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PubMed1998

Facilitation of learning after lesions of the tuberomammillary nucleus region in adult and aged rats.

The tuberomammillary nucleus (TM) located in the posterior part of the hypothalamus is the main source of neuronal histamine in the central nervous system. Recent work from our laboratories has indicated an involvement of the TM region in neuronal plasticity and reinforcement processes. In the present study, we investigated the effects of TM lesions on the performance of adult and aged Wistar rats in a set of learning tasks, which differed in terms of complexity and reward contingencies (habituation learning, inhibitory avoidance, discrimination learning, Morris water maze). An improvement was found in every test applied, indicating that TM lesions seem to generally enhance learning and memory capacities independent of the special demands of a given task. Age-related learning deficits were strongly diminished. Immunohistochemistry revealed that the excitotoxic lesions used to destroy the TM region led to a marked decrease in the number of histamine-positive neurons in the vicinity of the injection site, indicating an involvement of the brain histaminergic system in the observed behavioral changes.

Aging↗
PubMed2000

Induction of integrin-associated protein (IAP) mRNA expression during memory consolidation in rat hippocampus.

We have previously demonstrated that hippocampal integrin-associated protein (IAP) gene expression is associated with memory formation in a one-way inhibitory avoidance learning in rats. In the present study, we further investigated the role and mechanism of IAP involved in memory consolidation in rats. Because of the minute amount of IAP present in the brain, we have adopted the quantitative reverse transcription-polymerase chain reaction (RT-PCR) method. Our results revealed that hippocampal IAP mRNA expression is approximately fourfold higher in rats showing good memory retention (GM, retention score of 600 s) at 3 h, but not at other time points, after training when compared with the poor memory rats (retention score < 80 s). On the other hand, integrin alphav mRNA level was markedly increased ( approximately twofold), while integrin beta3 mRNA level was decreased ( approximately 50%) at 1 h post-training. Further, separate sets of RT-PCR analysis revealed that IAP5 and IAP6 mRNA expressions, but not that of IAP7, were markedly increased in GM rats 3 h post-training. Moreover, regional distribution studies revealed that different isoforms of the IAP gene are similarly distributed in different brain areas, while IAP7 has been the predominant form present in astrocyte cells. These results together suggest that IAP mRNA expression is indeed induced upon training, rather than that the GM rats have constitutively higher levels of IAP. The unparallel change of IAP and integrin mRNA expressions as far as time-course is concerned suggests that they are possibly involved in different forms and stages of memory processing. Further, IAP5 and IAP6 are more closely associated with memory consolidation, while IAP7 may constitute the major isotype for signal transduction in astrocyte cells.

Alternative Splicing↗
PubMed2004

Endocrinological responses during suckling in Hatano high- and low-avoidance rats.

Hatano high-avoidance (HAA) and low-avoidance (LAA) animals were originally selected from Sprague-Dawley rats for good and poor active avoidance learning in a shuttle box. We studied the endocrinological profile in lactating rats to determine the effect of suckling during mid-lactation in HAA and LAA rats. The pups were separated from their mother rats 6 h before the onset of suckling and blood samples were drawn from unanaesthetized mother rats via a jugular cannula at 0, 5 and 15 min after the suckling stimulus and then 15, 45 and 105 min after pups were removed. Plasma concentrations of oxytocin in HAA rats were significantly higher than in LAA rats during the suckling period. Plasma concentrations of prolactin and ACTH in HAA rats were significantly higher than in LAA rats during the suckling period, and at 15 min and 45 min after the pups were removed. However, there were no strain differences in circulating corticosterone between the two lines, indicating that the response of the hypothalamo-pituitary axis to the suckling stimulus was greater in HAA rats than in LAA rats, whereas the ACTH-induced adrenal response of corticosterone release was higher in LAA rats than in HAA rats. Since dopamine from the median eminence inhibits prolactin secretion from the lactotrophs of the anterior pituitary, and tuberoinfundibular dopaminergic neurones are partially regulated by the level of circulating prolactin, we evaluated the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis. TH, measured by the accumulation of 3,4-dihydroxyphenylalanine, was significantly higher in HAA rats than in LAA rats before the suckling stimulus. After the suckling stimulus, TH activity in HAA rats was significantly lower than before suckling, whereas TH activity in LAA rats was not changed. These findings clearly demonstrated that apparent differences between the two Hatano lines exist in endocrinological profiles during suckling. These strain differences probably originate from neurotransmitter changes, such as dopamine.

