo biloba extract (EGb 761) independently improves changes in passive avoidance learning and brain membrane fluidity in the aging mouse.

Decreases in cell membrane fluidity may be a major mechanism of age-related functional decline. A prime cause for the decline of membrane fluidity may be the presence of free radicals. Gingko biloba extract EGb 761 protects neuronal cell membranes from free radical damage in vitro. Further, EGb 761 has repeatedly been shown to improve cognitive functions in man and in laboratory animals. To test if there is a link between these two actions we assessed the effects of EGb 761 on passive avoidance learning and on neuronal membrane fluidity in vivo in young (three-month-old), middle-aged (12-month-old) and aged (22 to 24-month-old) female NMRI mice. The animals were treated daily with 100 mg/kg EGb 761 for three weeks. There was a significant improvement in short-term memory, measured by the avoidance latency 60 seconds after the aversive stimulus (p < 0.0311), and of membrane fluidity (p < 0.01) in the aged animals, but no improvement in long-term memory as measured by the avoidance latency 24 hours after shock. However, no significant correlation between membrane fluidity and short-term memory performance was found. Taken together, these results indicate that EGb 761 independently improves changes in passive avoidance learning and brain membrane fluidity.

Aging↗

The effect of different hypertension models on active avoidance learning.

This study tested the effects of different hypertension models on active avoidance learning in rats. Three-month-old male Wistar rats were divided randomly into six groups as follows: control (C), sham operated (sham), two kidney-one clip (2K-1C), one kidney-one clip (1K-1C), deoxycorticosterone-salt (DOCA), and N-omega-nitro-L-arginine-methyl ester (L-NAME) groups. Mean arterial blood pressures were significantly higher in four hypertensive groups compared with control and sham groups. The active avoidance training results indicated that hypertension state is associated with learning impairment. Thiobarbituric acid-reactive substances (TBARS) were determined as an indicator of lipid peroxidation in brain and hippocampus. Additionally, brain and hippocampus nitrite levels were studied.

Animals↗

Hyperalgesia, low-anxiety, and impairment of avoidance learning in neonatal caffeine-treated rats.

RATIONALE: The nonselective adenosine receptor antagonist caffeine is used clinically to treat apnea in preterm infants. The brain developmental stage of preterm infants is usually at a period of rapid brain growth, referred as brain growth spurt, which occurs during early postnatal life in rats and is highly sensitive to central nervous system (CNS) acting drugs. OBJECTIVES: The aim of this work was to study whether caffeine treatment during brain growth spurt produces long-term effects on the adenosine receptor-regulated behaviors including nociception, anxiety, learning, and memory. METHODS: Neonatal male and female Sprague-Dawley rats were administered either deionized water or caffeine (15-20 mg kg(-1) day(-1)) through gavage (0.05 ml/10 g) over postnatal days (PN) 2-6. The hot-plate test, elevated plus-maze, dark-light transition test, and step-through inhibitory avoidance learning task were examined in juvenile rats. Furthermore, the responses to adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA)-induced hypothermia and A(2A) receptor agonist CGS21680-induced locomotor depression were also compared. RESULTS: Caffeine-treated rats showed hyperalgesia in hot-plate test, less anxiety than controls in the elevated plus-maze and dark-light transition, and impairment in step-through avoidance learning test. Moreover, the responses to CPA-induced hypothermia and CGS21680-induced locomotor depression were enhanced in caffeine-treated rats. CONCLUSION: These results indicate that caffeine exposure during brain growth spurt alters the adenosine receptor-regulated behaviors and the responsiveness to adenosine agonists, suggesting the risk of adenosine receptor-related behavioral dysfunction may exist in preterm newborns treated for apnea with caffeine.

Adenosine↗

Intraseptal injection of scopolamine increases the effect of systemic diazepam on passive avoidance learning and emotionality in rats.

