Dissociating position and heading estimations: Rotated visual orientation cues perceived after walking reset headings but not positions

This project examined the roles of idiothetic cues due to individuals’ movement and allothetic cues independent of individuals’ movement in individuals’ estimations of their position and heading during locomotion. In an immersive virtual environment, participants learned the locations of five objects and then moved along two legs of a path before positioning the origin and the objects. Participants’ estimations of their test position and their test heading were calculated based on the responded objects’ locations, using a method of dissociating position estimation and heading estimation developed in this project. Results showed that when a conflicting visual orientation cue was presented after walking, participants relied on the allothetic cues (i.e., the visual orientation cue) for their heading estimation, but on idiothetic cues for their position estimation. These results indicate that after participants updated their position in terms the origin of the path (homing vector) via path integration, they estimated their heading. These results are inconsistent with the theoretical models stipulating that homing vectors are specified in terms of participants’ body coordinate systems, but are consistent with the models stipulating that both homing vectors and participants’ heading are specified in terms of a fixed reference direction in the environment.     

Cognitive performances and locomotor activity following dentate granule cell damage in rats: role of lesion extent and type of memory tested

Intradentate injection of colchicine is one of the techniques used to destroy granule cells. This study compared the behavioral effects of various amounts of colchicine (1.0, 3.0, and 6.0 microg; Col 1, Col 3, and Col 6, respectively) injected into the dentate gyrus of adult Long-Evans male rats. Starting 10 days after lesion surgery, behavioral testing assessed home-cage and open-field locomotion, alternation in a T-maze, water-maze, and radial-maze learning according to protocols placing emphasis on reference, and working memory. All of these tasks are sensitive to hippocampal disruption. Histological verifications showed that the extent of the lesions depends on the dose of colchicine (index of dentate gyrus shrinkage: -33% in Col 1, -54% in Col 3, and -67% in Col 6 rats). Colchicine dose-dependently increased nocturnal home cage activity (an effect found 10 days but not 5 months after surgery), but had no significant effect on open-field locomotion or T-maze alternation. A dose-dependent reference memory impairment was found during the acquisition of spatial navigation in the water maze; Col 3 and Col 6 rats were more impaired than Col 1 rats. During the probe trial (platform removed), control rats spent a longer distance swimming over the platform area than all rats with colchicine lesions. In the working memory version of the test, all rats with colchicine lesions showed significant deficits. The deficits were larger in Col 3 and Col 6 rats compared to Col 1 rats. The lesions had no effect on swimming speed. In the radial-maze test, there was also a dose-dependent working memory impairment. However, reference memory was disrupted in a manner that did not differ among the three groups of lesioned rats. Our data are in line with the view that the dentate gyrus plays an important role in the acquisition of new information and is an integral neural substrate for spatial reference and spatial working memory. They also suggest that damage to granule cells might have more pronounced effects on reference than on working memory in the radial maze. Finally, they demonstrate that part of the variability in the conclusions from previous experiments concerning the role of granule cells in cognitive processes, particularly in spatial learning and memory, may be due to the type of tests used and/or the extent of the damage produced.     

Dexamethasone Does Not Prevent Seven-Day ADX-Induced Apoptosis in the Dentate Gyrus of the Rat Hippocampus

Long-term adrenalectomy (ADX) is known to result in apoptosis within the dentate gyrus of the rat hippocampus. While the underlying mechanism is still unclear, adrenal steroids appear to play a pivotal role in granule cell survival, as administration of the mineralocorticoid receptor (MR) agonists, corticosterone and aldosterone, to ADX rats results in protection against the ADX-induced effect. The consequence of administration of the glucocorticoid receptor (GR) agonists, dexamethasone and RU28362, however, is less clear, and either complete or only partial protection for the ADX animal has been reported. This study investigated further the role played by GR in the degenerative process. After establishing the characteristics of seven-day ADX-induced apoptosis in the young male Wistar rat, the effect of chronically-implanted, subcutaneous pellets containing various doses of dexamethasone and corticosterone, on ADX-induced apoptosis was studied. Both high and low doses of corticosterone were found to be protective. In contrast to some other studies, however, neither dose of dexamethasone had any obvious protective effect and rather seemed to increase apoptosis in dentate gyrus of intact animals. Intracerebroventricular infusion of dexamethasone for seven days was also found to be ineffective in preventing apoptosis, demonstrating that it is occupation of MR, rather than GR, which is crucial to dentate gyrus granule cell survival.     