Adrenocorticotropic Hormone↗
PubMed2002

Alterations in the balance of protein kinase and phosphatase activities and age-related impairments of synaptic transmission and long-term potentiation.

Aging is associated with an impaired ability to maintain long-term potentiation (LTP), but the underlying cause of the impairment remains unclear. To gain a better understanding of the cellular and molecular mechanisms responsible for this impairment, the synaptic transmission and plasticity were studied in the CA1 region of hippocampal slices from adult (6-8 months) and poor-memory (PM)-aged (23-24 months) rats. The one-way inhibitory avoidance learning task was used as the behavioral paradigm to screen PM-aged rats. With intracellular recordings, CA1 neurons of PM-aged rats exhibited a more hyperpolarized resting membrane potential, reduced input resistance, and increased amplitude of afterhyperpolarization and spike threshold, compared with those in adult rats. Although a reduction in the size of excitatory synaptic response was observed in PM-aged rats, no obvious differences were found between adult and PM-aged rats in the pharmacological properties of excitatory synaptic response, paired-pulse facilitation, or frequency-dependent facilitation, which was tested with trains of 10 pulses at 1, 5, and 10 Hz. Slices from the PM-aged rats displayed significantly reduced early-phase long-term potentiation (E-LTP) and late-phase LTP (L-LTP), and the entire frequency-response curve of LTP and LTD is modified to favor LTD induction. The susceptibility of time-dependent reversal of LTP by low-frequency afferent stimulation was also facilitated in PM-aged rats. Bath application of the protein phosphatase inhibitor, calyculin A, enhanced synaptic response in slices from PM-aged, but not adult, rats. In contrast, application of the cAMP-dependent protein kinase inhibitors, Rp-8-CPT-cAMPS and KT5720, induced a decrease in synaptic transmission only in slices from the adult rats. Furthermore, the selective beta-adrenergic receptor agonist, isoproterenol, and pertussis toxin-sensitive G-protein inhibitor, N-ethylmaleimide, effectively restored the deficit in E-LTP and L-LTP of PM-aged rats. These results demonstrate that age-related impairments of synaptic transmission and LTP may result from alterations in the balance of protein kinase/phosphatase activities.

Action Potentials↗
PubMed1994

(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (ABT 418): a novel cholinergic ligand with cognition-enhancing and anxiolytic activities: II. In vivo characterization.

