Working memory deficits following muscarinic blockade combined with depletion of brain somatostatin in rats

In a working memory task with three-panel runway paradigm, cysteamine, a depletor of somatostatin, at 100 or 200 mg/kg i.p. given 24 h before testing, had no effect on the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points). Cysteamine at 100 mg/kg caused a significant reduction in somatostatin-like immunoreactivity in the rat brain, including the hippocampus and cerebral cortex. Working memory errors were significantly increased by scopolamine, a muscarinic receptor antagonist, at 0.32 mg/kg i.p. given 20 min before testing, whereas errors were not affected by the 0.1 mg/kg dose. Combined administration of 100 mg/kg cysteamine and 0.1 mg/kg scopolamine significantly increased the number of working memory errors. However, cysteamine at 100 mg/kg and scopolamine at 0.1 mg/kg had no effect on reference memory errors, whether they were administered alone or in combination. These results suggest that depletion of brain somatostatin aggravates working memory deficits induced by blockade of muscarinic receptors.     

Long-term effects of cysteamine on cognitive and locomotor behavior in rats: relationship to hippocampal glial pathology and somatostatin levels

Peroxidase-positive astrocytic inclusions, derived from effete, iron-laden mitochondria, accumulate in the rat hippocampus, striatum and other subcortical brain regions as a function of advancing age. The sulfhydryl agent, cysteamine (CSH), accelerates the appearance of this senescent glial phenotype both in primary astrocyte cultures and in the aging subcortical brain in situ. Earlier experiments have shown that short-term administration of CSH results in reversible depletion of brain somatostatin (SS) levels, cognitive deficits and decreases in locomotor activity. In the present study, we tested spatial learning/memory and motor functioning in rats at 4–5 weeks following cessation of chronic (6 week) CSH treatment to determine whether behavioral deficits may be associated with gliopathic changes within the dorsal hippocampus distinct from the behavioral abnormalities accruing to the immediate effects of the drug. CSH-treated rats displayed significantly impaired performance in the Morris water maze 4–5 weeks following termination of prolonged CSH treatment. In contrast, locomotor activity was not affected in this experimental paradigm. CSH-treated animals exhibited significantly higher numbers of peroxidase-positive astrocyte granules as well as total numbers of GFAP-positive astrocytes in the CA1 sector of the dorsal hippocampus relative to saline-treated controls. In the hilus of the dentate gyrus, numbers of both peroxidase-positive glial inclusions and astrocytes were unaffected by CSH exposure. At 5 weeks following cessation of CSH treatment, SS levels in the hippocampus and hypothalamus (but not cerebral cortex) were elevated relative to those of saline-treated controls. Our results indicate that chronic CSH exposure induces senescence-like changes in CA1 astrocytes which are associated with deficits in cognitive, but not locomotor, behavior and elevated levels of hippocampal and hypothalamic SS. Pathological glial-neuronal interactions within the hippocampus and other subcortical brain regions may play an important role in the cognitive decline observed during normal senescence and in aging-related neurodegenerative disorders.     

Cysteamine-induced depletion of central somatostatin-like immunoactivity: effects on behavior, learning, memory and brain neurochemistry

The effects of a wide range of doses of systemically administered cysteamine were studied on locomotor behavior, passive avoidance memory, cortical and cerebrospinal fluid somatostatin-like immunoactivity and cortical levels of dopamine and norepinephrine. High doses of cysteamine (200 and 250 mg/kg s.c.) led to sustained locomotor activation. Doses of 150 mg/kg and above resulted in head and neck tremor and increased defecation. When cysteamine was administered immediately following the acquisition of a passive avoidance response, doses of 50 mg/kg and above resulted in significant attenuation of passive avoidance retention test performance. Cysteamine in doses of 50 mg/kg and above depleted cortical somatostatin-like immunoactivity by approximately 50%. The depletion of cortical somatostatin-like immunoactivity was accompanied by a rapid rise in somatostatin-like immunoactivity in cerebrospinal fluid. In addition to the depletion of somatostatin-like immunoactivity, high doses of cysteamine (150 mg/kg and above) produced changes in cortical levels of norepinephrine and dopamine, reminiscent of dopamine-beta-hydroxylase inhibition. The results of this series of experiments suggest that somatostatin, in addition to its effects on hormonal regulation, may play an important role in behavior and passive avoidance learning and memory. It is possible that the amnesia produced by cysteamine may have been due to the release of somatostatin into CSF from tissue stores, rather than somatostatin depletion per se. It is also possible that the catecholaminergic effects of high doses of cysteamine contribute to the behavioral deficits observed.     