This experiment was designed to assess the role of the septo-hippocampal cholinergic (ACh) system in the deleterious effects produced by systemic benzodiazepine injection on learning processes in rats. Retention of a step through passive avoidance task was analysed after systemic injection of increasing doses of either scopolamine or diazepam applied alone 30 min before the acquisition phase. Results indicated a dose related impairment of retention by each drug: in addition, sub-threshold doses of scopolamine and diazepam applied in combination (diazepam: 2mg/kg plus scopolamine: 0.3mg/kg) produced a decrease of retention latencies, thus showing an additive effect of the combined treatment. Secondly, a sub-threshold dose of scopolamine (15microg/0.5microl) was also administered into the medial septal area, together with an i.p. injection of 2mg/kg of diazepam. This combined treatment produced a severe impairment of retention, in parallel with a large reduction in emotionality (number of faeces). The data are consistent with the hypothesis that peripheral administration of behaviorally effective doses of diazepam on passive avoidance learning might act partially via a septal ACh-GABA/benzodiazepine mechanism. It is also suggested that this mechanism subserves both anxiety and the memorisation of contextual stimuli associated with passive avoidance acquisition, through the modification of the septo-hippocampal activity.

Animals↗

The effects of cholinergic drugs support an avoidance learning hypothesis of brief footshock-induced analgesia.

Rats were tested for tail-flick responses and then immediately subjected to footshock for 30 sec. This procedure induced analgesia, i.e. prolonged the latency of the tail-flick response, which was maximal immediately after the shock and decayed to normal levels within 2 hr. No analgesia occurred if either the analgesia test before the shock or the shock itself was omitted. The dependence of the analgesia on the association between the test before the shock plus the shock, suggests that this was a form of avoidance learning. The effects of drugs injected immediately after the shock were determined on latency of the tail-flick response, measured 2 hr later. Drugs known to improve memory, including physostigmine, pramiracetam and the muscarinic agonists, oxotremorine and RS 86, selectively induced analgesia in rats subjected to test before the shock plus the shock, thereby supporting a hypothesis of avoidance learning. Neostigmine and atropine methyl nitrate had no effect, indicating that the effects were mediated centrally. The learning effects were distinguishable from analgesia induced by drugs, since morphine increased analgesia regardless of the presence or absence of the test before shock or the shock. Also, naloxone, which had no effect per se, blocked analgesia induced by morphine but enhanced physostigmine-induced analgesia. Neither chlordiazepoxide nor D-amphetamine produced any changes in the latency of the tail-flick responses indicating that neither anxiolytic/muscle relaxant nor stimulant actions were involved.

Analgesia↗

Effects of developmental lead exposure on inhibitory avoidance learning and glutamate receptors in rats.

Chronic lead (Pb) exposure during development is known to produce learning deficits. AMPA and NMDA receptors have been shown to participate in the synaptic mechanisms involved in certain forms of learning and memory. We investigated whether the effects of Pb on AMPA and NMDA receptors are associated with Pb-induced impairment in learning and memory. Rats were exposed to 0.2% lead acetate at different developmental stages including a maternally exposed group (including gestation and lactation period), a postweaning exposed group, and a continuously exposed group. Lead treatment impaired learning acquisition, but not memory retention in step-down avoidance learning task in all treatment groups. In parallel with the behavioral data, autoradiographic analyses of brain sections indicated that the [3H]AMPA binding was decreased in the CA1 and dentate gyrus of the hippocampus and entorhinal cortex in all three Pb-exposed groups. However, an increase in [3H]MK801 binding was only observed in CA1 of the hippocampus in the continuously Pb-exposed rats. The findings suggest that alterations in AMPA receptor may contribute to the Pb-induced deficits in learning acquisition of inhibitory avoidance.

Journal Article↗

Chronic aerial exposure to glucorticoids or beta-agonists affects avoidance learning and exploratory motivation in rats.

The purpose of the present work was to examine if the conventional asthma treatments in humans (inhalation of glucocorticoids or beta-agonists, administered in a chronic regimen) might affect behavioral processes (learning and exploratory motivation) in rats. Adult male rats were exposed to an atmosphere saturated with either saline, budesonide (a glucocorticoid), or salbutamol (a beta-adrenergic receptor agonist) in a forced ventilation cage, connected to a nebulizer for 5 min twice a day for 15 days at the same hours of the day. Doses of budesonide in the nebulizing solution were 0.116, 1.16, and 11.6mM. Doses of salbutamol in the nebulizing solution were 1.3, 13, and 130 mM. Forty-eight hours after treatment, the different groups were subjected to exploration of an elevated asymmetric plus-maze (APM, model of exploratory motivation), and 24h later to learning of an avoidance response to an ultrasonic tone in a two-compartment cage (model of memory and learning). Results showed that budesonide induces moderate effects on exploratory motivation. In one of the fear-inducing arms (single wall arm), exploration decreased and this effect was not dose dependent. In the cognitive model, glucocorticoids affected slightly the latency to escape but with no interference in memory efficiency. On the other hand, at the lower dose in the APM, salbutamol increased significantly the exploration of both fear-inducing arms (no walls and single wall arms). In the learning model, the beta-agonist induced two opposing effects. The lower dose (1.3mM) facilitated learning and the higher dose (13 mM) inhibited learning instead. In conclusion, results are compatible with the notion that inhaled glucocorticoids or beta-agonists might cross the lung aerial barrier into the blood compartment, exerting effects on learning and motivation functions.

