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Passive avoidance deficits following lesions of the posteroventral hippocampo-subiculo-entorhinal area in the developing rat.

Young rats, 13, 16, and 20 days of age, underwent discrete bilateral electrolytic lesions of the posteroventral hippocampo-subiculo-entorhinal area, and were trained on a cool-draft-stimulus passive avoidance task 20 min later. Significant deficits in passive avoidance learning were observed at all ages studied following either small or more extended damage as compared to performance of sham-lesioned animals. The impairment was dependent upon the size of the lesion. Extended bilateral lesions of the parietal cortex overlying hippocampus induced no deficit. These results confirm that this part of the hippocampal complex plays a role in passive avoidance learning in the rat. They also show that this control of behavior is already established by the second week of life, thus supporting our previous experiments that demonstrate a cholinergic nicotinic involvement of this region in acquisition of passive avoidance as early as the 11th day of age.

Age Factors↗

Response to electric shock in rats: effects of selective midbrain raphe lesions.

The forebrain serotonin (5-HT) concentrations of rats with lesions in the median (M; n equal to 5), dorsal (D; n equal to 5), and both (DM; n equal to 6) midbrain raphe nuclei were, respectively, 22, 48, and 70% lower than in control animals (n equal to 10). The lesion and control groups, however, did not evidence differences in pain sensitivity as measured by the flinch-jump technique. On the other hand, of the animals tested, those with M (n equal to 3) and DM (n equal to 4) lesions required more trials than controls (n equal to 6) to acquire a one-way avoidance response. D lesion rats (n equal to 2) did not differ from controls in one-way avoidance learning, except in terms of prolonged escape latencies during the first three trials. The previously reported increased sensitivity to painful stimuli subsequent to medial forebrain bundle lesions or para-chlorophenylalanine administration, therefore, does not appear to be due exclusively to disruption of ascending 5-HT fibers originating in the dorsal and median raphe nuclei. The effects of midbrain raphe lesions of avoidance learning, furthermore, depend on lesion locus, and are not due to either hypo- or hyperalgesia.

5,6-Dihydroxytryptamine↗

Effects of intracerebroventricularly administered somatostatin on passive avoidance, shuttle-box behaviour and open-field activity in rats.

Behavioural effects of somatostatin after intracerebroventricular (icv) administration have been investigated in male rats. In a passive avoidance learning test, somatostatin (1 microgram), given 30 min before the learning session, increased the avoidance latency at 24 h, but not at 48 h, after the injection, when compared to a 10 micrograms treated group. However, compared to a saline treated group, somatostatin (0.01, 0.1, 1, or 10 micrograms) did not significantly influence the avoidance latency. In a shuttle box experiment somatostatin (1 microgram) facilitated the learning process. In an open-field behaviour test, immediately after the 24 h passive avoidance test, 10 micrograms of the peptide decreased the rearing activity without influencing other open field behaviours, like locomotion, grooming and defecation. In a second open-field experiment somatostatin (1 microgram), given 30 min prior to the test, similarly as in the shuttle box learning experiment, increased the locomotion of the animals. These data suggest that somatostatin influences both the passive avoidance and shuttle box behaviours. The peptide-induced motor performance of the animals may play an important role in influencing the responses observed in these behavioural tests.

Animals↗

Effects of genetic and nutritional factors on post-natal reflex and behavioral development in the mouse.

The development of a number of reflex activities, of the electrocorticogram (ECoG), and measures of brain and body weight were assessed at different ages from birth to maturity in mice belonging to Swiss-Webster stock and two inbred strains (C57BL/6J and SEC/1Re). The animals also were tested at 60 days of age for exploratory activity and avoidance behavior. These effects of postnatal undernutrition on the measures of reflex and ECoG activity, brain and body weight and avoidance learning were determined at different ages after birth and in adult animals following dietary rehabilitation. Undernutrition during suckling period was introduced by increasing the litter size from 4 pups to 8 or 16 pups per litter. The results indicate that early malnutrition delayed the development of the reflex and ECoG activities and permanently altered brain growth and avoidance learning. The effects were different, depending on the genotype considered. The data indicate that strains characterized by a slower development of brain function do not show early signs of brain malfunction following undernutrition.

Age Factors↗

Behavioral and electrophysiological studies of chronic oral administration of L-type calcium channel blocker verapamil on learning and memory in rats.