Brain somatostatin depletion by cysteamine attenuates the penile erection induced by serotonergic and dopaminergic, but not by cholinergic, activation in rats

To clarify the role of brain somatostatin in the expression of penile erection, the effects of cysteamine, a somatostatin depletor, on the penile erection induced by serotonergic, cholinergic and dopaminergic stimulants were investigated in rats. Fenfluramine (0.1–10 mg/kg, i.p.), pilocarpine (0.032–3.2 mg/kg, i.p.) and apomorphine (0.01–1 mg/kg, i.p.) induced penile erection in rats, with bell-shaped dose-response curves. Pretreatment with cysteamine (200 mg/kg, s.c.) significantly attenuated the penile erection induced by fenfluramine and apomorphine, but scarcely affected that induced by pilocarpine. Neurochemical measures revealed that cysteamine pretreatment significantly reduced the somatostatin content in all brain regions examined. These results provide the first pharmacological evidence that the brain somatostatin may play an important role in drug-induced penile erection.     

Emergence of VIP rhythmicity following somatostatin depletion in the rat suprachiasmatic nucleus

Administration of a somatostatin (SS) depletor, cysteamine, markedly reduced SS levels in rat suprachiasmatic nucleus (SCN). At the same time, cysteamine administration induced a circadian rhythm of vasoactive intestinal polypeptide (VIP) content in the SCN, which otherwise remains constant under constant environmental conditions. These results suggest that the stable level of VIP in the SCN under constant conditions is not an intrinsic property of VIP neurons but a consequence of interactions with other components in the SCN.     

侧脑室注射Noggin对AD小鼠海马神经发生和学习记忆功能的影响

目的观察侧脑室给予Noggin对AD小鼠海马神经发生和学习记忆功能的影响。方法选取12月龄APP/PS1双转基因AD小鼠,实验组连续7d侧脑室注射Noggin,对照组向侧脑室注射等量生理盐水,Morris水迷宫检测其认知功能,免疫荧光检测海马齿回BrdU的表达。结果和生理盐水对照组相比,侧脑室注射Noggin组小鼠海马齿回BrdU阳性细胞数显著增加(P0.01),行为学检测显示逃逸潜伏期缩短、穿过原平台位置次数和在原平台象限探索时间百分率增加(P0.05)。结论侧脑室注射Noggin可促进AD小鼠海马神经发生并改善其学习记忆能力。     

Cysteamine effects on somatostatin, catecholamines, pineal NAT and melatonin in rats

The thiol reagent cysteamine was administered to adult male rats with the aim of investigating its effect on different neural and pineal components. As expected, immunoreactive somatostatin decreased in the median eminence (ME) (p less than 0.05) and gastric antrum (p less than 0.05) after cysteamine; however, no significant change was observed in the pineal IRS content after drug treatment. A decrease in norepinephrine was observed in the ME (p less than 0.001), hypothalamus (p less than 0.001) and pineal gland (p less than 0.05), together with a rise in ME (p less than 0.005) and hypothalamic dopamine (p less than 0.005) content; these results are consistent with a dopamine-beta-hydroxylase inhibiting effect of cysteamine. No effect was observed on hypothalamic serotonin and 5-hydroxyindole-acetic acid content. Pineal N-acetyltransferase (NAT) activity was significantly higher (p less than 0.05) after cysteamine than after saline, but no statistically significant effect was observed on pineal melatonin content. The mechanism involved in the NAT rise is presumably not related to the known stimulatory effect of norepinephrine, which fell after cysteamine. It is suggested that cysteamine may act at an intracellular level, inhibiting NAT degradation, an effect demonstrated in vitro and thought to be related to a thiol:disulfide exchange mechanism.     

