Calcineurin in memory and bidirectional plasticity

The molecular mechanisms of learning and memory, and the underlying bidirectional changes in synaptic plasticity that sustain them largely implicate protein kinases and phosphatases. Specifically, Ca(2+)-dependent kinases and phosphatases actively control neuronal processing by forming a tightly regulated balance in which they oppose each other. In this balance, calcineurin (PP2B) is a critical protein phosphatase whose main function is to negatively modulate learning, memory, and plasticity. It acts by dephosphorylating numerous substrates in different neuronal compartments. This review outlines some of CN neuronal targets and their implication in synaptic functions, and describes the role of CN in the acquisition, storage, retrieval, and extinction of memory, as well as in bidirectional plasticity.     

Role for brain-derived neurotrophic factor in learning and memory

In addition to its actions on neuronal survival and differentiation, brain-derived neurotrophic factor (BDNF) has a role in the regulation of synaptic strength. Long-term potentiation, a form of synaptic plasticity, is markedly impaired in BDNF mutant mice, but the changes were restored by the re-expression of BDNF. BDNF also influences the development of patterned connections and the growth and complexity of dendrites in the cerebral cortex. These results suggest a role for BDNF in learning and memory processes, since memory acquisition is considered to involve both short-term changes in electrical properties and long-term structural alterations in synapses. Memory acquisition is associated with an increase in BDNF mRNA and TrkB receptor activation in specific brain areas. Moreover, the pharmacologic and genetic deprivation of BDNF or its receptor TrkB results in severe impairment of learning and memory in mice, rats and chicks. The effect of BDNF on learning and memory may be linked to the modulation of NMDA and non-NMDA receptor functions as well as the expression of synaptic proteins required for exocytosis. Activation of the mitogen-associated protein kinase and/or phosphatidylinositol 3-kinase signaling pathways may be involved in BDNF-dependent learning and memory formation. It is concluded that BDNF/TrkB signaling plays an important role in learning and memory.     

Calcium-regulated GTPase activity in the calcium-binding protein calexcitin

Calexcitin (CE) is a calcium-binding protein, closely related to sarcoplasmic calcium-binding proteins, that is involved in invertebrate learning and memory. Early reports indicated that both Hermissenda and squid CE also could bind GTP; however, the biochemical significance of GTP-binding and its relationship to calcium binding have remained unclear. Here, we report that the GTPase activity of CE is strongly regulated by calcium. CE possessed a P-loop-like structure near the C-terminal similar to the phosphate-binding regions in other GTP-binding proteins. Site-directed mutagenesis of this region showed that Gly¹⁸², Phe¹⁸⁶ and Gly¹⁸⁷ are required for maximum affinity, suggesting that the GTP-binding motif is G-N-x-x-[FM]-G. CE cloned from Drosophila CNS possessed a similar C-terminal sequence and also bound and hydrolyzed GTP. GTPase activity in Drosophila CE was also strongly regulated by Ca²⁺, exhibiting over 23-fold higher activity in the presence of 0.3 μM calcium. Analysis of the conserved protein motifs defines a new family of Ca²⁺-binding proteins representing the first example of proteins endowed with both EF-hand calcium binding domains and a C-terminal, P-loop-like GTP-binding motif. These results establish that, in the absence of calcium, both squid and Drosophila CE bind GTP at near-physiological concentrations and hydrolyze GTP at rates comparable to unactivated ras. Calcium functions to increase GTP-binding and GTPase activity in CE, similar to the effect of GTPase activating proteins in other low-MW GTP-binding proteins. CE may, therefore, act as a molecular interface between Ca²⁺ cytosolic oscillations and the G protein-coupled signal transduction.     

Dehydroevodiamine.HCl prevents impairment of learning and memory and neuronal loss in rat models of cognitive disturbance

We previously reported that dehydroevodiamine.HCl (DHED) has anticholinesterase and antiamnesic activities. To verify the effects of DHED on cognitive deficits further, we tested it on the scopolamine-induced amnesia model of the rat using the passive avoidance and eight-arm radial maze tests. A single (20 mg/kg p.o.) and repeated (10 mg/kg p.o.) administrations of DHED could significantly reverse the latency time shortened by scopolamine (1 mg/kg i.p.) to control level. The impaired spatial working memory induced by scopolamine (1 mg/kg i.p.) was also improved significantly by a single injection (6.25 mg/kg i.p.) and repeated administrations of DHED (10 mg/kg p.o.) in the eight-arm radial maze test. In addition, we examined the effects of DHED on the memory impairment and the histological changes of the brain after unilateral electrolytic lesion of the entorhinal cortex (EC) and middle cerebral artery occlusion in rats. The cognitive deficits caused by EC lesion and middle cerebral artery occlusion were improved significantly by repeated administrations of DHED (6.25 mg/kg i.p.) after EC lesion or ischemic insult once a day for 7 days in the passive avoidance test. Histological analysis showed that the neuronal loss in the DHED-treated group was notably reduced in the hippocampal area (CA1) of ischemic rats and in the dentate gyrus and hippocampal area (CA1 and CA3) of EC-lesioned rats compared with the nontreated group. The infarction area was decreased significantly by a single administration of DHED (6.25 mg/kg i.p.) 30 min before ischemic insult for 6 h. These results suggest that DHED might be an effective drug for not only the Alzheimer's disease type, but also the vascular type of dementia.     

