Cerebellar nodulectomy impairs spatial memory of vestibular and optokinetic stimulation in rabbits

Natural vestibular and optokinetic stimulation were used to investigate the possible role of the cerebellar nodulus in the regulation and modification of reflexive eye movements in rabbits. The nodulus and folium 9d of the uvula were destroyed by surgical aspiration. Before and after nodulectomy the vertical and horizontal vestibuloocular reflexes (VVOR, HVOR) were measured during sinusoidal vestibular stimulation about the longitudinal (roll) and vertical (yaw) axes. Although the gain of the HVOR (G(HVOR) = peak eye movement velocity/peak head velocity) was not affected by the nodulectomy, the gain of the VVOR (G(VVOR)) was reduced. The gains of the vertical and horizontal optokinetic reflexes (G(VOKR), G(HOKR)) were measured during monocular, sinusoidal optokinetic stimulation (OKS) about the longitudinal and vertical axes. Following nodulectomy, there was no reduction in G(VOKR) or G(HOKR). Long-term binocular OKS was used to generate optokinetic afternystagmus, OKAN II, that lasts for hours. After OKAN II was induced, rabbits were subjected to static pitch and roll, to determine how the plane and velocity of OKAN II is influenced by a changing vestibular environment. During static pitch, OKAN II slow phase remained aligned with earth-horizontal. This was true for normal and nodulectomized rabbits. During static roll, OKAN II remained aligned with earth-horizontal in normal rabbits. During static roll in nodulectomized rabbits, OKAN II slow phase developed a centripetal vertical drift. We examined the suppression and recovery of G(VVOR) following exposure to conflicting vertical OKS for 10-30 min. This vestibular-optokinetic conflict reduced G(VVOR) in both normal and nodulectomized rabbits. The time course of recovery of G(VVOR) after conflicting OKS was the same before and after nodulectomy. In normal rabbits, the head pitch angle, at which peak OKAN II velocity occurred, corresponded to the head pitch angle maintained during long-term OKS. If the head was maintained in a "pitched-up" or "pitched-down" orientation during long-term OKS, the subsequently measured OKAN II peak velocity occurred at the same orientation. This was not true for nodulectomized rabbits, who had OKAN II peak velocities at head pitch angles independent of those maintained during long-term OKS. We conclude that the nodulus participates in the regulation of compensatory reflexive movements. The nodulus also influences "remembered" head position in space derived from previous optokinetic and vestibular stimulation.     

Temporary inactivation of the supramammillary area impairs spatial working memory and spatial reference memory retrieval

The aim of our study was to examine the supramammillary (SuM) area involvement in spatial memory. Sprague-Dawley rats with chronically implanted cannula in the supramammillary area were trained in two spatial memory tasks with different memory demands: reference and working memory. In the spatial reference memory task, the rats received microinjections in the SuM area of tetrodotoxin (TTX) (0.5 ng diluted in 0.5 microL of saline) or saline (0.5 microL). The microinjections were administered 30 min before the spatial training (day 4) (to assess the effect on acquisition) and on the following two days (days 5 and 6) the training was conducted without microinjections (to study the effect on consolidation). On the last training day (day 7), in order to assess the retrieval of spatial information, the rats received the microinjections 30 min before the spatial training. The spatial working memory used was a delayed-matching-to-position (DMTP) task. Spatial training was performed for seven days. During the first three days of the spatial training, the rats achieved a good spatial knowledge and learnt the working memory rule necessary to solve the spatial task. On days 4 and 6, the rats received microinjections to study involvement of the SuM area in working memory. The results showed that temporary inactivation of SuM area impairs both the rat's ability to solve a spatial working memory task with DMTP demands and the recovery of spatial information in a spatial reference memory task. We suggest that SuM area is involved in the rearrangement of spatial information during spatial working memory tasks with DMTP memory demands.     