Overexpression of wild-type human APP in mice causes cognitive deficits and pathological features unrelated to Aβ levels

Transgenic mice expressing mutant human amyloid precursor protein (APP) develop an age-dependent amyloid pathology and memory deficits, but no overt neuronal loss. Here, in mice overexpressing wild-type human APP (hAPP_wt) we found an early memory impairment, particularly in the water maze and to a lesser extent in the object recognition task, but β-amyloid peptide (Aβ₄₂) was barely detectable in the hippocampus. In these mice, hAPP processing was basically non-amyloidogenic, with high levels of APP carboxy-terminal fragments, C83 and APP intracellular domain. A tau pathology with an early increase in the levels of phosphorylated tau in the hippocampus, a likely consequence of enhanced ERK1/2 activation, was also observed. Furthermore, these mice presented a loss of synapse-associated proteins: PSD95, AMPA and NMDA receptor subunits and phosphorylated CaMKII. Importantly, signs of neurodegeneration were found in the hippocampal CA1 subfield and in the entorhinal cortex that were associated to a marked loss of MAP2 immunoreactivity. Conversely, in mice expressing mutant hAPP, high levels of Aβ₄₂ were found in the hippocampus, but no signs of neurodegeneration were apparent. The results support the notion of Aβ-independent pathogenic pathways in Alzheimer's disease.     

Learning deficits in aged rats pretreated chronically with barbital and tested late in abstinence: alleviation by tetrahydroaminoacridine

Summary Physostigmine and tetrahydroaminoacridine (THA) have been reported to improve cognitive function in patients with Alzheimer's disease. Two experiments were conducted to examine the effects of these anticholinesterase agents on learning in aged rats pretreated chronically with barbital. In the first experiment animals received barbital in their drinking water for 46 weeks. Controls were given only water. On days 100–104 of abstinence, when the animals were 20 months old, acquisition of the Morris maze task was initiated after treatment with physostigmine. It was found that physostigmine improved learning of the maze task in control but not barbital treated rats. In the second experiment animals received barbital solution or water as in experiment one. On days 100–103 of abstinence they were injected with THA before being tested in the Morris water maze. It was found that THA improved learning in both barbital treated and control rats. These results corroborate clinical findings of improved cognitive function following treatment with THA, and suggest that the therapeutic effects of THA may be mediated by mechanisms distinct from cholinesterase inhibition. Furthermore chronic barbital treatment could be used as a model to study cognitive disturbances in experimental animals.     

L—NA对大鼠学习记忆的影响及NO、SS相关性研究

目的 探讨一氧化氮（NO）和生长抑素（SS）在学习记忆过程中的作用及相互作用。方法 大鼠海马微量注射一氧化氮合酶（NOS）抑制剂N-ω硝基－L精氨酸（N-ω－Nitro-L-Arginine,L-NA) 后采用Y型电迷宫观察大鼠学习记忆能力的改变,以硝酸还原酶法测定海马NO含量,以放射免疫法测定海马SS含量,并进行学习记忆能力、NO含量和SS含量相关性分析。结果 海马微量注射L－NA组大鼠与生理盐水对照组和正常对照组比较,海马中NO、SS含量明显下降（P＜0．01）。Y型电迷宫测定次数明显增加（P＜0．01）,L－NA组大鼠海马NO水平和SS水平呈显著正相关,NO、SS水平均与Y型电迷宫测试次数呈显著负相关。结论 海马中NO、SS水平的正常是机体实现正常学习和记忆过程的重要因素;NO可能通过调节SS的合成和释放,共同促进学习和记忆过程。     

