The role of competitive learning in the generation of DG fields from EC inputs

We follow up on a suggestion by Rolls and co-workers, that the effects of competitive learning should be assessed on the shape and number of spatial fields that dentate gyrus (DG) granule cells may form when receiving input from medial entorhinal cortex (mEC) grid units. We consider a simple non-dynamical model where DG units are described by a threshold-linear transfer function, and receive feedforward inputs from 1,000 mEC model grid units of various spacing, orientation and spatial phase. Feedforward weights are updated according to a Hebbian rule as the virtual rodent follows a long simulated trajectory through a single environment. Dentate activity is constrained to be very sparse. We find that indeed competitive Hebbian learning tends to result in a few active DG units with a single place field each, rounded in shape and made larger by iterative weight changes. These effects are more pronounced when produced with thousands of DG units and inputs per DG unit, which the realistic system has available, than with fewer units and inputs, in which case several DG units persists with multiple fields. The emergence of single-field units with learning is in contrast, however, to recent data indicating that most active DG units do have multiple fields. We show how multiple irregularly arranged fields can be produced by the addition of non-space selective lateral entorhinal cortex (lEC) units, which are modelled as simply providing an additional effective input specific to each DG unit. The mean number of such multiple DG fields is enhanced, in particular, when lEC and mEC inputs have overall similar variance across DG units. Finally, we show that in a restricted environment the mean size of the fields is unaltered, while their mean number is scaled down with the area of the environment.

Effects of pregnancy on spatial cognition in female Hooded Long-Evans rats

Studies examining the roles of estrogens and progestins on spatial cognition have been highly contradictory. To determine if the hormonal environment of pregnancy affects spatial cognition, pregnant (n = 7) and virgin (n = 7) Hooded Long-Evans rats were tested in a Morris water maze throughout the 3 weeks of pregnancy and the second week postpartum. Latency to platform, path length, swim velocity, and time in quadrant were compared over trial-days. To compare water maze performance with changes in hormone levels, serum concentrations of estradiol and progesterone were measured on the first, third, and fifth days of testing during the third week of pregnancy. Subjects learned to find the platform as indicated by decreased time and distance to platform over each trial-week and increased time spent in the quadrant where the platform had been located the previous week. However, there were no differences between treatment groups on time or distance to platform over trial-days. Swim velocity did not differ between or within groups over the 4 weeks of testing. Although primigravid and virgin females were similar in their abilities to learn the novel location of a submerged platform and return to it over time, pregnant animals demonstrated less perseveration to previously learned information and were quicker to locate the platform when it moved to a new location. Thus, reproductive status did not affect reference memory but enhanced working memory in the Morris water maze.     

Developmental exposure to xenoestrogen enhances spatial learning in male rats

Steroid hormones have profound effects on the development and function of the nervous system. Environmental estrogens or xenoestrogens are manmade or are natural compounds, which mimics the action of estrogen hormones. The experimental evidence for impairment of cognitive functions in humans and mammals following exposure to xenoestrogens has been fiercely debated. The strongest arguments against such studies have been that the route, time course, and intensity of exposure did not simulate environmental exposure, and that the chemicals tested have additional, non-estrogenic toxic effects, hindering a generalization of actual "xenoestrogenic" effects. Here we show that an environmental-like exposure to the pure estrogen, 17alpha-ethynylestradiol (EE2) during development enhances spatial learning abilities in adult male Sprague-Dawley rats. To simulate an environmental exposure, we used a very low dose (4 ng/kg/day) of EE2 equivalent to concentrations measured in European and US streams which was given orally with a non-invasive method, and we extended the treatment for the entire course of development, from conception to puberty. The animals were tested in a Morris water maze protocol at 6 months of age. Male rats treated with EE2 during development showed a faster learning during the training phase, and remembered better the position of the hidden platform in the short term. Our study demonstrates that actual levels of exposure to xenoestrogens can permanently alter cognitive abilities of a mammalian species.     