Cerebellar lesions and prism adaptation in macaque monkeys

If a laterally displacing prism is placed in front of one eye of a person or monkey with the other eye occluded, they initially will point to one side of a target that is located directly in front of them. Normally, people and monkeys adapt easily to the displaced vision and correct their aim after a few trials. If the prism then is removed, there is a postadaptation shift in which the subject misses the target and points in the opposite direction for a few trials. We tested five Macaque monkeys for their ability to adapt to a laterally displacing prism and to show the expected postadaptation shift. When tested as normals, all five animals showed the typical pattern of adaptation and postadaptation shift. Like human subjects, the monkeys also showed complete interocular transfer of the adaptation but no transfer of the adaptation between the two arms. When preoperative training and testing was complete, we made lesions of various target areas on the cerebellar cortex. A cerebellar lesion that included the dorsal paraflocculus and uvula abolished completely the normal prism adaptation for the arm ipsilateral to the lesion in one of the five monkeys. The other four animals retained the ability to prism-adapt normally and showed the expected postadaptation shift. In the one case in which the lesion abolished prism adaptation, the damage included Crus I and II, paramedian lobule and the dorsal paraflocculus of the cerebellar hemispheres as well as lobule IX, of the vermis. Thus in this case, the lesion included virtually all the cerebellar cortex that receives mossy-fiber visual information relayed via the pontine nuclei from the cerebral cortex. The other four animals had damage to lobule V, the classical anterior lobe arm area and/or vermian lobules VI/VII, the oculomotor region. When tested postoperatively, some of these animals showed a degree of ataxia equivalent to that of the case in which prism adaptation was affected, but prism adaptation and the postadaptation shift remained normal. We conclude that in addition to its role in long-term motor learning and reflex adaptation, the region of the cerebellum that was ablated also may be a critical site for a short-term motor memory. Prism adaptation seems to involve a region of the cerebellum that receives a mossy-fiber visual error signal and probably a corollary discharge of the movement.     

Cerebellar damage impairs automaticity of a recently practiced movement

It has been suggested that the cerebellum plays a critical role in learning to make movements more "automatic" (i.e., requiring less attention to the details of a movement). We hypothesized that cerebellar damage compromises learning of movement automaticity, resulting in increased attentional demands for movement control. The purpose of our study was to determine whether cerebellar damage disrupts the ability to make a practiced movement more automatic. We developed a dual task paradigm using two tasks that did not have overlapping sensory or motor requirements for execution. Our motor task required subjects to maintain an upright posture while performing a figure-8 movement using their arm. This motor task was chosen to simulate requirements of everyday movements (e.g., standing while reaching for objects), but it was novel enough to require practice for improvement. Our secondary task was an auditory vigilance task where subjects listened to letter sequences and were asked to identify the number of times a target letter was heard. We tested controls and people with cerebellar damage as they practiced the movement task alone and then performed it with the auditory task. We recorded 3D position data from the arm, trunk, and leg during the movement task. Errors were recorded for both the movement and the letter tasks. Our results show that cerebellar subjects can improve the movement to a very limited extent with practice. Unlike controls, the motor performance of cerebellar subjects deteriorates to prepractice levels when attention is focused away from the movement during dual task trials. Control subjects' insensitivity to dual task interference after practice was due to learned movement automaticity and was not a reflection of better dual task performance generally. Overall, our findings suggest that the cerebellum may be important for shifting movement performance from an attentionally demanding (unpracticed) state to a more automatic (practiced) state.     