Inefficient response inhibition in individuals with mild cognitive impairment

Individuals diagnosed with mild cognitive impairment (MCI) show primary deficits in memory and are at increased risk for developing Alzheimer's disease (AD). In light of recent evidence that executive cognitive deficits are common in AD and may be detectable in individuals diagnosed with MCI, we extend these findings to the investigation of response inhibition, an essential aspect of executive cognitive control. Twenty MCI patients and 20 healthy controls (HC) completed an arrow version of the flanker task [Eriksen, B. A., & Eriksen, C. W. (1974). Effects of noise letters upon the identification of target letters in a non-search task. Perception & Psychophysics, 16, 143-149] in which participants responded to a target arrow surrounded by distractors (i.e., flankers) that signaled a same (congruent) or a conflicting (incongruent) response. Reaction time (RT) increased in both groups when flankers signaled an incongruent response, but more so among MCI patients. MCI patients taking a cholinesterase inhibitor showed smaller flanker interference effects than those not taking this medication. Analysis of the flanker effect as a function of the entire RT distribution indicated that MCI patients show increasing interference at the slowest segments of the distribution, a finding that implicates deficient inhibition of the incongruent response [Ridderinkhof, K. R. (2002). Activation and suppression in conflict tasks: Empirical clarification through distributional analyses. In W. Prinz & B. Hommel (Eds.), Common mechanisms in perception and action. Attention & performance, Vol. XIX (pp. 494-519). Oxford: Oxford University Press]. These results suggest that deficits in response inhibition are detectable in MCI patients and merit further investigation as to whether these changes aid prediction of which MCI patients convert to AD.     

Increased cognitive sensitivity to scopolamine with age and a perspective on the scopolamine model

18 older normal volunteers (mean age = 66.5 ± 7.9 years) and 46 younger volunteers (mean age = 27.0 ± 6.1 years) were administered the anticholinergic drug scopolamine (0.5 mg i.v.) followed by a battery of cognitive tests evaluating attention, learning and memory. The older subjects were significantly more impaired than the younger by scopolamine on some tests of learning and memory. This increased sensitivity of the older group to scopolamine is consistent with studies in animals and humans showing decreased cholinergic system function with age. The findings also indicate that age is an important variable to consider in using the scopolamine model of memory impairment. The cognitive impairment caused by scopolamine in younger subjects in this and prior studies is similar to some, but not all aspects of the impairment which occurs in normal aging^11,29,37. Scopolamine also caused impairments on digit span and word fluency tasks, which are not consistent with normal aging changes. In the older group of subjects, scopolamine produced aspects of the cognitive impairment which occurs in AD on tests of episodic memory and learning, vigilance-attention, category retrieval, digit span, and number of intrusions^64,86,88,91. Other areas of cognition that are of relevence to aging and AD such as psychomotor speed, praxis, concept formation and remote memory were not evaluated in this study. Some of these are being evaluated in ongoing studies, along with additional and more specific tests of retrieval from knowledge memory, implicit memory and attention. The scopolamine model has provided a fruitful pharmacologie starting point for the study of a number of cognitive operations. The idea of dissecting apart aspects of memory systems pharmacologically depends on the availability of neurochemically specific drugs and on the specificity and sensitivity of neuropsychological tests for distinct cognitive operations or domains. Further studies using such tools will aid not only in the understanding of the impairments which occur in aging and in AD, but also of the conceptualization of memory and other cognitive operations and ultimately the physiological mechanisms involved in memory and learning.     

Forebrain serotonin depletion facilitates the acquisition and performance of a conditional visual discrimination task in rats

Three experiments examined the effects of depleting forebrain 5-hydroxytryptamine (5-HT) on the acquisition and performance of an operant conditional discrimination in the visual modality. In the first experiment, rats with 5-HT lesions induced by infusing the neurotoxin 5,7-dihydroxytryptamine intracerebroventricularly acquired the conditional visual discrimination more rapidly than the sham-operated controls. Following acquisition, a series of manipulations of the task parameters tested the effects of the lesion on cognitive, sensory and motivational aspects of performance. In experiment two, the performance of rats that had acquired the task to asymptote before receiving lesions was assessed. The performance of this second group of serotonin-lesioned rats was similar to that of the pre-acquisition lesioned group following all but one manipulation of the task parameters. When the rate of stimulus presentations was increased, rats with forebrain 5-HT depletions were protected from the disruptive effects on performance seen in the sham-operated controls. This latter finding was also observed in a third experiment, in which the infusion of the 5-HT1A receptor partial agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT), directly into the dorsal raphé nucleus improved the performance of unlesioned rats following an increase in the rate of stimulus presentations. The results are discussed in terms of the behavioural, neurochemical and neuroanatomical specificity of serotonin function in appetitive learning and the implications for general theories of the function of serotoninergic processes in cognition.     