Map-based navigation in mobile robots:: I. A review of localization strategies

For a robot, an animal, and even for man, to be able to use an internal representation of the spatial layout of its environment to position itself is a very complex task, which raises numerous issues of perception, categorization and motor control that must all be solved in an integrated manner to promote survival. This point is illustrated here, within the framework of a review of localization strategies in mobile robots. The allothetic and idiothetic sensors that may be used by these robots to build internal representations of their environment, and the maps in which these representations may be instantiated, are first described. Then map-based navigation systems are categorized according to a three-level hierarchy of localization strategies, which respectively call upon direct position inference, single-hypothesis tracking, and multiple-hypothesis tracking. The advantages and drawbacks of these strategies, notably with respect to the limitations of the sensors on which they rely, are discussed throughout the text.     

Alzheimer amyloid beta-peptide inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus

The perforant path projecting from the entorhinal cortex to the hippocampal dentate gyrus is a particularly vulnerable target to the early deposition of amyloid beta (Abeta) peptides in Alzheimer's brain. The authors previously showed that brief applications of Abeta at subneurotoxic concentrations suppressed the early-phase long-term potentiation (E-LTP) in rat dentate gyrus. The current study further examines the effect of Abeta on the late-phase LTP (L-LTP) in this area. Using multiple high-frequency stimulus trains, a stable L-LTP lasting for at least 3 h was induced in the medial perforant path of rat hippocampal slices. Bath application of Abeta(1-42) (0.2-1.0 microM) during the induction trains attenuated both the initial and late stages of L-LTP. On the other hand, Abeta(1-42) perfusion within the first hour following the induction primarily impaired the late stage of L-LTP, which resembled the action of the protein synthesis inhibitor emetine. Blockade of calcineurin activity with FK506 or cyclosporin A completely prevented Abeta-induced L-LTP deficits. These results suggest that Abeta(1-42) impaired both the induction and maintenance phase of dentate L-LTP through calcineurin-dependent mechanisms. In the concentration range effective for inhibiting L-LTP, Abeta(1-42) also reduced the amplitude of NMDA receptor-mediated synaptic currents in dentate granule cells via a postsynaptic mechanism. In addition, concurrent applications of Abeta(1-42) with the protein synthesis inhibitor caused no additive reduction of L-LTP, indicating a common mechanism underlying the action of both. Thus, inhibition of NMDA receptor channels and disruption of protein synthesis were two possible mechanisms contributing to Abeta-induced L-LTP impairment.     

5-HT1a receptor antagonists block perforant path-dentate LTP induced in novel, but not familiar, environments

Numerous studies suggest roles for monoamines in modulating long-term potentiation (LTP). Previously, we reported that both induction and maintenance of perforant path-dentate gyrus LTP is enhanced when induced while animals explore novel environments. Here we investigate the contribution of serotonin and 5-HT1a receptors to the novelty-mediated enhancement of LTP. In freely moving animals, systemic administration of the selective 5-HT1a antagonist WAY-100635 (WAY) attenuated LTP in a dose-dependent manner when LTP was induced while animals explored novel cages. In contrast, LTP was completely unaffected by WAY when induced in familiar environments. LTP was also blocked in anesthetized animals by direct application of WAY to the dentate gyrus, but not to the median raphe nucleus (MRN), suggesting the effect of systemic WAY is mediated by a block of dentate 5-HT1a receptors. Paradoxically, systemic administration of the 5-HT1a agonist 8-OH-DPAT also attenuated LTP. This attenuation was mimicked in anesthetized animals following application of 8-OH-DPAT to the MRN, but not the dentate gyrus. In addition, application of a 5-HT1a agonist to the dentate gyrus reduced somatic GABAergic inhibition. Because serotonergic projections from the MRN terminate on dentate inhibitory interneurons, these data suggest 5-HT1a receptors contribute to LTP induction via inhibition of GABAergic interneurons. Moreover, activation of raphe 5-HT1a autoreceptors, which inhibits serotonin release, attenuated LTP induction even in familiar environments. This suggests that serotonin normally contributes to dentate LTP induction in a variety of behavioral states. Together, these data suggest that serotonin and dentate 5-HT1a receptors play a permissive role in dentate LTP induction, particularly in novel conditions, and presumably, during the encoding of novel, hippocampus-relevant information.     