Stress impairs consolidation of recognition memory after blocking drug memory reconsolidation

When a consolidated memory is retrieved, it returns to a vulnerable state. To persist it must undergo another process, called memory reconsolidation. It has been demonstrated that disrupting the reconsolidation of a drug-specific memory is a powerful method for intervention in drug addiction. More specifically, previous studies suggested that certain types of stress can successfully disrupt reconsolidation of drug memories. While it is typically used for a single purpose, stress contributes to a myriad of different memory paradigms and processes. These additional effects of stress on unrelated memory processes are often overlooked. In this study, cold water stress was used to assess its effects on drug memory. Rats were trained to acquire methamphetamine (MA) conditioned place preference (CPP) by confining rats to a MA-paired chamber for 10 min. The new object recognition task (NOR) was given before and after stress-interrupting reconsolidation of MA-induced memory. Our data demonstrate that stress impairs the consolidation process of NOR memory when it is used to block drug memory reconsolidation, while stress exhibits no effect on acquiring a new memory, suggesting potential strategies of stress for therapeutic invention in drug addiction.     

Androgen deprivation impairs memory in older men

Androgen deprivation leads to a profound loss of synaptic density in the hippocampus and changes in learning and memory in animal models. The authors examined group differences in verbal memory between men on androgen deprivation therapy (ADT), a commonly used treatment for prostate cancer, and healthy men. The authors found that men on ADT have a specific impairment of retention but normal encoding and retrieval processes on a word list-learning task. Speed and accuracy for both perceptual and semantic encoding, as well as retrieval at a very short retention interval, were not affected; however, recognition fell to chance after a 2-min retention interval in men on ADT. Healthy men showed only moderate forgetting, and performance was still above chance at 12 min. This pattern of preserved encoding and retrieval but impaired retention suggests that androgens play a role in hippocampally mediated memory processes, possibly having a specific affect on consolidation.     

Oxidation of multiple methionine residues impairs rapid sodium channel inactivation

Reactive oxygen species (ROS) readily oxidize the sulfur-containing amino acids cysteine and methionine (Met). The impact of Met oxidation on the fast inactivation of the skeletal muscle sodium channel Na(V)1.4 expressed in mammalian cells was studied by applying the Met-preferring oxidant chloramine-T or by irradiating the ROS-producing dye Lucifer Yellow in the patch pipettes. Both interventions dramatically slowed down inactivation of the sodium channels. Replacement of Met in the Ile-Phe-Met inactivation motif with Leu (M1305L) strongly attenuated the oxidizing effect on inactivation but did not eliminate it completely. Mutagenesis of Met1470 in the putative receptor of the inactivation lid also markedly diminished the oxidation sensitivity of the channel, while that of other conserved Met residues in intracellular linkers connecting the membrane-spanning segments (442, 1139, 1154, 1316, 1469) were of minor importance. The results of mutagenesis, assays of other Na(V) channel isoforms (Na(V)1.2, Na(V)1.5, Na(V)1.7), and the kinetics of the oxidation-induced removal of inactivation collectively indicate that multiple Met residues need to be oxidized to completely impair inactivation. This arrangement using multiple Met residues confers a finely graded oxidative modulation of Na(V) channels and allows organisms to adapt to a variety of oxidative stress conditions, such as ischemic reperfusion.     

Alzheimer-associated mutant ubiquitin impairs spatial reference memory

UBB^+ 1 is a mutant ubiquitin which accumulates in the hallmarks of tauopathies, including Alzheimer's disease. Transgenic mice expressing high levels of neuronal UBB^+ 1 exhibit moderately decreased proteasome activity and spatial reference memory deficits at 9 months of age. In the present study, we characterized the behavioral phenotype of male UBB^+ 1 transgenic mice at different ages. We show that UBB^+ 1 transgenic mice displayed an age-related functional decline similar to wild-type littermates, without gross neurological abnormalities or alterations in procedural motor-learning and motor coordination. At 15 months of age, a transgene-specific spatial learning deficit was dependent on the period of training in the Morris watermaze. This deficit could be eliminated after additional training. We conclude that the previously reported spatial reference memory deficits of UBB^+ 1 transgenic mice persist during aging. In addition, our results demonstrate that the subtle defect in spatial reference memory formation, caused by a decrease in forebrain proteasome activity, is a persistent defect and not a structural defect.     