Human cerebrospinal fluid somatostatin in neurologic disease

Concentrations of somatostatin-like immunoreactivity (SLI) were examined in human cerebrospinal fluid (CSF). To validate the assay it was shown that CSF which had been run over a somatostatin immunoaffinity column showed no interference with binding of synthetic standards. Reversed phase HPLC showed that the immunoreactive material coeluted with SS14 and SS28 as well as a higher molecular weight precursor. Concentrations of human CSF SLI were stable at both room temperature and 4 degrees C for up to 72 h while repeated freezing and thawing resulted in a significant loss of immunoreactive material after the 3rd repetition. In normal control patients less than 55 years of age, CSF SLI was 54.7 +/- 1.9 pg/ml, while in those older than 55 CSF SLI was 56.2 +/- 2.2 pg/ml. Febrile infants had significantly higher levels (75.4 +/- 7.3) pg/ml. CSF SLI was normal in patients with aseptic meningitis (54.4 +/- 3.4 pg/ml), suggesting that increased CSF protein and white cell counts do not affect concentrations. Concentrations of CSF SLI were significantly increased in intervertebral disc disease (65.1 +/- 5.6 pg/ml), intrinsic spinal cord pathology (101.0 +/- 23.9 pg/ml), central nervous system tumors (78.0 +/- 7.8 pg/ml) and acute cortical damage of varied etiology (277.8 +/- 81.6 pg/ml). Patients with pseudotumor cerebri had concentrations of 43.2 +/- 2.5 pg/ml. Concentrations of CSF SLI were significantly reduced (P less than 0.01) in multiple sclerosis (38.8 +/- 5.5 pg/ml) and old cortical pathology (23.2 +/- 3.9 pg/ml). Serial CSF analysis in patients with acute CNS lesions, suggest that CSF SLI may be a neurochemical marker of acute pathology, as the initially elevated levels fell to or below normal with resolution of the pathologic process.     

Anosognosia in Alzheimer's disease: association with patient characteristics, psychiatric symptoms and cognitive deficits

Anosognosia is one of the major problems in the treatment and care of Alzheimer's disease (AD) patients. The aim of the study was to determine the patient characteristics, psychiatric symptoms, and cognitive deficits associated with anosognosia, because these are currently poorly understood. Eighty-four patients who met the National Institute of Neurological and Communicative Disease and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable AD were examined for anosognosia based on the difference between questionnaire scores of the patient and their caregiver. The relationship of anosognosia with patient characteristics (age, age at onset, duration of illness, education, Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), Hyogo Activities of Daily Living Scale (HADLS)), psychiatric symptoms (Neuropsychiatric Inventory (NPI), Geriatric Depression Scale (GDS)), and cognitive function (Digit Span, Word Fluency Test, Trail Making Test, Stroop Test, Raven's Coloured Progressive Matrices Test) were studied. Anosognosia showed positive correlations with age, age at onset, duration of illness, CDR, HADLS, and NPI disinhibition, and negative correlations with MMSE and GDS. Regarding cognitive function, only Part III of the Stroop Test was a predictor of anosognosia. The severity of anosognosia increased with disease progression and with a later age at onset. Subjective complaints of depression requiring self-monitoring of mood tended to decrease and, in contrast, inhibition of socially unsuitable behavior became more difficult as anosognosia worsened. Regarding cognitive function, anosognosia appeared to be associated with response inhibition impairment. Both disinhibition, as a psychiatric symptom, and response inhibition impairment are known to be correlated with disturbance of orbitofrontal function, which therefore may be associated with anosognosia.     

Sensorimotor and cognitive deficits after transient middle cerebral artery occlusion in the mouse

Whereas behavioral impairments after stroke are increasingly studied in the rat, little is known about the long-term functional consequences of focal ischemia in the mouse. To address this issue, Swiss mice underwent transient (60 min) intraluminal occlusion of the middle cerebral artery (MCAo) or sham surgery. Sensorimotor (chimney, accelerating rotarod, pole, corner, adhesive removal and staircase tests) and cognitive (passive avoidance and Morris water maze) performances were regularly assessed during 1 month, after which the final histological lesion was measured. Motor coordination and balance, assessed by the chimney and rotarod tests, were transiently altered by MCAo. Moreover, bradykinesia was evidenced by the pole test. The most striking and long-lasting (1 month) sensorimotor deficits were postural asymmetries on the corner test, bilateral skilled forepaw reaching deficits on the staircase test and a contralateral sensorimotor impairment on the adhesive removal test. MCAo animals showed normal spatial learning abilities on the Morris water maze test, but they displayed learning deficits measured by the passive avoidance test. This latter deficit was significantly correlated with both cortical and striatal damage. Our findings demonstrate the usefulness of three tests that had never been reported in the mouse after ischemia: the adhesive removal, staircase and pole tests, which showed deficits 1 month after ischemia and should therefore constitute meaningful tools in mice for assessing both neuroprotective and regenerative therapies in stroke preclinical studies.     