Effect of intrahippocampal administration of anti-melanin-concentrating hormone on spatial food-seeking behavior in rats

Melanin-concentrating hormone (MCH) is a hypothalamic peptide that plays a critical role in the regulation of food intake and energy metabolism. In this study, we investigated the potential role of dense hippocampal MCH innervation in the spatially oriented food-seeking component of feeding behavior. Rats were trained for eight sessions to seek food buried in an arena using the working memory version of the food-seeking behavior (FSB) task. The testing day involved a bilateral anti-MCH injection into the hippocampal formation followed by two trials. The anti-MCH injection did not interfere with the performance during the first trial on the testing day, which was similar to the training trials. However, during the second testing trial, when no food was presented in the arena, the control subjects exhibited a dramatic increase in the latency to initiate digging. Treatment with an anti-MCH antibody did not interfere with either the food-seeking behavior or the spatial orientation of the subjects, but the increase in the latency to start digging observed in the control subjects was prevented. These results are discussed in terms of a potential MCH-mediated hippocampal role in the integration of the sensory information necessary for decision-making in the pre-ingestive component of feeding behavior.     

Acute pretreatment with estradiol protects against CA1 cell loss and spatial learning impairments resulting from transient global ischemia

Estradiol can act to protect against hippocampal damage resulting from transient global ischemia, but little is known about the functional consequences of such neuroprotection. The present study examines whether acute estradiol administered prior to the induction of transient global ischemia protects against hippocampal cell death and deficits in performance on a spatial learning task. Ovariectomized female rats were primed with estradiol benzoate or oil vehicle 48 and 24 h prior to experiencing one of three durations of 4-vessel occlusion (0, 5, or 10 min). Performance on the cued and hidden platform versions of the Morris water maze was assessed 1 week following ischemia. On the cued platform task, neither hormone treatment nor ischemia significantly influenced acquisition. When tested on the hidden platform task, however, oil-treated rats exhibited impairments in spatial learning after either 5 or 10 min of ischemia while estradiol-treated rats showed no impairments after 5 min of ischemia and only mild impairments after 10 min of ischemia. Immediately following behavioral testing, rats were perfused and survival of CA1 pyramidal cells was assessed. Ischemia was associated with the loss of CA1 pyramidal cells but rats that received estradiol prior to ischemia showed less severe damage. Furthermore, the extent of cell loss was correlated with degree of spatial bias expressed on a probe trial following hidden platform training. These findings indicate that acute exposure to estradiol prior to ischemia is both neuroprotective and functionally protective.     

Effects of genistein in the maternal diet on reproductive development and spatial learning in male rats

Endocrine disruptors, chemicals that disturb the actions of endogenous hormones, have been implicated in birth defects associated with hormone-dependent development. Phytoestrogens are a class of endocrine disruptors found in plants. In the current study we examined the effects of exposure at various perinatal time periods to genistein, a soy phytoestrogen, on reproductive development and learning in male rats. Dams were fed genistein-containing (5 mg/kg feed) food during both gestation and lactation, during gestation only, during lactation only, or during neither period. Measures of reproductive development and body mass were taken in the male offspring during postnatal development, and learning and memory performance was assessed in adulthood. Genistein exposure via the maternal diet decreased body mass in the male offspring of dams fed genistein during both gestation and lactation, during lactation only, but not during gestation only. Genistein decreased anogenital distance when exposure was during both gestation and lactation, but there was no effect when exposure was limited to one of these time periods. Similarly, spatial learning in the Morris water maze was impaired in male rats exposed to genistein during both gestation and lactation, but not in rats exposed during only one of these time periods. There was no effect of genistein on cued or contextual fear conditioning. In summary, the data indicate that exposure to genistein through the maternal diet significantly impacts growth in male offspring if exposure is during lactation. The effects of genistein on reproductive development and spatial learning required exposure throughout the pre- and postnatal periods.     

Precedence of spatial pattern learning revealed by immediate reversal performance

Human participants learned to choose eight correct locations in a 4 × 4 matrix on a computer display. The locations were arranged either in a structured spatial pattern or an unstructured but consistent spatial arrangement. When the assignment of correct and incorrect locations was reversed after initial learning, participants in the spatial pattern condition demonstrated reversal performance immediately (i.e., following the first choice after reversal of the contingencies). Follow-up experiments confirmed that immediate reversal performance depends on a structured spatial pattern among the locations and that a learned motor pattern cannot explain the immediate reversal performance. This pattern of results shows that learning the spatial relations among locations has precedence over learning about the individual locations, even when the individual locations are completely valid predictive cues.     