Aging and Spatial Navigation: What Do We Know and Where Do We Go?

Spatial navigation is a complex cognitive skill that is necessary for everyday functioning in the environment. However, navigational skills are not typically measured in most test batteries assessing cognitive aging. The present paper reviews what we know about behavioral differences between older and younger adults in navigational skill and reviews the putative neural mechanisms that may underlie these behavioral differences. Empirical studies to date clearly identify navigation as an aspect of cognitive function that is vulnerable to the aging process. The few functional and structural neuroimaging studies that speak to neurological correlates of these age-related differences point to the hippocampus, parahippocampal gyrus, posterior cingulate gyrus (retrosplenial cortex), parietal lobes and pre-frontal cortex as structures critically involved in age effects on navigation. Outstanding issues in the field are addressed and productive avenues of future research are suggested. Among these outstanding issues include the necessity of performing longitudinal studies and differentiating between hippocampal and extra-hippocampal contributions to aging in navigation. The field may also be advanced by empirical assessment of navigational strategies and investigations into the multisensory nature of navigation including assessing the relative contributions of visual, vestibular, and proprioceptive function to age differences in navigational skill.     

An attractor network in the hippocampus: theory and neurophysiology

A quantitative computational theory of the operation of the CA3 system as an attractor or autoassociation network is described. Based on the proposal that CA3-CA3 autoassociative networks are important for episodic or event memory in which space is a component (place in rodents and spatial view in primates), it has been shown behaviorally that the CA3 supports spatial rapid one-trial learning and learning of arbitrary associations and pattern completion where space is a component. Consistent with the theory, single neurons in the primate CA3 respond to combinations of spatial view and object, and spatial view and reward. Furthermore, single CA3 neurons reflect the recall of a place from an object in a one-trial object-place event memory task. CA3 neurons also reflect in their firing a memory of spatial view that is retained and updated by idiothetic information to implement path integration when the spatial view is obscured. Based on the computational proposal that the dentate gyrus produces sparse representations by competitive learning and via the mossy fiber pathway forces new representations on the CA3 during learning (encoding), it has been shown behaviorally that the dentate gyrus supports spatial pattern separation during learning, and that the mossy fiber system to CA3 connections are involved in learning but not in recall. The perforant path input to CA3 is quantitatively appropriate to provide the cue for recall in CA3. The concept that the CA1 recodes information from CA3 and sets up associatively learned back-projections to neocortex to allow subsequent retrieval of information to neocortex provides a quantitative account of the large number of hippocampo-neocortical back-projections.     

Changes in cytochrome oxidase activity following spatial working memory learning in rats treated with tacrine

We evaluated change in cytochrome oxidase (COx) activity of the hippocampus and related structures of the limbic system following spatial working memory learning in rats after treatment with tacrine (8.0mg/kg). Control groups treated with saline and tacrine and an untreated group were added. Acetylcholinesterase optical density levels were also measured. The tacrine and saline groups showed similar behavioral results, but a decrease in COx activity was found in the tacrine group in the prefrontal cortex, nucleus accumbens, anterior thalamus, hippocampus and nucleus basalis of Meynert. Similarly, acetylcholinesterase levels of the tacrine group were lower in most of the regions. Learning-related increase in COx activity was found in the prefrontal cortex and dentate gyrus in the saline group. The tacrine group presented the same increase in the anterodorsal thalamus, dentate gyrus, CA3 and mammillary nuclei. These results suggest that inhibition of the acetylcholinesterase produces a different pattern of learning-related neuronal activity in the limbic system of the rat.     