(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (ABT 418), an isoxazole analog of (-)-nicotine, is a potent agonist at the alpha-4/beta-2 subtype of neuronal nicotinic acetylcholine receptor (nAChR) that exists in mammalian brain (Arneric et al., 1994). Compared to (-)-nicotine, ABT 418 has reduced potency to interact with the subunit isoforms of nAChR found in sympathetic ganglia, and it does not compete for alpha-bungarotoxin binding sites in brain or at the neuromuscular junction. ABT 418 [minimum effective dose (MED), 0.062 mumol/kg i.p.) was 10-fold more potent in improving retention of avoidance learning in normal mice than (-)-nicotine, whereas the (R)-enantiomer of ABT 418, A-81754, was inactive. The memory-enhancing effect of ABT 418 was prevented by the nAChR channel blocker, mecamylamine. In the elevated plus-maze model of anxiety, ABT 418 (MED, 0.19 mumol/kg i.p.) increased open-arm exploration in mice, as previously shown for (-)-nicotine (MED, 0.62 mumol/kg i.p.). A-81754, did not have anxiolytic-like effects in this test. Unlike the classical anxiolytic, diazepam, ABT 418 did not impair rotorod performance in the dose range where beneficial effects occurred. In rats, ABT 418 (MED, 0.002 mumol/kg i.v.) was remarkably potent in enhancing basal forebrain-elicited increases in cortical cerebral blood flow, whereas resting cerebral blood flow was unaffected. Free running cortical electroencephalography in rats was unaffected by ABT 418 at a dose of 1.9 mumol/kg i.p., whereas the same dose of (-)-nicotine caused cortical activation (decreased power in the 1-13 Hz range and increased power in the 25-50 Hz range). Whereas ABT 418 was approximately 3- to 10-fold more potent than (-)-nicotine in memory enhancement and anxiolytic test paradigms, the compound had less emetic liability in dogs as compared to (-)-nicotine, and was less potent than (-)-nicotine in eliciting hypothermia, seizures, death and reduction of locomotor activity in mice. The measured pharmacokinetic or brain disposition properties of ABT 418 in rats did not account for the observed enhancement in efficacy with reduced toxicity as compared to (-)-nicotine. The potent cognitive-enhancing and anxiolytic properties obtained for ABT 418 in animal models without eliciting significant side effects suggest that this ligand is a selective activator of cholinergic channel-mediated behaviors. Thus, ABT 418 may represent a novel, safe and effective treatment of the cognitive and emotional dysfunctions associated with Alzheimer's disease.

Alzheimer Disease↗
PubMed1989

[Exchange of the hematopoietic system changes chemosensory identity].

It has been shown that the scent of mice changes after a bone marrow transplantation. Previously obtained results were re-examined with a new design that rules out possible avoidance learning effects. Two BALB/c mice, deprived of water for 20 hours each day, were trained in a Y-maze to discriminate two fully allogeneic mice strains (C3H = S+ and C57 = S-) via their urine odor. Reinforcement for correct choice was provided by a drop of water. Urine samples of different fully allogeneic mice strains (C3H, C57 and A/J) and bone marrow transplanted chimeras (C57----C3H and C3H----C57) were submitted to different "transfer of training" -tests. In the conditioning paradigm used, the animals learn to identify S+ and also do not avoid S- after the training. The urine odor of the C57----C3H-chimeras was found to be different from the strain-specific urine odor of C3H animals. Since this change could not be found in syngeneic transplanted chimeras, it is concluded that it is caused by the graft. The experiments failed, however to demonstrate that the urine odor of allogeneic chimeras is constituted solely by donor- and recipient-specific components.

Animals↗
PubMed1980

Effect of clonazepam and electrolesions of the dorsal and medial raphe nuclei on learning.

The benzodiazepine Clonazepam, as well as electrolesions of the serotoninergic raphe nuclei, dorsalis and medianus, in rats have a learning-facilitating effect using the system of two-way avoidance. The animals with lesions manifest twice higher values of the index for avoidance learning compared with the control animals. In repeated training, the animals treated with Clonazepam in doses of 1 mg/kg for five successive days, show almost twice higher learning index compared with the controls, the index of Clonazepam-treated animals with lesions being four times higher than the controls. Clonazepam-treated animals manifest a higher number of conditioned-reflex avoidance responses compared with the controls throughout the entire 5-day period. Clonazepam-treated rats with raphe lesions reveal a significantly higher number of conditioned-reflex avoidance responses compared with the control group and with the group of Clonazepam-treated animals. Clonazepam-treated animals show a lower number of inadequate avoidance responses compared with the control animals, while in the Clonazepam-treated animals with lesions there are almost no inadequate reactions. The positive effects of Clonazepam and raphe lesions on avoidance training demonstrate the influence of the serotoninergic system on the processes of learning and memory.

Animals↗
PubMed1990

Buspirone impairment of performance of passive avoidance and spatial learning tasks in the rat.