Route and landmark learning by rats searching for food

Many foraging animals rely on visual landmarks and/or habitual paths to locate important resources. We examined the degree to which rats rely on these cues when they predicted conflicting food locations. In this foraging task, rats were required to find food which could be located using either a fixed route or a nearby visual landmark. In tests, we found that their subsequent search-based estimates of the food location were the same when animals had acquired a long-term memory of the route, the landmark, or both. We show that the degree to which animals rely on the cues depends not only on the discrepancy between the two cues, but also on whether animals can match the testing “view” with a learned “view” that has been acquired during training.     

Roles of oxytocin in spatial learning and memory in the nucleus basalis of Meynert in rats

The present study was performed to explore the role of oxytocin (OT) in spatial learning and memory in the nucleus basalis of Meynert (NBM) of rats. The latency, distance and swimming path to find the platform were tested by Morris water maze and recorded by a video camera connected to a computer. Intra-NBM injections of 2 or 10 nmol of OT, but not 0.2 nmol of OT, induced significant increase on the latency of spatial learning. Rats receiving intra-NBM administrations of 2 or 10 nmol of OT showed a more random search pattern. There were no significant changes in the swimming speed in Morris water maze test after the injection of OT. Furthermore, the impaired effect of OT on the latency of spatial learning was blocked by intra-NBM injection of the selective OT antagonist Atosiban, indicating that the effect of OT was mediated by OT receptor in the NBM of rats. Moreover, there were no influences of OT or Atosiban on the retention performance in rats. The results suggest that OT plays an inhibitory role in spatial learning in the NBM; the effect is mediated by OT receptor.     

Aluminum affects glial system and behavior of rats

Aluminum (Al) has been associated with neuronal dysfunction. These neuronal changes may involve glial alterations. We intend to evaluate the consequence of Al on the glial system and the behavior of rats exposed chronically to 0.3% of aluminum chloride in drinking water during 4 months in adulthood (A) or since intra-uterine age (IU); animals from this latter group were sacrificed at four months of age. Our data show an intense glial fibrillary acidic protein (GFAP)-immunoreactivity with a high density of astrocytes in both treated groups compared with controls. However, in IU rats, astrocytes display prominent glial cell bodies and processes. A and IU rat groups perform a significantly reduced locomotor activity. However, using the dark/light box test, the IU rats prefer to spend more time in the enlightened compartment compared to other groups. Behavioral and glial changes caused by Al exposure bring support for the role of Al in brain dysfunction involving glial alterations.     

Spontaneous alternation, motor activity, and spatial learning in hot-foot mutant mice

Hot-foot mutant mice, characterized by defective innervation of Purkinje cells and an ataxic gait, were less active than normal mice in a T-maze. In spontaneous alternation testing with either single or multiple trials, hot-foot mutants, contrary to normal mice, did not alternate above chance. Moreover, the mutants had a higher number of errors and higher escape latencies in a water-filled Z-maze. These results indicate that in addition to motor coordination deficits, these cerebellar mutants have deficits in spatial learning and perseverate choices of maze arms.     

The development and stability of estrogen-modulated spatial navigation strategies in female rats

Adult female rats with high levels of circulating estradiol are biased to use a place strategy to solve an ambiguous spatial navigation task and those with low levels are biased to use a response strategy. We examined the development of this hormonal modulation of strategy use by training juvenile female rats on an ambiguous navigation task and probing them for strategy use at postnatal day (PD) 16, 21, or 26, after administration of 17 β-estradiol or oil 48 and 24 h prior to testing. We found that rats could use either strategy successfully by PD21 but that estradiol did not bias rats to use a place strategy until PD26. In order to evaluate the stability of this effect over multiple navigation experiences, we retested oil-treated juveniles three times during adulthood. On the first adult navigation experience, rats were significantly more likely to use the same navigation strategy they used as juveniles, regardless of current estrous cycle phase. On the second and third adult tests, after rats had more experience with the task, previous navigation experience did not predict strategy use. Rats in proestrus were significantly more likely to use a place strategy while rats in estrus and diestrus did not appear to have a group bias to use either strategy. These results suggest that estradiol can modulate spatial navigation strategy use before puberty but that this effect interacts with previous navigation experience. This study sheds light on when and under what circumstances estradiol gains control over spatial navigation behavior in the female rat.     