Cognition and immunity; antibody impairs memory

Patients with lupus (SLE) experience progressive cognitive loss without evidence of CNS vascular disease or inflammation. SLE patients produce anti-DNA antibodies that crossreact with NMDA receptors and are capable of mediating excitotoxic death. We now show that mice induced by antigen to express these antibodies have no neuronal damage until breakdown of the blood-brain barrier occurs. Following administration of lipopolysaccharide (LPS) to immunized mice, antibodies gain access to the brain. They bind preferentially to hippocampal neurons and cause neuronal death with resulting cognitive dysfunction and altered hippocampal metabolism on magnetic resonance spectroscopy. Memantine, an NMDA receptor antagonist, given prior to LPS administration, prevents neuronal damage. Thus, systemic immune responses can cause cognitive impairment in the absence of an inflammatory cascade, implicating the immune system in yet another arena of human pathobiology. Furthermore, NMDA receptor antagonists prevent antibody-mediated damage and may constitute a new approach to therapy in SLE.     

Cerebellar control of constrained and unconstrained movements. I. Nuclear inactivation

The aim of this study was to determine in monkeys if inactivation of dentate and lateral interposed deep cerebellar nuclei preferentially impairs certain movements relative to others. Constrained movements of the digits were trained with digits, hand, and elbow constrained in a cast. Simple movements were flexion of Thumb or Index. A compound movement was simultaneous flexion of Thumb+Index. An unconstrained movement consisted of a reach to, pinch of, and retrieval of a small food reward (Reach+Pinch). In two monkeys we mapped the dentate and interpositus with 66 injections of muscimol (3 microl of 5 microg/microl). Thirty-two percent of the injections resulted in increased reaction times of Thumb, Index, and Thumb+Index (mean = 24, 24, 28 + 26, respectively). Fifty percent of the injections impaired Reach+Pinch, producing target overshoot, curved reach trajectory, missed target (X and Y errors), and clumsy pinch with dropped fruit bits. Inactivation impaired each and all of Thumb, Index, Thumb+Index, and Reach+Pinch in 27%, only Reach+Pinch in 23%, and only Thumb, Index, Thumb+Index in 5% of injections. In sum, all types of movement were impaired. Thumb+Index was no more impaired than Thumb or Index alone, suggesting that the lateral cerebellar nuclei are not specifically required for combining movements of the two digits when constrained. Reach+Pinch appeared so greatly impaired and Thumb, Index, Thumb+Index so little as to be consistent with the hypothesis that a principal role of the cerebellum is to control those interactions that occur between body segments in natural unconstrained movements. However, the fact that all movements were impaired shows that the cerebellum contributes to the control of all movements.     

Cerebellar contributions to sequence prediction in verbal working memory

Brain Structure and Function - Verbal working memory is one of the most studied non-motor functions with robust cerebellar involvement. While the superior cerebellum (lobule VI) has been associated...     

Brain serotonin depletion impairs short-term memory, but not long-term memory in rats

Intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT) (150 microg; 4.5 microl/ventricle), a serotonergic neurotoxin, significantly decreased spontaneous alternation in Y-maze task and working memory in radial 8 arm-maze task, suggesting effects on short-term memory, without affecting long-term memory, explored by reference memory in radial 8 arm-maze task and step-through latency in multi-trial passive avoidance task. Parachlorophenylalanine (PCPA) (3 days treatment 200 microg, i.c.v.), a serotonin synthesis inhibitor, did not impair step-through-latency in multi-trial passive avoidance task, suggesting no effects on long-term memory. These results suggest that serotonin, among other neurotransmitters, play an important role in cognitive functions, especially short-term memory.     