The effects of buspirone on the execution of step-through passive avoidance and spatial navigation learning tasks were assessed. In view of the anxiolytic properties of the drug, its effects on shock induced ultrasonic vocalizations and shock suppressed locomotor activity in a hole-board were also determined. Doses (0.5, 1 and 2 mg/kg, IP) which did not affect exploratory activity in a novel environment (light/dark box and hole-board apparatus) were used. Buspirone (1 and 2 mg/kg) impaired performance on the 24 h passive avoidance recall test when given prior to the training and the test sessions or prior to the test session only but not when given before the training trial only. The stress response to the mild footshock, as measured in terms of suppressed locomotor activity in the hole-board apparatus and post-shock ultrasonic vocalizations, was reduced by buspirone (at 1 and 2 mg/kg, respectively), indicating that its effect on behavior in the passive avoidance learning task is probably due to its anxiolytic properties. Evidence for a possible amnesic effect of buspirone (2 mg/kg) was found on the acquisition and probe test trials in the spatial navigation task. During training the latency to find a submerged escape platform in a water maze was increased. Performance on a probe test was also impaired but this effect was not apparent in animals which had received buspirone only prior to the probe test. Although these changes may be attributable to alterations in many aspects of cognitive processing, the possibility of a direct effect on memory warrants further investigation.

Animals↗
PubMed1981

Extrapolation of two-factor learning theory of infrahuman avoidance behavior to psychopathology.

This paper involves a theoretical attempt to extend O. H. Mowrer's two-factor theory of infrahuman avoidance behavior to the area of human psychopathology, Central to any such theoretical extrapolation is the need to explain why human fears and avoidance behavior manifest such strong resistance to extinction while the abundance of infrahuman findings suggests that the extinction of such behaviors is rapid. The position is advanced that this noted paradox can be resolved both theoretically and empirically by modifying and extending the Solomon and Wynne conservation of anxiety hypothesis to include complex, serial ordered cues. The model presented also provides the rationale for an extinction approach to psychotherapy, referred to as implosive therapy which is briefly described. Supporting data for the model as well as alternative explanations are provided and discussed.

Animals↗
PubMedDate not supplied

Neurobehavioral effects of prenatal lamivudine (3TC) exposure in preweaning mice.

The present study provides a characterization of the behavioral changes induced in preweaning mice by prenatal exposure to lamivudine (3TC), an antiviral drug recently entered in the clinical practice to treat HIV patients. Pregnant CD1 mice were given per os bidaily either 3TC at different doses (125, 250, or 500 mg/kg) or vehicle solution (saline 0.9%) from pregnancy day 10 to delivery. Data on reproductive performance, such as gestation length, litter size, and offspring viability, were collected. Offspring were then examined for a series of different somatic and behavioral end points, including sensorimotor development, ontogenetic pattern of ultrasonic vocalization, passive avoidance learning, and locomotor activity. In the absence of gross changes in somatic and sensorimotor development, a slight change in ultrasound emission was found on postnatal day (PND) 3, with 125 and 500 mg/kg 3TC-treated offspring emitting a lower number of ultrasounds. Learning and retention performances of a passive-avoidance task on PND 20-21 were unaffected by 3TC treatment, while decreased habituation in an automated locomotor activity test was evident in male offspring exposed to 250 and 500 mg/kg 3TC.

Animals↗
PubMed1998

The uterine environment enhances cognitive competence.

Genetically identical mouse embryos were transferred into same-strain uteri (transfer controls) or into hybrid uteri. A third group was not transferred. When adult, the mice were given a series of behavioral tests. In-strain transfer controls differed from non-transfer mice only on two activity measures, and did not differ on any cognitive variable. In contrast, mice reared in hybrid uteri were found to be superior to in-strain transfer mice on discrimination learning, Lashley maze learning and Morris maze learning; they also showed better adaptation in an avoidance learning shuttlebox. To our knowledge this is the first study showing that the uterine environment can have a general enhancing effect upon cognitive competence across a broad range of behaviors.

Animals↗