去甲肾上腺素对习得性长时程突触增强的影响

在大鼠条件性饮水反应的建立和巩固过程中,在每天训练之前,通过预先与记录电极一起埋植在海马齿状回的注药管,微量注射去甲肾上腺素(NE),观察其对海马齿状回的习得性长时程突触增强的影响。结果表明:NE能增强突触效应;训练作业前注NE易化了习得性长时程突触增强的形成,但对其巩固无影响;同时相应地易化了动物条件反应的建立。提示NE参与海马齿状回的习得性长时程增强的形成。本文对其可能的作用机制进行了讨论。     

Electrical self-stimulation of dentate gyrus granule cells

Male albino rats implanted with a chronic stimulating electrode electrophysiologically guided into the granule cell layer of the dorsal dentate gyrus were tested in a self-stimulation paradigm. It was found that subjects self-administer electrical stimulation to the granule cells at low, steady rates. Consistent with the presence of opioid-like immunoreactivity in the granule cell mossy fiber pathway, intraperitoneal injection of the opiate antagonist naloxone diminishes granule cell self-stimulation in a dose-related fashion. The results suggest that a granule cell opioid synapse participates in expression of reward at this site.     

Neurogenesis decreases with age in the canine hippocampus and correlates with cognitive function

New neurons are continually produced in the adult mammalian brain from progenitor cells located in specific brain regions, including the subgranular zone (SGZ) of the dentate gyrus of the hippocampus. We hypothesized that neurogenesis occurs in the canine brain and is reduced with age. We examined neurogenesis in the hippocampus of five young and five aged animals using doublecortin (DCX) and bromodeoxyuridine (BrdU) immunostaining. The total unilateral number of new neurons in the canine SGZ and granule cell layer (GCL) was estimated using stereological techniques based upon unbiased principles of systematic uniformly random sampling. Animals received 25mg/kg of BrdU once a day for 5 days and were euthanized 9 days after the last injection. We found evidence of neurogenesis in the canine brain and that cell genesis and neurogenesis are greatly reduced in the SGZ/GCL of aged animals compared to young. We further tested the hypothesis that an antioxidant fortified food or behavioral enrichment would improve neurogenesis in the aged canine brain and neurogenesis may correlate with cognitive function. Aged animals were treated for 2.8 years and tissue was available for six that received the antioxidant food, five that received the enrichment and six receiving both treatments. There were no significant differences in the absolute number of DCX or DCX-BrdU neurons or BrdU nuclei between the treatment groups compared to control animals. The number of DCX-positive neurons and double-labeled DCX-BrdU-positive neurons, but not BrdU-positive nuclei alone, significantly correlated with performance on several cognitive tasks including spatial memory and discrimination learning. These results suggest that new neurons in the aged canine dentate gyrus may participate in modulating cognitive functions.     

Androgens are neuroprotective in the dentate gyrus of adrenalectomized female rats

Neuroprotective effects of androgens have not been well-characterized, but there is evidence that 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol) has anti-seizure effects. To further examine androgens' neuroprotective effects, testosterone (T), dihydrotestosterone (DHT), 3 alpha-diol (1.0 mg/kg SC daily), or sesame oil vehicle was administered to adrenalectomized or sham-operated, young, female Long Evans rats (N = 52). After seven days, animals were perfused and trunk blood was collected for radioimmunoassay of plasma corticosterone and androgens. No pyknotic cells were seen in the dentate of the sham-operated animals or those animals that had incomplete adrenalectomies (n = 20); however, cresyl violet and TUNEL stains revealed pyknotic cells in the granule layer of the dentate gyrus of adrenalectomized rats (n = 28). Testosterone, DHT, or 3 alpha-diol significantly reduced the number of pyknotic cells in the dentate gyrus compared to vehicle administered, adrenalectomized rats. Steroid-administered animals had levels of T, DHT, or 3 alpha-diol within physiological concentrations. These findings suggest that T, DHT, or 3 alpha-diol may have neuroprotective effects via a common mechanism of action.     