Evidence for the Colocalization of Parvalbumin and Glutamate, but Not GABA, in the Perforant Path of the Gerbil Hippocampal Formation: A Combined Immunocytochemical and Microquantitative Analysis

Abstract: Gerbils ( Meriones unguiculatus ) are known for their seizure sensitivity, which is dependent on an intact perforant path from the entorhinal cortex to the hippocampus. In contrast with other species, the perforant path in gerbils contains parvalbumin, a cytosolic high-affinity calcium-binding protein. Parvalbumin is known to be present in a subpopulation of GABA-containing neurons and is thought to be responsible for their physiological characteristics of fast spiking activity and lack of spike adaptation. Therefore, the question arose of whether this projection in gerbils is GABAergic or glutamatergic as in other species. In a first approach to this question, the effect of lesioning the origin of the perforant path, the entorhinal cortex, on levels of GABA and glutamate was determined by enzymatic-luminometric assay in single layers of the dentate gyrus of lyophilized brain sections. Parallel sections were cryofixed using an acidified acetone-formaldehyde mixture at -20°C for 48 h, and subsequently stained for parvalbumin immunocytochemistry. Seven days after ablation of the entorhinal cortex, parvalbumin staining was undetectable in the termination zone of the perforant path, the outer two-thirds of the stratum moleculare. In parallel, glutamate content was reduced to 80% of controls (and of the unoperated contralateral side) but unchanged in the inner third of the stratum moleculare and in stratum granulare. GABA content was not significantly altered by the lesion. From these results, we conclude that in the gerbil as in other species, the perforant path contains glutamate. The association of glutamate with parvalbumin suggests, however, that in the gerbil the calcium-dependent release of the transmitter is carefully controlled in the entorhinal perforant path.     

Differential involvement of the mu and kappa opioid receptors in spatial learning

In order to test the role of mu and kappa opioid receptors (Mu opioid receptor (MOR) and Kappa opioid receptor (KOR)) in hippocampal-dependent spatial learning, we analyzed genetically engineered null mutant mice missing the functional MOR or KOR gene. Compared to wild-type mice, the homozygous MOR null mutants exhibited an impairment in the ultimate level of spatial learning as shown in two distinct tasks, the 8-arm radial-maze and the Morris water-maze. Control behaviors were normal. The learning impairment could be associated with the impairment we found in the maintenance of long-term potentiation in mossy fibers in CA3. In comparison, there was no impairment in spatial learning in our KOR mutants or in mossy fibers (mf) in CA3 region long-term potentiation (LTP). Our work suggests that the MOR may play a positive role in learning and memory by increasing LTP in CA3 neurons.     

LTD windows of the STDP learning rule and synaptic connections having a large transmission delay enable robust sequence learning amid background noise

Spike-timing-dependent synaptic plasticity (STDP) is a simple and effective learning rule for sequence learning. However, synapses being subject to STDP rules are readily influenced in noisy circumstances because synaptic conductances are modified by pre- and postsynaptic spikes elicited within a few tens of milliseconds, regardless of whether those spikes convey information or not. Noisy firing existing everywhere in the brain may induce irrelevant enhancement of synaptic connections through STDP rules and would result in uncertain memory encoding and obscure memory patterns. We will here show that the LTD windows of the STDP rules enable robust sequence learning amid background noise in cooperation with a large signal transmission delay between neurons and a theta rhythm, using a network model of the entorhinal cortex layer II with entorhinal-hippocampal loop connections. The important element of the present model for robust sequence learning amid background noise is the symmetric STDP rule having LTD windows on both sides of the LTP window, in addition to the loop connections having a large signal transmission delay and the theta rhythm pacing activities of stellate cells. Above all, the LTD window in the range of positive spike-timing is important to prevent influences of noise with the progress of sequence learning.     

Place cells, neocortex and spatial navigation: a short review

Hippocampal place cells are characterized by location-specific firing, that is each cell fires in a restricted region of the environment explored by the rat. In this review, we briefly examine the sensory information used by place cells to anchor their firing fields in space and show that, among the various sensory cues that can influence place cell activity, visual and motion-related cues are the most relevant. We then explore the contribution of several cortical areas to the generation of the place cell signal with an emphasis on the role of the visual cortex and parietal cortex. Finally, we address the functional significance of place cell activity and demonstrate the existence of a clear relationship between place cell positional activity and spatial navigation performance. We conclude that place cells, together with head direction cells, provide information useful for spatially guided movements, and thus provide a unique model of how spatial information is encoded in the brain.     