Recollection and familiarity in amnestic mild cognitive impairment: a global decline in recognition memory

Despite memory failures being a central feature of amnestic mild cognitive impairment (a-MCI), there is limited research into the nature of the memory impairment associated with this condition. A further understanding could lead to refinement of criteria needed to qualify for this designation and aid in prediction of who will progress to development of clinical Alzheimer's disease. Dual process models posit that recognition memory is supported by the dissociable processes of recollection and familiarity. The present study sought to evaluate recognition memory in a-MCI in the framework of the dual process model. Patients with a-MCI and age- and education-matched controls were tested on three memory paradigms. Two paradigms were modifications of the process-dissociation procedure in which recollection required either memory of word-pair associations (associative) or the font color of words at study (featural). A final paradigm utilized the task-dissociation methodology comparing performance for item and visual spatial source memory. All three tasks revealed that familiarity was impaired to at least the same extent as recollection. As familiarity is thought to be spared in normal aging, its measurement may provide a relatively specific marker for the early pathological changes of Alzheimer's disease.     

Early life exposure to extended general anesthesia with isoflurane and nitrous oxide reduces responsivity on a cognitive test battery in the nonhuman primate

Despite the widespread use of general anesthesia, a growing body of research suggests that anesthesia exposure early in life may be associated with acute neurotoxicity and lasting behavioral changes. To better evaluate the risk posed by early life anesthesia on cognitive development, infant rhesus monkeys were exposed to an anesthesia regimen previously shown to be neurotoxic and their cognitive development was subsequently measured using a translational operant test battery. On postnatal day 5 or 6, animals were exposed to 8 h of isoflurane (n = 6, 1% isoflurane in a vehicle gas of 70% nitrous oxide and 30% oxygen) or a control condition (n = 8). Starting at 7 months of age, the monkeys were continuously trained and assessed on the NCTR Operant Test Battery (OTB). The OTB consists of cognitive tests which also exist in near identical forms for use in rats and humans, and includes tests of learning, memory, color discrimination, and motivation. Monkeys previously exposed to anesthesia showed a clear decrease in responding in a measure of motivation, as well as a lower response rate in a learning task. These data further support the hypothesis that prolonged anesthesia early in life may increase the risk of developing cognitive impairments later in life.     

Caffeine and adenosine A(2a) receptor antagonists prevent beta-amyloid (25-35)-induced cognitive deficits in mice

Consumption of caffeine, an adenosine receptor antagonist, was found to be inversely associated with the incidence of Alzheimer's disease. Moreover, caffeine protects cultured neurons against beta-amyloid-induced toxicity, an effect mimicked by adenosine A(2A) but not A(1) receptor antagonists. We now tested if caffeine administration would prevent beta-amyloid-induced cognitive impairment in mice and if this was mimicked by A(2A) receptor blockade. One week after icv administration of the 25-35 fragment of beta-amyloid (Abeta, 3 nmol), mice displayed impaired performance in both inhibitory avoidance and spontaneous alternation tests. Prolonged treatment with caffeine (1 mg/ml) had no effect alone but prevented the Abeta-induced cognitive impairment in both tasks when associated with acute caffeine (30 mg/kg) 30 min treatment before Abeta administration. The same protective effect was observed after subchronic (4 days) treatment with daily injections of either caffeine (30 mg/kg) or the selective adenosine A(2A) receptor antagonist SCH58261 (0.5 mg/kg). This provides the first direct in vivo evidence that caffeine and A(2A) receptor antagonists afford a protection against Abeta-induced amnesia, which prompts their interest for managing Alzheimer's disease.