Attenuation of Hippocampal 11beta-Hydroxysteroid Dehydrogenase Type 1 by Chronic Psychosocial Stress in the Tree Shrew

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) catalyses the interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone, thus regulating glucocorticoid access to intracellular receptors. In rats, chronic glucocorticoid excess or stress increases 11beta-HSD-1 in the hippocampus, producing suggestions that it may attenuate the deleterious effects of chronic glucocorticoid excess. However, 11beta-HSD-1 predominantly catalyses 11beta-reduction in the intact liver and hippocampal cells, thus regenerating active glucocorticoids from inert substrate. We studied 11beta-HSD activity in the tissues of male tree shrews following 28 days of sustained psychosocial stress or exogenous administration of cortisol. In the hippocampus, chronic psychosocial stress attenuated 11-HSD-1 activity (69 +/- 9% of control), whereas cortisol alone had no effect. In the liver, both chronic stress and cortisol administration decreased 11beta-HSD-1 activity (47 +/- 11% and 49 +/- 4% fall, resp.). Attenuation of 11beta-HSD-1 within tissues may reflect a homeostatic mechanism designed to minimise the adverse effects of prolonged stress and/or glucocorticoid excess.     

Excitotoxic lesions of the parafascicular nucleus produce deficits in a socially transmitted food preference

The parafascicular (PF) nucleus, a posterior component of the intralaminar nuclei of the thalamus, is considered to be an essential structure in the feedback circuits of basal ganglia-thalamo-cortical systems that critically participate in cognitive processes. To study the PF contribution to processing of behaviorally significant information during specific episodes of learning, we investigated the effects of damaging the PF nucleus in the acquisition of a natural form of social olfactory learning, the socially transmitted food preference (STFP) task. This task is a non-spatial paradigm that exhibits some of the characteristics of relational memory because it requires that animals use information obtained in one episode to guide later behavior in different circumstances. Adult male Wistar rats were submitted to pretraining bilateral N-methyl-D-aspartate (0.15 M, pH 7.4) lesions of the PF (0.4 microl/side, 0.2 microl/min). The behavioral effects of PF lesions were compared to vehicle- and sham-operated control groups and two retention delays were considered in separate groups: immediately (Lesion-I, Vehicle-I, and Sham-I groups) and 24h after training (Lesion-24, Vehicle-24, and Sham-24 groups). PF lesions produced delay-independent impairments in the STFP suggesting that this nucleus might modulate the acquisition of this odor-odor association task. Results are discussed in the context of medial prefrontal cortex deafferentation induced by PF damage.     

Effects of genetic vestibular defects on behavior related to spatial orientation and emotionality.

A large battery of behavioral tests was administered to normal mice and to mice with varying degrees of otoconial agenesis due to genes affecting vestibular development. Many significant differences were found, but a factor analysis revealed that the variance on the 11 best tests could be accounted for in terms of two underlying variables. Factor I, the more important of the two, was associated with activity, habituation, and spontaneous alternation. Factor II appeared to represent a fear of new stimuli or situations. In both cases factor scores were highly related to the degree of otoconial deficiency. One subgroup of mice with severe otoconial agenesis displayed hyperactivity and a total absence of either habituation or spontaneous alternation. In these animals, brain and body development were stunted, and the reactions to amphetamine and physostigmine were opposite to those seen in normal mice. The results support the idea that the static organs contribute importantly to spatial orientation and suggest that early-onset vestibular defects can result in profound alterations of emotionality.     

Norepinephrine and brain damage: alpha noradrenergic pharmacology alters functional recovery after cortical trauma