It has been shown that L-type voltage dependent calcium channels (VDCCs) have important role in learning and memory. In vivo and in vitro electrophysiological recordings of hippocampal neurons have demonstrated their involvement in long-term potentiation (LTP), which considers being one possible cellular mechanism underlying learning and memory. The long-term effect of VDCCs of hippocampal dentate gyrus (DG) so far on synaptic plasticity has not received much attention. In this study, the effect of chronic (60 days) oral administration of L-type calcium channel blocker verapamil on learning and memory and synaptic plasticity of hippocampal dentate gyrus in rats has been investigated. L-type calcium channel antagonist, verapamil chronically and orally at different doses (10, 20 and 50 mg/kg) was used to investigate learning and memory by passive avoidance learning. LTP in perforant-DG synapses was assessed (by either 200 or 400 Hz tetanization) in order to investigate long-term effect of verapamil on synaptic plasticity. In this case, field excitatory postsynaptic potential (fEPSP) slope and population spike (PS) amplitude were measured. Our behavioral study has shown that chronic oral treatment of verapamil has no effect on learning whereas verapamil (50 mg/kg) decreased memory retrieval. Verapamil (20 and 50 mg/kg) inhibited EPSP-LTP induction at 400 Hz but not at 200 Hz tetanization. Furthermore, only verapamil (50mg/kg) decreased PS-LTP with respect to control group. These data suggest that 400 Hz LTP is required for activation of L-type VDCCs and it seems that verapamil is more effective on L-type calcium channels of DG dendrites than their soma.

Administration, Oral↗

Early handling influences on behavioral and physiological responses during active avoidance.

The effects of early handling on behavioral and physiological responses of the rat during active avoidance learning were investigated. Handled and nonhandled males and females were run in a 2-way shuttlebox task with an unconditioned stimulus of either .5 mA or .8 mA. Animals exposed to .8 mA showed a higher corticosterone response, a shorter response latency, and increased defecation. Early handling did not affect performance of the task, however handling did alter the patterns of the plasma corticosterone response over the course of avoidance training. Handled females showed less elevation of plasma corticosterone than nonhandled females, but all females showed a decrease in corticosterone over the course of avoidance learning. All males showed the drop in corticoids if run at .5 mA shock, but only handled males showed this change at .8 mA shock.

Animals↗

The effect of delta 9-tetrahydrocannabinol and LSD on the acquisition of an active avoidance response in the rat.

The course of active avoidance learning of rats in a symmetrical Y-maze under the influence of 1, 3, and 9 mg/kg of delta 9-THC i.p., and 5, 20, and mug/kg of LSD was investigated. Delta-THC in a dosage of 1 mg/kg had no effect on avoidance learning. Three to a lesser extent 9 mg/kg produced more rapid learning with a significantly better performance. Learning under delta 9-THC proved to be state-dependent. The withdrawal of delta 9-THC caused a decrease in the avoidance rate, which was dependent on the dosage. Upon renewal of the THC doses, the animals reattained their earlier preformance. In the course of the experiment there was rapid tolerance development, especially of the sedative properties of THC. LSD retarded the rate of acquisition of the active avoidance response. Whereas the control animals displayed over 80% successful active avoidance from the 14th session onwards, this was achieved by the LSD groups only after the 20th session. However, in contrast to the control group the LSD animals were able to increase their avoidance rate to over 90%, and this was maintained to the end of the experiment (a total of 24 sessions with LSD). The sudden withdrawal of LSD produced a fall in avoidance rate, which was dependent on the pervious training dosage; as with delta 9-THC state-dependent learning can also be assumed for LSD.

Animals↗

Learning: neural analysis in the isolated brain of a previously trained mollusc, Pleurobranchaea californica.

The neural manifestations of food avoidance learning in the mollusc, Pleurobranchaea, survive the surgical reduction of the preparation to the nearly isolated brain. These manifestations include increased synaptic inhibition and reduced synaptic excitation of the phasic paracerebral feeding command interneurons (PCps) in the brain in response to food stimulation of chemosensory structures left attached to the brain. The same changes are not evident, however, in brains removed from naive, control or satiated specimens. Therefore the nearly isolated brain preparation permits analysis of the cellular substrates of learning in relative isolation from non-associative motivational variables. The isolated brain preparation is here used to show that the increased synaptic inhibition consequent to associative training is distributed not only to the PCps but also to their identified central presynaptic inputs, including other identified feeding command interneurons (PSEs and ETIIs; ref. 21). The decrease in PCp excitation is explained in part by a training-induced inhibition of excitatory inputs to the PCps, and in part by a training-induced reduction in the efficacy of an identified polysynaptic excitatory pathway presynaptic to the PCps.

