Role of the dorsomedial hypothalamus in mediating the response to benzodiazepines on trial 2 in the elevated plus-maze test of anxiety.
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Trial 2 in the elevated plus-maze provides an animal model of specific phobia (fear of heights). On this trial, rats no longer respond to benzodiazepines. The present experiment examined the role of the dorsomedial hypothalamus in mediating insensitivity to chlordiazepoxide on trial 2. Rats received a 5 min exposure to the maze, undrugged. Forty-eight hours later, rats injected with control infusions into the dorsomedial hypothalamus showed the usual lack of response to chlordiazepoxide (5 mg/kg, i.p.). However, those receiving lidocaine injections (40 micrograms/microliter in a volume of 0.2 microliter) in the dorsomedial hypothalamus (producing functional inactivation), immediately before trial 2, responded with an anxiolytic response to chlordiazepoxide, characterised by an increased percentage of time on the open arms and by an increased number of entries into, and time spent on, the distal portions of the open arms. Since the lidocaine injections were without anxiolytic effects, our results suggest that this region of the hypothalamus regulates the functional state of benzodiazepine receptors in other brain regions. (+info)
Rat hippocampal neurons are critically involved in physiological improvement of memory processes induced by cholecystokinin-B receptor stimulation.
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The involvement in memory processes of the neuropeptide cholecystokinin (CCK) through its interaction with the CCK-B receptors was studied. The two-trial recognition memory task was used. Control animals showed recognition memory after a 2 hr time interval but not after a 6 hr time interval between the two trials. The improving effect of a selective CCK-B agonist, BC 264, intraperitoneally administered (0.3 microgram/kg) in the retrieval phase of the task (6 hr time interval), was also observed after its injection (1 pmol/0.5 microliter) in the dorsal subiculum/CA1 of the hippocampus but not in the caudate/putamen nucleus or in the prefrontal cortex of rats. The CCK-B antagonist L-365,260 injected (10 ng/0.5 microliter) into this region of the hippocampus abolished the improving effect of BC 264 injected intraperitoneally. Furthermore, L-365,260 injected in the hippocampus suppressed the recognition of the novel arm normally found in the controls (2 hr time interval) when it was injected before the acquisition or the retrieval phase of the task. In addition, an increase of the extracellular levels of CCK-like immunoreactivity in the hippocampus of rats during the acquisition and retention phase of the task was observed. Finally, CCK-B receptor-deficient mice have an impairment of performance in the memory task (2 hr time interval). Together, these results support the physiological involvement of the CCKergic system through its interaction with CCK-B receptors in the hippocampus to improve performance of rodents in the spatial recognition memory test. (+info)
Attenuation of scopolamine-induced deficits in navigational memory performance in rats by bis(7)-tacrine, a novel dimeric AChE inhibitor.
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AIM: To study the effects of 1,7-N-heptylene-bis-9,9'-amino-1,2,3,4-tetrahydroacridine [bis(7)-tacrine], a novel dimeric acetylcholine-sterase inhibitor (AChEI) derived from 9-amino-1,2,3,4-tetrahydroaminoacridine (tacrine), on scopolamine-induced spatial memory impairment. METHODS: The effects of bis(7)-tacrine were investigated on the 5-d performance of young adult rats in the Morris water maze. The latency to find the platform in the water maze was measured to evaluate performance. Tacrine was used as a reference drug. RESULTS: Scopolamine (0.3 mg.kg-1, i.p.) resulted in an increase in latency period (> 100% increase) as compared with saline treated controls. Both bis(7)-tacrine and tacrine lessened the increased latency induced by scopolamine to the level of saline control group. The relative potency of bis(7)-tacrine (0.35 mumol.kg-1, i.g. or i.p.) to shorten the escape latency was 24 or 12 times of tacrine (8.52 mumol.kg-1 i.g., 4.26 mumol.kg-1 i.p.) following i.g. or i.p. administration, respectively. There appeared to be an inverse bell-shape dose-dependent effect for both compounds tested. CONCLUSION: Bis(7)-tacrine is a more potent and orally active AChEI than tacrine, and has potential for the palliative treatment of Alzheimer disease. (+info)
Reduced K+ channel inactivation, spike broadening, and after-hyperpolarization in Kvbeta1.1-deficient mice with impaired learning.
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A-type K+ channels are known to regulate neuronal firing, but their role in repetitive firing and learning in mammals is not well characterized. To determine the contribution of the auxiliary K+ channel subunit Kvbeta1.1 to A-type K+ currents and to study the physiological role of A-type K+ channels in repetitive firing and learning, we deleted the Kvbeta1.1 gene in mice. The loss of Kvbeta1.1 resulted in a reduced K+ current inactivation in hippocampal CA1 pyramidal neurons. Furthermore, in the mutant neurons, frequency-dependent spike broadening and the slow afterhyperpolarization (sAHP) were reduced. This suggests that Kvbeta1.1-dependent A-type K+ channels contribute to frequency-dependent spike broadening and may regulate the sAHP by controlling Ca2+ influx during action potentials. The Kvbeta1.1-deficient mice showed normal synaptic plasticity but were impaired in the learning of a water maze test and in the social transmission of food preference task, indicating that the Kvbeta1.1 subunit contributes to certain types of learning and memory. (+info)
Deficits in memory tasks of mice with CREB mutations depend on gene dosage.