The goal of these experiments was to evaluate the effects of some drugs affecting noradrenergic (NE) synaptic transmission, commonly prescribed following stroke or traumatic brain injury, on functional recovery. Measurement of recovery from a transient hemiplegia produced by a traumatic unilateral focal contusion in sensorimotor cortex (SMCX) of rats was used to assess the effects of chronic haloperidol (HAL) treatment begun early (1 day) or late (18 days to recovered animals) after injury. Additionally, using the same model, the effects of a single administration of drugs with selective action at NE receptors were also evaluated early or late (30 days) after injury. These drugs were: phenoxybenzamine (PBZ), an alpha 1-NE antagonist; prazosin (PRAZ), an alpha 1-NE antagonist; yohimbine (YOH), an alpha 2-NE antagonist; propranolol (PROP), a beta 1- and 2-NE receptor antagonist; methoxymine (METHOX), an alpha 1-NE agonist; and clonidine (CLON), an alpha 2-NE agonist. The data indicate that drugs with antagonistic effects at alpha 1 NE receptors, including HAL and PRAZ but not PROP, administered early after SMCX contusion retard locomotor recovery. Beneficial effects of enhancing NE transmission by METHOX or YOH were not observed. In animals recovered from beam walk (BW) deficits, a single administration of PBZ or PRAZ (alpha 1 NE antagonists) or CLON (alpha 2 NE agonist) transiently reinstated hemiplegic symptoms. The nonspecific beta NE receptor antagonist PROP had no effect in recovered animals. A single dose of HAL had no effect in recovered animals, but a BW deficit transiently developed in some animals following chronic treatment. The data are discussed with reference to drug contraindications noted in clinical studies of recovery from poststroke aphasia and cognition in demented patients with degenerative brain disease.     

How vestibular stimulation interacts with illusory hand ownership

Artificial stimulation of the peripheral vestibular system has been shown to improve ownership of body parts in neurological patients, suggesting vestibular contributions to bodily self-consciousness. Here, we investigated whether galvanic vestibular stimulation (GVS) interferes with the mechanisms underlying ownership, touch, and the localization of one’s own hand in healthy participants by using the “rubber hand illusion” paradigm. Our results show that left anodal GVS increases illusory ownership of the fake hand and illusory location of touch. We propose that these changes are due to vestibular interference with spatial and/or temporal mechanisms of visual-tactile integration leading to an enhancement of visual capture. As only left anodal GVS lead to such changes, and based on neurological data on body part ownership, we suggest that this vestibular interference is mediated by the right temporo-parietal junction and the posterior insula.     

Weighting and reweighting of visual input via head mounted display given unilateral peripheral vestibular dysfunction

We translated a well-established laboratory paradigm to study sensory integration into a Head-Mounted-Display (HMD). In the current study, a group of 23 individuals with unilateral vestibular dysfunction and 16 age-matched controls observed moving spheres projected from the Oculus Rift. We confirmed increased visual weighting with an unstable surface and decreased visual weighting (i.e., reweighting) with increased visual amplitude. We did not observe significant differences in gains and phases between individuals with vestibular dysfunction and age-matched controls. The vestibular group increased sway in mid and high frequencies significantly more than controls with the change in surface or visual amplitude. Mild visual perturbations within HMDs carry the potential to become a useful portable assessment of postural control in individuals with vestibular disorders.     

Response suppression produced by vestibular stimulation in the rat

Seven rats were trained to stable performance levels on either Fixed Ratio 47, Variable Ratio 47, Variable Interval 1-min, or Fixed Interval 1-min schedules of food reinforcement. Subjects were then tested for sensitivity to vestibular stimulation from rotation, using an ascending method of limits technique with increments in velocity of one revolution per minute every 5 min. Centrifugal forces were minimized by locating the test chamber over the axis of rotation. Response rates decreased in all subjects as a function of increasing rotation speed. In addition, characteristic differences in the patterns of response decrement were found between subjects on ratio and on interval schedules. Repeated tests indicated high intra-subject reliability in sensitivity to rotation. Similarities of these data to "motion sickness" phenomena in other species were noted. It is suggested that this behavioral approach provides a sensitive and quantifiable technique for assessing the effects of vestibular stimulation in animals.     

CRF受体对五羟色胺系统的调节作用及早期环境因素的影响

早期环境因素持续影响脑与行为的发展,增加个体成年后应激相关精神疾病患病的易感性.应激反应的中枢启动因子促肾上腺皮质激素释放因子(corticotropin-releasing factor,CRF)通过两种受体CRF1和CRF2调节中缝背核(dorsal raphe nucleus,DRN)-五-羟色胺(serotonin,5-HT)系统,后者已被证实在应激相关情绪疾患发病和治疗过程中发挥重要作用.已知CRF受体以相互影响相互拮抗的方式动态调节DRN-5-HT系统,提示这两种受体相对作用的调节对于协调复杂环境中DRN-5-HT系统的应激反应过程起着关键性作用.早期环境因素和遗传因素交互作用导致CRF受体的分布和反应性持续改变并造成DRN-5-HT系统反应异常,可能是导致应激反应和精神疾病易感性个体差异的重要神经基础.     