Administration, Inhalation↗

Odour and colour as cues for taste-avoidance learning in domestic chicks

In addition to being visually conspicuous, many chemically defended insects also produce olfactants when attacked. These olfactants may constitute 'warning odours', comparable in their effects to warning colours. This hypothesis was tested by examining the ability of two odours, almond and vanilla, to act as cues for avoidance of quinine-flavoured water in domestic chicks, Gallus gallus domesticusIn experiment 1, chicks were trained to avoid familiar-coloured quinine solution, novel-coloured solution, or novel-smelling solution. When the novel smell was almond it enhanced the rate of avoidance learning, as did the novel colour cue; but vanilla odour had no effect on rate of learning. In experiment 2, chicks were trained to avoid quinine solution that was paired with a compound cue involving both colour and odour. They were then tested in extinction with both cues, either cue alone, or neither cue. When the odour cue was almond it overshadowed the colour cue: chicks that had learned to avoid almond-smelling quinine solution of a particular colour subsequently avoided almond-smelling water and drank water that did not smell of almond, regardless of its colour. Vanilla odour, by contrast, exerted no control over behaviour when paired with a colour cue during acquisition. In experiment 3, chicks were trained to discriminate palatable from quinine-flavoured water when the latter was distinguished solely by an odour cue. The discrimination was learned more readily when the cue was almond than when it was vanilla; and a memory test revealed significant avoidance of almond odour, but not of vanilla, after 24 h. We conclude that odours can act as discriminative stimuli for taste-avoidance learning in birds and that they can sometimes exert more powerful control over behaviour than do visual cues. However, not all odours are equally efficacious. The results are discussed in relation to aposematism and mimicry.

Journal Article↗

Medial geniculate, amygdalar and cingulate cortical training-induced neuronal activity during discriminative avoidance learning in rabbits with auditory cortical lesions.

This study addressed the neural mediation of discriminative avoidance learning, wherein rabbits step in a wheel apparatus in response to an acoustic conditional stimulus, the CS+, to avoid a foot shock, and they learn to ignore a different stimulus, the CS-, not followed by foot shock. Previously, muscimol-induced inactivation of the amygdala in the first session of training prevented learning during the inactivation and permanently blocked the development of discriminative training-induced neuronal activity (TIA) in the medial division of the medial geniculate nucleus (MGm). These results suggested that amygdalar neurons induce discriminative TIA in the MGm via basolateral (BL) amygdalar axonal projections to the auditory cortex. To test this hypothesis, the activity of neurons in the MGm was recorded during learning in rabbits with lesions of the auditory cortex. Recordings were also made in the lateral and BL amygdalar nuclei and in the cingulate cortex. In support of the hypothesis, discriminative learning in rabbits with lesions was impaired significantly during early training sessions 1-4; in these same sessions, discriminative TIA was abolished in the MGm, the BL nucleus, and the anterior cingulate cortex. The lesions also blocked posterior cingulate cortical discriminative TIA in training sessions 1-2 but spared TIA in sessions 3-7. Lateral amygdalar neurons showed gradual development of discrimination that was not significantly affected by the lesions. The results demonstrate a critical role of auditory cortex in early discriminative learning and in the production of early discriminative TIA in multiple areas.

Acoustic Stimulation↗

Changes in binding to muscarinic and nicotinic cholinergic receptors in the chick telencephalon, following passive avoidance learning.

Changes in nicotinic and muscarinic cholinergic receptors 30 min after one-trial passive avoidance training were studied in day-old chicks (Gallus domesticus), by quantitative receptor autoradiography. [3H]-alpha-bungarotoxin (alpha-BgT) and [3H]-quinuclidinyl benzilate (QNB) were used to monitor changes in 15 forebrain regions for nicotinic and muscarinic receptors, respectively. A significant increase occurred bilaterally in the quantity of bound alpha-BgT in the lobus parolfactorius, while the amount of bound QNB decreased significantly, and bilaterally, in the hippocampus, hyperstriatum ventrale, lobus parolfactorius and posterolateral telencephalon, pars dorsalis. The data support an involvement of cholinergic receptor types in the neural mechanisms underlying passive avoidance learning.