Animals↗

Hyperactivity to novelty induced by social isolation is not correlated with changes in D2 receptor function and binding in striatum.

RATIONALE: Prolonged social isolation has been reported to induce different behavioral disturbances, among the most consistent of which are the increased locomotor response to novelty and the effects of psychostimulants. While these behavioral changes have been partly related to a dysregulation of dopaminergic activity in striatum (dorsal and ventral), the involvement of changes in the function of dopamine receptors is still a matter of controversy. OBJECTIVES: To investigate the effects of prolonged social isolation on the function of D2 receptors at both the behavioral and biochemical levels. METHODS: Sprague-Dawley rats were randomly placed at 21 days of age in groups or isolation for 2 months. Horizontal and vertical locomotor activities induced by novelty and also by systemic injections of the D2 agonist quinpirole (0.15, 0.50 and 1.5 mg/kg i.p.) and their modulation by the A2A agonist CGS 21680 (0.1 mg/kg i.p.) were studied. The effects of social isolation on the avoidance learning assessed by the passive avoidance test were also studied. Binding experiments were performed to study the number and affinity of D2 receptors by means of saturation and competition experiments with the D2 antagonist [(3)H]-raclopride and the interaction between D2 receptors and the G-protein by means of [(35)S]-GTPgammas binding in dorsal/ventral striatal membranes of both grouped and isolated rats. RESULTS: Rats reared in isolation were hyperactive to a novel environment and showed shorter retention latencies in the passive avoidance test. Isolation rearing did not modify the increase in motor activity produced by quinpirole nor the counteraction of these effects by the simultaneous stimulation of A2A receptors. Likewise, the number, affinity and functional efficacy of D2 receptors were not changed by social isolation. CONCLUSIONS: These results suggest that the hyperactivity to novelty and psychostimulants as well as other behavioral changes induced by social isolation do not parallel changes in the in vivo function or binding of D2 receptors in dorsal/ventral striatum.

Animals↗

State-dependent recall can be induced by protein synthesis inhibition: behavioural and morphological observations.

The possibility that the amnesia induced by protein synthesis inhibition is state dependent was investigated. Chicks injected with the protein synthesis inhibitor anisomycin and then trained in a single-trial passive avoidance learning task showed no recall for the task when tested 6 h later in the absence of the drug. If, however, the same chicks were subsequently retested 30 min after a second administration of the drug they demonstrated clear recall for the task. Control groups showed that this effect was not the result of the administration of anisomycin per se but was due to state-dependent recall. Quantitative morphological characterisation of synapses in a region of the chick forebrain (the intermediate part of the medial hyperstriatum ventrale (IMHV) previously shown to be involved in passive avoidance learning was performed. The characteristic increase in the length of the postsynaptic density in the left IMHV was only evident in chicks killed after the behavioural test in which they had demonstrated recall. No synaptic changes were observed in chicks in which state-dependent recall had been demonstrated in a previous test but which were killed after a test in which they appeared amnestic. These results suggest that a memory trace may be established even in the absence of protein synthesis but that this trace may not normally be accessible. It is also suggested that the synaptic changes observed following learning may be dependent on some aspect of the recall phenomenon.

Animals↗

An analog technique for recording leg position learning in the cockroach.

Past studies of shock avoidance learning in the cockroach have used an all-or-none method of recording leg position. Leg position was recorded indirectly in terms of the number of shocks the leg initiated. The measure of learning was the decrease in the number of times the leg initiated shock. An analog procedure is described that allows the pattern of leg behavior change to be assessed directly. Thus, the time course and relative magnitude of leg flexions and extensions prior to, during, and following shock can be studied. It will be possible to record peripheral motor nerve activity simultaneously with the behavior and to examine the excitatory and inhibitory interactions of individual neurons that may be involved in such learning.

Animals↗

Freely accessible water does not decrease consumption of ethanol liquid diets.