Sympathetic arousal to a vestibular stressor in high and low hostile men

The aim of the present experiment was to extend the literature on hostility and a cerebral systems based model of sympathetic arousal to a vestibular-based stress. Several authors have concluded that autonomic stress reactivity in high hostile individuals must be interpersonally based, whereas healthy vestibular system functioning does not depend on interpersonal features. Utilizing a vestibular activation paradigm, skin conductance levels of 15 high hostile and 15 low hostile men were recorded after brief passive rotation about the vertical neuroaxis. It was expected that hostile individuals would exhibit higher skin conductance levels after rotation compared with low hostile individuals. The results confirmed expectations of heightened sympathetic tone among high hostiles subsequent to vestibular stress. Overall, the findings are interpreted to support a cerebral model of frontal region capacity limitation for regulation of vestibular stress that is independent of psychosocial mechanisms.     

The GM1 ganglioside hastens the reduction of hyperemotionality after septal lesions

The purpose of the present study was to assess the effects of ganglioside treatment on changes in emotional, activity, and avoidance behaviors following septal brain damage. Rats were treated with GM1-gangliosides either before and after septal lesions, or only after septal lesions and tested for emotionality on 10 consecutive days beginning on the second day after surgery. The ganglioside treatment decreased the emotionality of rats with septal damage on the first test day, and enhanced their rate of recovery to control levels of emotionality. Septal rats treated with gangliosides had activity, rearing, and avoidance behaviors equivalent to nontreated septal rats; however, lesioned rats treated with GM1 showed reduced intertrial crossings during avoidance conditioning. These results suggest that the changes in emotional behavior of septal rats treated with GM1 occur shortly after the lesion.     

Effects of vestibular stimulation on motor development and stereotyped behavior of developmentally delayed children

Four developmentally delayed babies were given semicircular canal stimulation in an effort to facilitate their motor and reflex development. Each of the children also exhibited abnormal stereotyped movements. The theory was advanced that these movements are related to motor development and that significant improvements in motor abilities will produce changes in the intensity and/or form of stereotypic responding. Semicircular canal stimulation was provided by rotating the children in a motor-driven chair at a velocity of about 17 rpm for 10 minutes daily over a period of 2 weeks. Standard motor and reflex measures were taken before, during, and after the rotation treatment period. Daily observations were made of the children's stereotyped movements. Over the course of the study all of the children showed motor and/or reflex changes that were attributable to the vestibular stimulation. In addition, some evidence was obtained linking changes in stereotypic responding to the vestibular stimulation.This work was supported by PHS Grant Nos.HD15051 and HD13344.     

Maternal separation exaggerates the toxic effects of 6-hydroxydopamine in rats: implications for neurodegenerative disorders

Many studies have shown that early life stress may lead to impaired brain development, and may be a risk factor for developing psychiatric pathologies such as depression. However, few studies have investigated the impact that early life stress might have on the onset and development of neurodegenerative disorders, such as Parkinson's disease, which is characterized in part by the degeneration of dopaminergic neurons in the nigrostriatal pathway. The present study subjected rat pups to a maternal separation paradigm that has been shown to model adverse early life events, and investigated the effects that it has on motor deficits induced by a unilateral, intrastriatal injection of 6-hydroxydopamine (12 microg/4 microl). The female rats were assessed for behavioral changes at 28 days post-lesion with a battery of tests that are sensitive to the degree of dopamine loss. The results showed that rats that had been subjected to maternal separation display significantly impaired performance in the vibrissae and single-limb akinesia test when compared to normally reared animals. In addition, there was a significant increase in the loss of tyrosine hydroxylase staining in maternally separated rats. Our results therefore suggest that adverse experiences sustained during early life contribute to making dopamine neurons more susceptible to subsequent insults occurring during more mature stages of life and may therefore play a role in the etiopathogenesis of Parkinson's disease.     