Moderate hypoglycemia impairs multiple memory functions in healthy adults

The effects of acute insulin-induced hypoglycemia on short-term, delayed, and working memory were examined in healthy adults. A hyperinsulinemic glucose clamp was used to maintain arterialized blood glucose at either 4.5 (euglycemia) or 2.5 (hypoglycemia) mmol/L on 2 separate occasions in 16 healthy volunteers. Tests of immediate and delayed verbal memory, immediate and delayed visual memory, and working memory were administered during each experimental condition. All memory systems were impaired during acute hypoglycemia, with working memory and delayed memory being particularly susceptible. These findings are informative concerning the metabolic basis of adequate memory function and are of practical importance to people with insulin-treated diabetes, in whom hypoglycemia is common.     

Fornix transection impairs visuospatial memory acquisition more than retrieval

It has been hypothesized that some fornical fibres may instantiate a neuromodulatory reinforcement signal supporting memory acquisition in medial temporal cortical regions. This suggests that fornix transection should impair postoperative new learning more severely than the recall of preoperatively acquired information. Here, postoperative recall of 288 concurrent visuo-spatial discrimination problems acquired preoperatively was unaffected after fornix transection in the macaque, whereas new postoperative learning of 72 problems was impaired. This and other recent evidence supports the idea that the main function of the fornix in macaque monkeys is to support new learning about spatio-temporal context.     

Scopolamine impairs human recognition memory: data and modeling

Eight subjects studied a set of complex visual images after administration of 0.4 mg scopolamine. Another 8 subjects performed the same task without drug administration. On a subsequent item recognition test, subjects rated, on a 5-point scale, their confidence that the studied pictures and an equal number of unstudied lures were actually presented. Results showed that scopolamine affected responses to studied items, but not unstudied lures, demonstrating an unambiguous effect of scopolamine on recognition memory. To describe the scopolamine-injected subjects' data, the authors constructed a new model of 2-process recognition that includes the A. P. Yonelinas (1994) model as a limiting case. The model analysis suggests that scopolamine affected both familiarity and recollection. In particular, scopolamine did not affect the frequency with which recollection took place, but rather, affected the amount of recollected information.     

Leu-enkephalin impairs memory of an appetitive maze response in mice

Leu-enkephalin (300 micrograms/kg) impaired memory of a Y-maze response in mice when the animals were trained to obtain food in one arm of the maze. The dose-response function was U-shaped, with neither 100 nor 600 micrograms/kg having any effect. Des-Tyr-Leu-enkephalin, a nonopioid peptide, had no effect at doses equimolar to the leu-enkephalin. Finally, the leu-enkephalin (300 micrograms/kg) was without effect if the drug injection was delayed 90 min. The results show that leu-enkephalin affects appetitive conditioning in much the same way as avoidance conditioning, a finding that suggests that leu-enkephalin may generally influence learning and memory.     

Nitrous oxide impairs selective stages of working memory in rats

Working memory impairment under narcosis has never been investigated. Furthermore, mechanisms by which narcosis disturbs working memory processes remain relatively unknown. The present work was aimed at answering to these two questions using a well-known normobaric narcotic gas, nitrous oxide (N2O), and a classical working memory task (a two-trial recognition memory task). Ten Long-Evans rats were tested in this behavioral task under nitrous oxide exposure. The results showed (i) a dose-related impairment of working memory, (ii) a selective effect of N2O on two out of three mnemonic processes: acquisition, and retention, and (iii) a compensatory effect of increasing the acquisition phase duration on these impairments. These results, as previously suggested for long-term memory, agree with the fact that nitrous oxide disrupts in a dose-related manner working memory by notably slowing down acquisition processes.     

皮质酮损害大鼠新颖物体识别记忆的再巩固

BACKGROUND: The formation of long-term memory includes acquisition, consolidation and reconsolidation. Reconsolidation is very important for the new memory transforming into stable memory. Stress is an important environmental factor in the process of learning and memory. Corticosterone is very important for stress response. At present, research about the impact of corticosterone on reconsolidation of novel object recognition memory is less. Thus, it is very important to test the impact of corticosterone on reconsolidation of novel object recognition memory in rats.