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Studies in Aplysia, Drosophila, and mice have shown that the transcription factor CREB is involved in formation and retention of long-term memory. To analyze the impact of differential CREB levels on learning and memory, we varied the gene dosage of CREB in two strains of mutant mice: (1) CREBalphadelta mice, in which the alpha and delta isoforms are disrupted, but a third isoform beta is strongly up-regulated; (2) CREBcomp, a compound strain with one alphadelta allele and one CREBnull allele in which all CREB isoforms are disrupted. To minimize genetic background effects, CREB mutations were backcrossed into a C57BL/6 and a FVB/N strain, respectively, and studies were performed in F1 hybrids from these lines. CREBcomp but not CREBalphadelta F1 hybrids were impaired in water maze learning and fear conditioning, demonstrating a CREB gene dosage effect. However, analysis of the platform searching strategies in the water maze task suggested that CREBcomp mutants are impaired in behavioral flexibility rather than in spatial memory. In contrast to previous experiments using CREBalphadelta mice with different genetic background, the F1 hybrid CREBalphadelta and CREBcomp mice did not show deficits in a social transmission of food preference task nor in dentate gyrus and CA1 LTP as recorded from slice preparations. These data indicate that the hybrid vigor typical for F1 hybrids may compensate for a reduction in CREB levels in some tests. On the other hand, the persistence of clear behavioral deficits as shown by the F1 hybrid CREBcomp mice in water maze and fear conditioning indicates a robust and repeatable phenomenon that will permit further functional analysis of CREB. (+info)
Enhanced hippocampal CA1 LTP but normal spatial learning in inositol 1,4,5-trisphosphate 3-kinase(A)-deficient mice.
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To define the physiological role of IP(3)3-kinase(A) in vivo, we have generated a mouse strain with a null mutation of the IP(3)3-kinase(A) locus by gene targeting. Homozygous mutant mice were fully viable, fertile, apparently normal, and did not show any morphological anomaly in brain sections. In the mutant brain, the IP4 level was significantly decreased whereas the IP3 level did not change, demonstrating a major role of IP(3)3-kinase(A) in the generation of IP4. Nevertheless, no significant difference was detected in the hippocampal neuronal cells of the wild-type and the mutant mice in the kinetics of Ca2+ regulation after glutamate stimulation. Electrophysiological analyses carried out in hippocampal slices showed that the mutation significantly enhanced the LTP in the hippocampal CA1 region, but had no effect on the LTP in dentate gyrus (DG). No difference was noted, however, between the mutant and the wild-type mice in the Morris water maze task. Our results indicate that IP(3)3-kinase(A) may play an important role in the regulation of LTP in hippocampal CA1 region through the generation of IP4, but the enhanced LTP in the hippocampal CA1 does not affect spatial learning and memory. (+info)
Increase in syntaxin 1B mRNA in hippocampal and cortical circuits during spatial learning reflects a mechanism of trans-synaptic plasticity involved in establishing a memory trace.
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It has long been proposed that the cellular and molecular mechanisms responsible for LTP may well involve the mechanisms that lead to the type of synaptic modification that occurs during learning. However, it is also known that a single memory trace is encoded in spatially distributed networks; implying that alterations of synaptic strength occur at multiple sites along circuits of connected cells. Recent evidence suggests that regulation of the gene encoding syntaxin 1B, a presynaptic protein involved in exocytosis, plays an important role in the mediation of trans-synaptic LTP, a candidate mechanism for the propagation of plasticity in neural circuits during learning. Using in situ hybridization to measure the mRNA levels at different time points after learning a spatial working or reference memory task, we show that expression of the gene encoding this protein in the hippocampal and corticoprefrontal circuits increases linearly with performance at a critical window of learning when rats are reaching between 75% and 100% of their maximal performance. No changes were observed during the early phases of learning or when rats where overtrained. The correlational analysis indicates that coordinated increases in syntaxin 1B expression occurs in hippocampal circuits during working memory and in more widespread hippocampocortical circuits during reference memory. These results suggest that a form of trans-synaptic plasticity mediated in part by regulation of the expression of syntaxin 1B may play an active role in configuring specific spatially distributed circuits during the laying down of memories. (+info)
Functional integrity of NMDA-dependent LTP induction mechanisms across the lifespan of F-344 rats.
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Previous studies have reported a lack of an age effect in the induction of long-term potentiation (LTP) at CA1 synapses, using robust (supramaximal) stimulation parameters, but an apparent age effect on the induction threshold of LTP using less robust stimulation, in the perithreshold region. These findings have led to the suggestion that old animals may experience an alteration either in the efficacy of activation of N-methyl-D-aspartate (NMDA) receptors or in the metabolic processes subsequent to NMDA receptor activation that lead to LTP expression. An alternative explanation for the apparent threshold change in old animals is that, because of the known reduction of the intracellularly recorded, compound EPSP magnitude in old rats, equivalent electrical stimulation results in a smaller effective depolarization of the postsynaptic cells and a consequently less effective activation of NMDA receptors, which are otherwise functionally normal. To distinguish between these two hypotheses, weak orthodromic stimulation was paired with intracellularly applied current pulses, thus holding constant the degree of postsynaptic depolarization. No differences in LTP induction threshold or magnitude were observed in a large sample of rats from three age groups. It is concluded that the NMDA receptor mechanisms and associated biochemical processes leading to LTP induction are not altered in aged F-344 rats. The reduced compound EPSP in old animals was reconfirmed in the present study, and a significant correlation was found in old rats between the magnitude of the EPSP at a fixed stimulus level and their performance on a spatial memory task. (+info)