Impaired, spared, and enhanced ACh efflux across the hippocampus and striatum in diencephalic amnesia is dependent on task demands

Diencephalic amnesia manifests itself through a host of neurological and memory impairments. A commonly employed animal model of diencephalic amnesia, pyrithiamine-induced thiamine deficiency (PTD), results in brain lesions and impairments similar in nature and distribution to those observed in humans with Wernicke–Korsakoff syndrome (WKS). In the current investigation, 2 separate experiments were conducted in which acetylcholine (ACh) efflux was assessed in the hippocampus and striatum of PTD-treated and pair-fed (PF) control male Sprague–Dawley rats. The goal was to determine under what behavioral conditions and in which brain structures ACh efflux was spared, impaired, or adaptively enhanced. In Experiment 1, rats were assessed on a spontaneous alternation task; in Experiment 2, rats were tested on a T-maze discrimination task that could be learned via a hippocampal- or striatal-based strategy. In Experiment 1, PTD-treated rats were impaired on the spontaneous alternation task and ACh efflux in the hippocampus during testing was significantly reduced, but spared in the striatum. In Experiment 2, PTD- and PF-treated rats did not differ in the number of trials to criterion, but PTD-treated rats demonstrated greater reliance upon egocentric cues to solve the task. Furthermore, ACh efflux in the striatum was greater during maze learning in the PTD-treated animals when compared to the PF animals. These results suggest that there is behavioral and systems level plasticity that can facilitate the use of alternative strategies to solve a task following diencephalic damage and WKS.     

Effects of moderate chronic ethanol consumption on hippocampal nicotinic receptors and associative learning

A number of studies have reported that ethanol exposure induces changes in different brain systems. The hippocampus is a brain region that is very vulnerable to ethanol exposition, which functionally results in impairment of learning and memory processes reported in heavy drinkers. Hippocampal nicotinic receptors are involved in learning and memory. In this study, we determined the effects of ethanol on the main hippocampal subtypes of neural nicotinic receptors (α7 and α4β2) in rats non-selected for alcohol consumption, in order to check for possible changes on these receptors that could be linked with alterations in learning acquisition. Binding assays were carried out with [³H]methyllycaconitine ([³H]MLA) to study the α7 and [³H]nicotine to study α4β2 receptors. Auto-shaping, continuous ratio and extinction procedures were used as behavioral tests. The results show that moderate chronic ethanol consumption for 10 weeks produces: (a) a decrease of both hippocampal nicotinic receptor subtypes without alterations in affinity; (b) no differences in behavioral performance between control rats and ethanol-drinking rats in auto-shaping and continuous ratio; (c) an improvement of performance of extinction paradigm. These results indicate that chronic ethanol consumption, at moderate levels, induces changes in hippocampal nicotinic receptors but does not impair acquisition and performance of new associative learning and even improves some kind of paradigms. These results may have implications in the biochemical basis of interactions between alcohol and nicotine and the effects of these drugs on behavior.     

Posttraining activation of CB1 cannabinoid receptors in the CA1 region of the dorsal hippocampus impairs object recognition long-term memory

Evidence indicates that brain endocannabinoids are involved in memory processing. However, the participation of CB1 and CB2 cannabinoid receptors in recognition memory has not been yet conclusively determined. Therefore, we evaluated the effect of the posttraining activation of hippocampal cannabinoid receptors on the consolidation of object recognition memory. Rats with infusion cannulae stereotaxically aimed to the CA1 region of the dorsal hippocampus were trained in an object recognition learning task involving exposure to two different stimulus objects. Memory retention was assessed at different times after training. In the test sessions, one of the objects presented during training was replaced by a novel one. When infused in the CA1 region immediately after training, the non-selective cannabinoid receptor agonist WIN-55,212-2 and the endocannabinoid membrane transporter inhibitor VDM-11 blocked long-term memory retention in a dose-dependent manner without affecting short-term memory, exploratory behavior, anxiety state or the functionality of the hippocampus. The amnesic effect of WIN-55,212-2 and VDM-11 was not due to state-dependency and was completely reversed by co-infusion of the CB1 receptor antagonist AM-251 and mimicked by the CB1 receptor agonist ACEA but not by the CB2 receptor agonists JWH-015 and palmitoylethanolamide. Our data indicate that activation of hippocampal CB1 receptors early after training hampers consolidation of object recognition memory.     