Animals↗

Effects of NMDA receptor antagonists on passive avoidance learning and retrieval in rats and mice.

The effects of NMDA antagonists on passive avoidance learning, shock sensitivity and locomotor activity were examined. Pre-training administration of the antagonists 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) in mice and rats resulted in impaired performance in a retention test 24 h later. No such impairment resulted from immediate post-training administration of either compound in either species. In addition neither compound, given only before the retention test, reduced the retention latencies of mice. In rats CPP was similarly ineffective whereas MK-801 reduced retention latencies, but only at a dose which significantly elevated locomotor activity at the time of the retention test. As assessed by vocalization threshold in mice and by the proportion of animals vocalizing in response to the passive avoidance training shock, neither compound produced analgesia. The vocalization threshold was, in fact, slightly reduced by both compounds. MK-801, but not CPP, stimulated locomotor activity in mice. These results indicate that in the passive avoidance task activation of NMDA receptors is involved in memory formation, but is not critical for the maintenance of memory or its retrieval.

Animals↗

Genetic determinants of individual differences in avoidance learning: behavioral and endocrine characteristics.

Bidirectional genetic selection for good and poor active avoidance learning in a shuttle box has been carried out in three independent laboratories using remarkably similar discrete-trial training procedures. The resulting strains are known as the Roman High and Low Avoidance (RHA and RLA), the Syracuse High and Low Avoidance (SHA and SLA) and the Australian High and Low Avoidance (AHA and ALA) strains, respectively. An additional unidirectionally selected strain, known as the Tokai High Avoider (THA) strain was developed in Japan using a free-operant Sidman avoidance procedure in a Skinner box. This paper reviews the selection of the Syracuse strains, enumerates the various behavioral and endocrine characteristics of the strains, and compares them to the other similarly selected strains. The behavioral work suggests that genetic selection from diverse breeding stocks has resulted in common characteristics that differentiate the strains in the emotional, not learning, domain. The endocrine data, however, are somewhat at odds. The Syracuse strains differentiate one way with respect to endocrine function, and the Roman strains differentiate in the opposite way. We suggest, therefore, that the endocrine correlates are not tightly linked to the avoidance genotype. Genetic analysis of all of the selected strains for both the avoidance phenotype and the endocrine correlates will be needed to test this hypothesis.

Animals↗

Role of brain-derived neurotrophic factor and presynaptic proteins in passive avoidance learning in day-old domestic chicks.

The consolidation of a one-trial passive avoidance learning task in the day-old chick involves a number of transient and longer-term biochemical processes, including increased release of glutamate. This study demonstrated that brain-derived neurotrophic factor, a proposed modulator of synaptic transmission and neurotransmitter release, is involved in the cascade associated with memory consolidation in the chick and that its actions were linked to modulation of expression of SNAP-25, syntaxin and synaptophysin, required for exocytosis. Intracerebral injections of 5 microl of antibodies to brain-derived neurotrophic factor into the left and right intermediate medial hyperstriatum ventrale resulted in a dose-dependent reduction in avoidance of an "aversive" bead by 3 h after training. Neurotrophin antibodies (0.5 microg/chick) administered between 1 h before, and up to 30 min after, training induced amnesia by 3 h which was sustained for at least 24 h. Injections of recombinant brain-derived neurotrophic factor (50 microg/ml; 0.5 microg/chick) just before training maintained avoidance in birds trained with a weaker aversant (10% methylanthranilate), such that chicks showed enhanced recall at times (24 h) beyond that when shorter-term forms of memory have decayed. In lysed synaptosomal membranes prepared from chicks injected with antibodies to brain-derived neurotrophic factor there was a decrease in expression of SNAP-25 and syntaxin in the left, but not the right, intermediate medial hyperstriatum ventrale, a region known to be associated with memory formation, which correlated with the decrease in neurotrophin concentration. Thus, these data indicate that brain-derived neurotrophic factor is involved in the formation of a long-term memory for an aversive stimulus and may function as a modulator of presynaptic proteins associated with exocytosis, enabling increases in neurotransmitter release.

Animals↗