In experimental studies, liquid ethanol diets are usually given as the sole source of nutrition and fluid. Two series of experiments were conducted to examine the effect of freely accessible water on the consumption of ethanol liquid diets in male Long-Evans rats. The consumption of diets and subsequent learning ability of rats were first examined in animals given twice-daily saline injections. One group received diet with no access to water for 12 weeks and was subsequently given free access to water with diets for an additional 12 weeks. A second group was given diet and water ad libitum for 24 weeks. Control animals received an isocaloric sucrose-containing diet (with or without ad libitum access to water). Subsequently, rats were tested for active avoidance learning. In the first 12 weeks, animals with ad libitum access to water drank more diet than did water-restricted animals, and previously water-restricted animals increased their diet consumption when access to water was freely available. All water-restricted animals, in both ethanol- and sucrose-treated groups, showed deficits in active avoidance learning, whereas only ethanol-treated animals in groups with ad libitum access to water showed learning deficits. In the second series of experiments, the effect of saline injections on diet consumption, both in the presence and absence of water, was examined. Although saline injections were associated with decreased diet consumption, there was no effect of free access to water. No differences in blood ethanol concentration were seen among groups. Findings obtained from both series of studies demonstrate that consumption of a Sustacal-based liquid ethanol diet does not decrease if access to water is freely available.

Alcohol Drinking↗

Conditioned taste and taste-potentiated odor aversions in the Syracuse high- and low-avoidance (SHA/Bru and SLA/Bru) strains of rats (Rattus norvegicus).

Syracuse high- and low-avoidance Long-Evans rats (Rattus norvegicus; SHA/Bru and SLA/Bru) were selectively bred for good and poor active-avoidance learning. However, SLA/Bru animals are superior to SHA/Bru rats in conditioned suppression and passive avoidance learning. In this experiment, saccharin taste and almond odor were the components of a compound conditioned stimulus (flavor) in an illness-induced aversive conditioning paradigm. SLA/Bru rats (n = 17) showed stronger conditioned flavor, taste, and odor aversion than did SHA/Bru animals (n = 18). Unselected Long-Evans rats (n = 18) were intermediate between the selected strains. SLA/Bru and Long-Evans rats showed taste-potentiated odor aversions in this experiment, whereas SHA/Bru animals did not. The results provide evidence that genetic factors, as exemplified by the different strains, are importantly involved in the mechanisms underlying interoceptive and exteroceptive aversive conditioning.

Animals↗

Protein synthesis in the hippocampus associated with memory facilitation by corticotropin-releasing factor in rats.

The present study used pharmacological, biochemical, and behavioral methods to examine the role of protein synthesis in the hippocampus in memory processes of a passive avoidance learning in rats. Results indicated that corticotropin-releasing factor (CRF) significantly improved memory retention in rats. Both cycloheximide (CHX) and actinomycin-D (ACT-D) impaired memory at high doses. At doses of CHX and ACT-D that did not affect memory alone, they both antagonized the memory-enhancing effect of CRF. Biochemically, there were specific increases in the optical density of three protein bands in the cytosolic fraction of hippocampal cells in rats showing good memory. There were also marked increases in the optical density of two protein bands in the nucleus fraction of the same animals. Similar results were observed in animals injected with CRF. However, no significant protein alteration was observed in animals receiving stress. These results together suggest that there are new protein syntheses in the hippocampus that are specifically associated with passive avoidance learning in rats.

Animals↗

Dextromethorphan ameliorates effects of neonatal hypoxia on brain morphology and seizure threshold in rats.

Hypoxic injury to the brain is mediated in part by NMDA receptors. Therefore, NMDA receptor blockade with dextromethorphan (DM), a non-competitive channel blocker, was hypothesized to ameliorate injury even when given after the hypoxic insult. Rats were exposed to 8% oxygen for 3 h on postnatal day 7. Within 20 min of exposure, animals received 30 mg/kg i.p. DM or normal saline. Littermates maintained in room air for 3 h also received DM or saline. At 14 days of age, 7 days after exposure, cortical thickness and hippocampal area were measured. At 70-90 days of age, approximately two months after exposure, in a separate group of rats, seizure threshold using pentylenetetrazol (PTZ) and passive avoidance learning and retention were determined. There were no gross changes in cellular morphology and no evidence for cellular necrosis in any of the exposure groups. However, cortical thickness was decreased in animals exposed to hypoxia. DM administration prevented this decrease. Hippocampal area was unaffected. Seizure susceptibility in adulthood was increased in animals exposed to hypoxia in the neonatal period. DM prevented the decrease in seizure threshold. There was no difference in passive avoidance learning or retention as a function of neonatal exposure condition. Mild to moderate hypoxia, previously thought not to produce any histologic changes, causes significant short-term loss of cortical thickness and long-term decrease in seizure threshold. DM appears to ameliorate these effects even when given after the hypoxic insult. These results implicate the glutamate receptor system in the pathophysiology of hypoxia damage and suggest that treatment with a glutamate receptor blocker when neonatal asphyxia is suspected would help ameliorate the consequences of such an insult.