Bilateral lesion of the cerebellar-dentate nucleus impairs egocentric sequential learning but not egocentric navigation in the rat

The involvement of the cerebellum in procedural learning is demonstrated in visuomotor-sequence tasks, as lesion of this area impedes the acquisition of new sequences. Likewise, the lateral cerebellum appears to be involved in the acquisition of new sequences, but not in the execution of learned sequences. In contrast, the dentate nucleus participates only in the execution of learned visuomotor sequences. In previous studies, disruption of the procedural elements of spatial navigation following cerebellar or dentate lesions has been reported. However, as praxic strategies (egocentric learning) are included in the procedural elements of the navigation, the participation of the cerebellar-dentate nucleus in egocentric procedural learning processes has not been evaluated. Therefore, using colchicine, bilateral lesions were made in the cerebellar-dentate nucleus of Sprague-Dawley rats, and these rats were given two tasks: egocentric-based motor sequence learning in the radial maze and egocentric navigation in the Morris water maze. The lesioned rats were unable to use the sequential information in the short term and showed delayed long-term acquisition, which was probably due to the inability to detect the sequence. No effects on the egocentric navigation task were observed. Our results indicate that the cerebellar-dentate nucleus is involved in the detection of egocentric sequential information but not in the use of this information in the navigation process. Further, they show differential involvement of the cerebellar-dentate nucleus in the execution of learned visuomotor sequences, as the dentate lesion disrupted the acquisition of new egocentric-motor-based sequences.     

Children's use of geometry for reorientation

Research on navigation has shown that humans and laboratory animals recover their sense of orientation primarily by detecting geometric properties of large-scale surface layouts (e.g. room shape), but the reasons for the primacy of layout geometry have not been clarified. In four experiments, we tested whether 4-year-old children reorient by the geometry of extended wall-like surfaces because such surfaces are large and perceived as stable, because they serve as barriers to vision or to locomotion, or because they form a single, connected geometric figure. Disoriented children successfully reoriented by the shape of an arena formed by surfaces that were short enough to see and step over. In contrast, children failed to reorient by the shape of an arena defined by large and stable columns or by connected lines on the floor. We conclude that preschool children's reorientation is not guided by the functional relevance of the immediate environmental properties, but rather by a specific sensitivity to the geometric properties of the extended three-dimensional surface layout.     

Cannabinoid CB1 receptor deficiency increases contextual fear memory under highly aversive conditions and long-term potentiation in vivo

The cannabinoid receptor type 1 (CB1) is abundantly expressed in the central nervous system where it negatively controls the release of several neurotransmitters. CB1 activity plays a crucial role in learning and memory and in synaptic plasticity. In the present study, the role of CB1 was investigated in three different hippocampus-dependent memory tasks and in in vivo hippocampal synaptic plasticity in knockout (CB1-ko) and wildtype mice. There was no difference in short-term and long-term social and object recognition memory between CB1-ko and wildtype mice. In contrast, in background contextual fear conditioning CB1-ko mice showed enhanced freezing levels in the conditioning context and increased generalised contextual fear after a high-intensity conditioning foot shock of 1.5 mA, but not after 0.7 mA. In in vivo field potential recordings in the dentate gyrus, CB1-ko mice displayed a decreased paired-pulse facilitation of the populations spikes, suggesting an altered inhibitory synaptic drive onto hippocampal granule cells. Furthermore, CB1-ko mice displayed significantly higher levels of in vivo long-term potentiation (LTP) in the dentate gyrus. In conclusion, CB1 deficiency leads to enhanced contextual fear memory and altered synaptic plasticity in the hippocampus, supporting the key role of endocannabinoid signalling in learning and memory, in particular following highly aversive encounters.     