Electrophysiological effects of exogenous and endogenous kynurenic acid in the rat brain: studies in vivo and in vitro

Summary. In this review, recent studies on the electrophysiological effects of de novo synthesized ("endogenous") kynurenic acid (KYNA) are discussed. Endogenous KYNA is normally formed as a byproduct of tryptophan metabolism. Evidence for a physiological role in neuronal excitability has not been strong, in part because brain levels are much lower than the K_D of KYNA at the glycine site of the NMDA receptor, where KYNA is thought to exert its most potent effect. The results suggest that, unexpectedly, even low concentrations of endogenous KYNA have physiological consequences. These levels of KYNA reduced the number of hippocampal slices with spontaneous epileptiform discharges after exposure to buffer lacking magnesium. However, effects on evoked responses to single afferent stimuli were not detected. Taken together, the data argue for a potentially important role of endogenous KYNA in suppression of seizure-like activity, and suggest a novel approach to anticonvulsant drug development that could have few side effects. Received August 31, 1999 Accepted September 20, 1999     

Circuits,hormones, and learning: Vocal behavior in songbirds

Species-typical vocal patterns subserve species identification and communication for individual organisms. Only a few groups of organisms learn the sounds used for vocal communication, including songbirds, humans, and cetaceans. Vocal learning in songbirds has come to serve as a model system for the study of brain-behavior relationships and neural mechanisms of learning and memory. Songbirds learn specific vocal patterns during a sensitive period of development via a complex assortment of neurobehavioral mechanisms. In many species of songbirds, the production of vocal behavior by adult males is used to defend territories and attract females, and both males and females must perceive vocal patterns and respond to them. In both juveniles and adults, specific types of auditory experience are necessary for initial song learning as well as the maintenance of stable song patterns. External sources of experience such as acoustic cues must be integrated with internal regulatory factors such as hormones, neurotransmitters, and cytokines for vocal patterns to be learned and produced. Thus, vocal behavior in songbirds is a culturally acquired trait that is regulated by multiple intrinsic as well as extrinsic factors. Here, we focus on functional relationships between circuitry and behavior in male songbirds. In that context, we consider in particular the influence of sex hormones on vocal behavior and its underlying circuitry, as well as the regulatory and functional mechanisms suggested by morphologic changes in the neural substrate for song control. We describe new data on the architecture of the song system that suggests strong similarities between the songbird vocal control system and neural circuits for memory, cognition, and use-dependent plasticity in the mammalian brain. © 1997 John Wiley & Sons, Inc. J Neurobiol 33: 602–618, 1997     

老年学习记忆减退的神经行为学基础

用改良Ｍｏｒｒｉｓ水迷宫将老年大鼠分为老年学习记忆减退组和老年学习记忆正常组,并与青年组对照,检测其空间参考记忆和空间工作记忆,并对海马结构内胶质纤维酸性蛋白（ＧＦＡＰ）阳性胶质细胞和ＧＡＢＡ能中间神经元在光镜和电镜水平进行定量分析。结果显示老年学习记忆减退大鼠的空间参考记忆能力明显下降,并且其行为模式发生了改变,空间工作记忆改变不明显;齿状回分子层的病理改变非常明显,表现为ＧＡＢＡ能神经元丢失和     

Temporal and spatial variations in the behavior of shrubsteppe birds

Summary We documented patterns of activity and microhabitat use by breeding male Sage Sparrows (Amphispiza belli) and Brewer's Sparrows (Spizella breweri) in the semiarid shrubsteppe of northwestern U.S.A. to determine how their behavior varies in space and time and how these variations relate to environmental features. In analyses of several sites with multiple plots that were studied for 2–4 yr, the frequencies of activities and substrate use varied significantly with year, plot, and location. The major activities, foraging and singing, varied inversely with one another. Thus, although the general structure of the activity budgets of these species was stable (i.e. foraging and singing were always the most frequent activities), there was considerable variation in the quantitative details of their behavior in space and time. Using stepwise regression, we related these variations in behavior to variations in environmental features such as the densities of the same or other species, the number of species in the community, and coverages of the different substrate types. Few patterns emerged, and those that did were generally not in accord with our expectations. In particular, patterns of substrate use were not related to variations in coverages of those substrates. Sage Sparrows, for example, increased their use of sagebrush and grass with increasing grass coverage and with increasing densities of Sage Sparrows. Responses to both variables suggested nonlinear threshold patterns.We interpret the variations in behavior as indicating a loose coupling between behavior and proximate environmental conditions for these species. In such situations, the variability of behavior complicates attempts to test ecological hypotheses (e.g. behavioral niche partitioning) with data from a limited number of locations or years.