Aging↗

Some central effects in mice of compounds related to nicotine.

1. Some hydroxy-, amino-, and methoxy- phenylalkyltrimethylammonium compounds, beta-pyridylmethyl- dimethylamine and pyrrolidine, and beta-pyridylethyltrimethylammonium, were tested on avoidance learning in mice and their effects were compared with those of (-)-nicotine.2. The o- and m- hydroxybenzyl-, o-hydroxyphenethyl- and m-hydroxyphenylpropyl- trimethylammonium compounds improved performance; (-)-nicotine, in one-quarter of the dose, had similar effects. The m- and p-hydroxyphenethyl-, o-hydroxyphenylpropyl- and o- and p- aminobenzyl, and o-, m-, and p- aminophenethyl-trimethylammonium compounds impaired performance.3. (-)-Nicotine and m-hydroxyphenylpropyltrimethylammonium appeared also to enhance memory consolidating processes.4. The central actions of some of the compounds suggest that the possibility that they can penetrate into the central nervous system should not be ruled out even though they are quaternary salts.5. No correlation was found between the effects of the compounds on avoidance learning and on the frog rectus muscle. Though the differences may be due to differences in access to the central nervous system, it is also possible that the receptors associated with learning processes are different from those in the frog rectus and possibly more specialized.

Animals↗

Spatio-temporal activation of cyclic AMP response element-binding protein, activity-regulated cytoskeletal-associated protein and brain-derived nerve growth factor: a mechanism for pontine-wave generator activation-dependent two-way active-avoidance memory processing in the rat.

The present study explored possible physiological and molecular mechanisms of pontine-wave (P-wave) generator activation-dependent memory processing in the rat using a two-way active-avoidance learning paradigm. The results show that learning training increased rapid eye movement sleep and activated brainstem cells in the P-wave generator. During this period, there was a time-dependent increase in phosphorylation of cAMP response element-binding protein (CREB) in the dorsal hippocampus and amygdala and increased synthesis of activity-regulated cytoskeletal-associated protein (Arc) in the dorsal hippocampus, amygdala, frontal cortex and occipital cortex. Learning training also increased synthesis of brain-derived nerve growth factor (BDNF) in the occipital cortex, amygdala and dorsal hippocampus at different time intervals. During this time, the levels of nerve growth factor did not change. The results also show that the increase in rapid eye movement sleep P-wave density during the post-training 3-h recording session is positively correlated with the increased levels of phosphorylated CREB, BDNF and Arc in the dorsal hippocampus. These results suggest that memory processing of two-way active-avoidance learning may involve excitation of P-wave-generating cells in the brainstem and increased expression of phosphorylated CREB, Arc and BDNF in a time-dependent manner in the forebrain. These dynamic changes in cellular and molecular features provide considerable insight into the mechanisms of the P-wave generator activation-dependent memory consolidation process.

Amygdala↗

Developmental exposure to chlorpyrifos alters reactivity to environmental and social cues in adolescent mice.

Neonatal mice were treated daily on postnatal days (pnds) 1 through 4 or 11 through 14 with the organophosphate pesticide chlorpyrifos (CPF), at doses (1 or 3 mg/kg) that do not evoke systemic toxicity. Brain acetylcholinesterase (AChE) activity was evaluated within 24 h from termination of treatments. Pups treated on pnds 1-4 underwent ultrasonic vocalization tests (pnds 5, 8, and 11) and a homing test (orientation to home nest material, pnd 10). Pups in both treatment schedules were then assessed for locomotor activity (pnd 25), novelty-seeking response (pnd 35), social interactions with an unfamiliar conspecific (pnd 45), and passive avoidance learning (pnd 60). AChE activity was reduced by 25% after CPF 1-4 but not after CPF 11-14 treatment. CPF selectively affected only the G(4) (tetramer) molecular isoform of AChE. Behavioral analysis showed that early CPF treatment failed to affect neonatal behaviors. Locomotor activity on pnd 25 was increased in 11-14 CPF-treated mice at both doses, and CPF-treated animals in both treatment schedules were more active when exposed to environmental novelty in the novelty-seeking test. All CPF-treated mice displayed more agonistic responses, and such effect was more marked in male mice exposed to the low CPF dose on pnds 11-14. Passive avoidance learning was not affected by CPF. These data indicate that developmental exposure to CPF induces long-term behavioral alterations in the mouse species and support the involvement of neural systems in addition to the cholinergic system in the delayed behavioral toxicity of CPF.

Acetylcholinesterase↗