Social stress in tree shrews as an animal model of depression: an example of a behavioral model of a CNS disorder

Animal models are invaluable in preclinical research on human psychopathology. Valid animal models to study the pathophysiology of depression and specific biological and behavioral responses to antidepressant drug treatments are of prime interest. In order to improve our knowledge of the causal mechanisms of stress-related disorders such as depression, we need animal models that mirror the situation seen in patients. One promising model is the chronic psychosocial stress paradigm in male tree shrews. Coexistence of two males in visual and olfactory contact leads to a stable dominant/subordinate relationship, with the subordinates showing obvious changes in behavioral, neuroendocrine, and central nervous activity that are similar to the signs and symptoms observed during episodes of depression in patients. To discover whether this model, besides its "face validity" for depression, also has "predictive validity," we treated subordinate animals with the tricyclic antidepressant clomipramine and found a time-dependent recovery of both endocrine function and normal behavior. In contrast, the anxiolytic diazepam was ineffective. Chronic psychosocial stress in male tree shrews significantly decreased hippocampal volume and the proliferation rate of the granule precursor cells in the dentate gyrus. These stress-induced changes can be prevented by treating the animals with clomipramine, tianeptine, or the selective neurokinin receptor antagonist L-760,735. In addition to its apparent face and predictive validity, the tree shrew model also has a "molecular validity" due to the degradation routes of psychotropic compounds and gene sequences of receptors are very similar to those in humans. Although further research is required to validate this model fully, it provides an adequate and interesting non-rodent experimental paradigm for preclinical research on depression.     

Learning and adult neurogenesis: survival with or without proliferation?

Recent high quality papers have renewed interest in the phenomenon of neurogenesis within the adult mammalian brain. Many studies now show that neurogenesis can be modulated by environmental factors including physical activity, stress, and learning. These findings have considerable implications for neuroscience in general, including the study of learning and memory, neural network plasticity, aging, neurodegeneration, and the recovery from brain injury. Although new light has been shed on this field, many contradictory findings have been reported. Here we propose two principle issues which underlie these inconsistencies, with particular focus on the interaction between learning and neurogenesis. The first issue relates to the basic methodology of measuring the generation of new brain cells, i.e., proliferation, as compared to survival of the newly made cells. Mostly, measures of neurogenesis reported are a combination of proliferation and survival, making it impossible to distinguish between these separate processes. The second aspect is in regards to the role of environmental factors which can affect both proliferation and survival independently. Especially the interaction between stress and learning is of importance since these might counteract each other in some circumstances. Reviewing the literature while taking these issues into account indicates that, in contrast to some findings, cell proliferation in the dentate gyrus of the hippocampus as a result of learning cannot be ruled out yet. On the other hand, increased survival of granule cells in the dentate gyrus as a result of hippocampal-dependent learning has been clearly demonstrated. Moreover, this learning-induced survival of granule cells, which were born before the actual learning experience, might provide a molecular mechanism for the 'use it or lose it' principle.     

同一学习中海马不同区的习得性长时程突触增强的形成

本研究探查大鼠分辨学习中海马齿状回(DG)和CA_3区突触效应的变化及其相互关系,以探讨同一学习中海马不同区突触可塑性变化的特点及其相互关系,进一步论证习得性长时程增强(LTP)是学习和记忆的神经基础。发现:(1)穿通纤维的单个刺激可在DG和CA_3同时记录到潜伏期、峰值和波形各异的群体峰电位(PS);在一定范围内PS随刺激强度的增加而增大,但DG的PS增大程度比CA_3的小;据此,检测刺激的强度应选在该范围内。(2)随着行为训练,DG和CA_3区的突触传递同时产生LTP,两者LTP的发展是显著正相关关系(P<0.01),PS峰值同时达到最高水平,且先于分辨反应达学会标准,首次表明在同一学习中大鼠海马的DG和CA_3的习得性LTP是同时产生的。本研究还表明,在慢性实验下同时记录和分析行为学习中海马两个区突触效应的变化及其相互关系是可能的,这给从神经环路角度研究学习和记忆的突触机制提供了有用的模型。