慢性应激性抑郁发生中大鼠眶额叶多巴胺D1受体对谷氨酸及其NMDA受体的调节

本文旨在探讨慢性应激性抑郁发生过程中眶额叶多巴胺D1受体对谷氨酸(glutamic acid, Glu)及其N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid, NMDA)受体的NR2B亚基的影响。实验通过建立慢性不可预见性温和应激(chronic unpredictable mild stress, CUMS)抑郁模型, 结合眶额叶微量注射多巴胺D1受体激动剂SKF38393和多巴胺D1受体拮抗剂SCH23390, 运用糖水偏爱测试、悬尾实验和敞箱实验等方法检测动物的行为表现, 采用高效液相色谱法(high-performance liquid chromatography, HPLC)和蛋白质免疫印迹法(Western blot, WB)来检测眶额叶内谷氨酸、多巴胺含量及NR2B和多巴胺D1受体的表达。结果显示, 与对照组相比, CUMS组大鼠表现出明显的抑郁样行为变化, 且眶额叶多巴胺含量降低, 其D1型受体表达降低, 谷氨酸含量升高, 其NMDA受体的NR2B亚基也明显上调; 注射SKF38393后可明显改善应激引起的抑郁样行为, 且眶额叶谷氨酸含量显著下降, NMDA受体的NR2B亚基表达也有所降低; 正常大鼠注射多巴胺D1受体拮抗剂SCH23390, 大鼠表现出和CUMS模型组相似的抑郁样行为, 且眶额叶谷氨酸含量升高, 其NMDA受体的NR2B亚基也明显上调。以上结果表明, 慢性不可预见性应激可能使眶额叶多巴胺释放减少, 从而使谷氨酸过量释放, NMDA受体过度激活, 导致抑郁发生。多巴胺抗抑郁作用是通过D1型受体抑制谷氨酸及其NMDA受体NR2B亚基表达来实现。     

Neurotoxic lesion of the rostral perirhinal cortex blocks stress-induced exploratory behavioral changes in male rats

Exposure to stress leads to adaptive responses including both behavioral and physiological changes. This process is induced by the activation of multiple brain regions. The present study examined the role of the rostral perirhinal cortex (rPRh) in behavioral changes following electrical foot shock-induced stress. The rPRh of rats was lesioned bilaterally by local microinjections of 10 microg N-methyl-D-aspartic acid (NMDA) before foot shocks (0.7 mA, 1 s). The effects of these lesions on foot shock-induced changes in exploratory behaviors were tested in the open field (4 h, 48 h, 72 h, and 14 days after foot shocks) and the light-dark box (7 days after foot shocks). Foot-shocked and sham-lesioned rats showed several well known behavioral changes in the open field (e.g., immobility, reduction of exploratory activity) most marked at 48 h after foot shocks, and the light-dark box (e.g., reduction of time spent and activity in the lit compartment). All these stress-induced behavioral changes were blocked by neurotoxic lesions of the rPRh. Furthermore, rPRh lesions did not affect behavior in the open field and the light-dark box in unstressed rats. Taken together, these data indicate that the rPRh is involved in neurophysiological mechanisms that mediate changes induced by foot-shock stress in exploratory behaviors which indicate unconditioned fear or anxiety.     

Contribution of the parafascicular nucleus in the spontaneous object recognition task

The parafascicular (PF) nucleus, a posterior component of the intralaminar nuclei of the thalamus, is considered to be an essential structure in the feedback systems of basal ganglia–thalamo-cortical circuits critically involved in cognitive processes. The specific role played by multimodal information encoded in PF neurons in learning and memory processes is still unclear. We conducted two experiments to investigate the role of the PF in the spontaneous object recognition (SOR) task. The behavioral effects of pretraining rats with bilateral lesions of PF with N-methyl-D-aspartate (NMDA) were compared to vehicle controls. In the first experiment, rats were tested on their ability to remember the association immediately after training trials and in the second experiment after a 24 h delay. Our findings provide evidence that PF lesions critically affect both SOR tests and support its role in that non-spatial form of relational memory.     

Studies on retrograde and anterograde amnesia of olfactory memory after denervation of the hippocampus by entorhinal cortex lesions

The effect of hippocampal denervation on olfactory memory in rats was tested after interrupting the lateral olfactory tract projections at the level of the entorhinal cortex. When lesioned animals were trained to learn new odors, they showed no evidence of retention 3 h after acquisition. These results confirm earlier data on rapid forgetting in rats after hippocampal deafferentation and are in parallel to the anterograde amnesia typically found in humans with hippocampal damage. On the other hand, preoperatively learned information was minimally impaired after hippocampal deafferentation even if it was acquired within less than 1 h before the lesion. This finding differs from reports on humans as well as monkeys with hippocampal damage where memories formed during a critical time span of months or even years before the lesion are found to be impaired. This may suggest that the consolidation process in humans and rodents has different time scales or that the roles of the human and the rat hippocampal structure in memory formation are somewhat different.