褪黑激素对D-半乳糖处理小鼠学习记忆和脑组织超氧物歧化酶活力的影响

采用Ｍｏｒｒｉｓ水迷宫法和ＮＢＴ法分别检测了褪黑激素对Ｄ－半乳糖处理小鼠的空间学习记忆能力和脑组织超氧物歧化酶活力的影响。结果表明,Ｄ－半乳糖对小鼠的逃避潜伏期无显著影响,但降低小鼠的穿环系数,还促使小鼠的脑组织超氧物歧化酶活力明显升高;褪黑激素可提高小鼠的空间学习记忆能力,降低Ｄ－半乳糖所引起的超氧物歧化酶活力升高。     

Characterization of a Dopamine D1 Receptor from Apis mellifera: Cloning, Functional Expression, Pharmacology, and mRNA Localization in the Brain

Abstract: The neurotransmitter dopamine is an important regulator of physiological and behavioral functions in both vertebrates and invertebrates. We have isolated a homologue of the vertebrate dopamine D1 receptor subfamily from the honeybee Apis mellifera . [³H]Lysergic acid diethylamide specifically binds to the heterologously expressed receptor with K _D∼5 n M . Dopaminergic receptor ligands compete for this high-affinity binding, with the following order of potency: R (+)-lisuride > chlorpromazine = cis ( Z )-flupentixol > dopamine > S (+)-butaclamol > R (+)-SCH 23390 > haloperidol. Activation of the heterologously expressed receptor of Apis mellifera leads to cyclic AMP production. Receptor mRNA is expressed in perikarya of different brain neuropils, including those of mushroom body intrinsic neurons. These results suggest that this dopamine receptor is involved in signal processing of visual and olfactory information in the honeybee.     

Endogenous opiates: 1997

This paper is the twentieth installment of our annual review of research concerning the opiate system. It summarizes papers published during 1997 that studied the behavioral effects of the opiate peptides and antagonists, excluding the purely analgesic effects, although stress-induced analgesia is included. The specific topics covered this year include stress; tolerance and dependence; eating and drinking; alcohol; gastrointestinal, renal, and hepatic function; mental illness and mood; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurologic disorders; electrical-related activity; general activity and locomotion; sex, pregnancy, and development; immunologic responses; and other behaviors.     

Ultimate mechanisms of age-biased flea parasitism

Mechanisms that cause nonrandom patterns of parasite distribution among host individuals may influence the population and evolutionary dynamics of both parasites and hosts, but are still poorly understood. We studied whether survival, reproduction, and behavioral responses of fleas (Xenopsylla conformis) changed with the age of their rodent hosts (Meriones crassus), experimentally disentangling two possible mechanisms: (a) differential survival and/or fitness reward of parasites due to host age, and (b) active parasite choice of a host of a particular age. To explore the first mechanism, we raised fleas on rodents of two age groups and assessed flea survival as well as the quantity and quality of their offspring. To explore the second mechanism, three groups of fleas that differed in their previous feeding experience (no experience, experience on juvenile or experience on adult rodents) were given an opportunity to choose between juvenile and adult rodents in a Y-maze. Fleas raised on juvenile rodents had higher survival and had more offspring that emerged earlier than fleas raised on adults. However, fleas did not show any innate preference for juvenile rodents, nor were they able to learn to choose them. In contrast to our predictions, based on a single previous exposure, fleas learned to choose adult rodents. The results suggest that two mechanisms—differential survival and fitness reward of fleas, and associative learning by them—affect patterns of flea distribution between juvenile and adult rodents. The former increases whereas the latter reduces flea densities on juvenile rodents. The ability of fleas to learn to choose adult but not juvenile hosts may be due to: (a) a stronger stimulus from adults, (b) a higher profitability of adults in terms of predictability and abundance, or (c) the evolutionary importance of recognizing adult but not juvenile hosts as representatives of the species.     

A Learning Strategy for Predator Preying on Edible and Inedible Prey

In this paper I propose a reinforcement learning model for a predator preying upon two types of prey, the unpalatable (noxious) models, and the palatable mimics. The latter type of prey resembles the models in appearance so as to derive some protection from the predator who must avoid the unpalatable models. Essentially the predator is treated as a learning automaton adopting a simple reinforcement learning strategy in order to increase its consumption of palatable prey and reduce the consumption of unpalatable ones. The populations of both mimics and models are assumed to grow logistically.