Rapamycin Reverses Status Epilepticus-Induced Memory Deficits and Dendritic Damage

Cognitive impairments are prominent sequelae of prolonged continuous seizures (status epilepticus; SE) in humans and animal models. While often associated with dendritic injury, the underlying mechanisms remain elusive. The mammalian target of rapamycin complex 1 (mTORC1) pathway is hyperactivated following SE. This pathway modulates learning and memory and is associated with regulation of neuronal, dendritic, and glial properties. Thus, in the present study we tested the hypothesis that SE-induced mTORC1 hyperactivation is a candidate mechanism underlying cognitive deficits and dendritic pathology seen following SE. We examined the effects of rapamycin, an mTORC1 inhibitor, on the early hippocampal-dependent spatial learning and memory deficits associated with an episode of pilocarpine-induced SE. Rapamycin-treated SE rats performed significantly better than the vehicle-treated rats in two spatial memory tasks, the Morris water maze and the novel object recognition test. At the molecular level, we found that the SE-induced increase in mTORC1 signaling was localized in neurons and microglia. Rapamycin decreased the SE-induced mTOR activation and attenuated microgliosis which was mostly localized within the CA1 area. These findings paralleled a reversal of the SE-induced decreases in dendritic Map2 and ion channels levels as well as improved dendritic branching and spine density in area CA1 following rapamycin treatment. Taken together, these findings suggest that mTORC1 hyperactivity contributes to early hippocampal-dependent spatial learning and memory deficits and dendritic dysregulation associated with SE.     

大鼠眶额叶皮质受损破坏新异性探索行为

利用旷场测试和Y-迷宫测试两种行为模型检测了双侧眶额叶（orbitofrontal cortex, OFC）电损伤或假损伤雄性SD大鼠的新异性探索行为, 探讨了OFC在大鼠探索新异环境中的作用。旷场测试的结果发现,OFC损伤大鼠的行走距离和直立次数较假损组有明显降低;同时,在Y-迷宫测试中与假损伤组大鼠相比,OFC损伤大鼠在新异臂的访问时间和穿梭次数明显降低。提示眶额叶皮质在大鼠新异性探索行为中起着重要作用。     

Object/Context Specific Memory Deficits following Medial Frontal Cortex Damage in Mice

Recent evidence suggests that the medial prefrontal cortex (MFC) is important for processing contextual information. Here we evaluate the performance of mice with MFC damage in a discrimination task that requires an association between an object and the context in which it was experienced (the object/context mismatch task), as well as a version of the novel object preference task that does not require knowledge of contextual information to resolve. Adult C57/BL6 mice received aspiration lesions of the MFC or control surgery. Upon recovery, mice were tested in the object/context mismatch and novel object preference tasks. The object/context mismatch task involved exposing mice to two different contexts, each of which housed a unique pair of identical objects. After a brief delay, mice were re-exposed to one of the contexts, this time with one object that was congruent with that context and one that was not. Novel object preference was performed within a single context, housing an identical pair of objects. After the initial exposure and following a brief delay, mice were re-exposed to the context, this time housing a familiar and a novel object. Control mice were able to successfully resolve the object/context mismatch and novel object preference discriminations, investigating the incongruent/novel object within each task significantly greater than chance. Mice with MFC damage experienced deficits in the object/context mismatch task but not the novel object preference task. These findings add to a growing body of evidence that demonstrate a critical role for the MFC in contextual information processing.     

Involvement of Nitric Oxide in Spatial Memory Deficits in Status Epilepticus Rats

Status epilepticus (SE) is associated with a significant risk of cognitive impairment, and the increase of nitric oxide (NO) releasing has been reported during SE. We investigated the effects of neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7-NI) and inducible nitric oxide synthase (iNOS) inhibitor, aminoguanidine (AG), on spatial performance of rats in the Morris water maze. Treatment with 7-NI, but not with AG, improved the performance of rats after SE not only in acquisition of the task but also in probe test. Furthermore, the level of SE-induced malondialdehyde (MDA), end product of lipid peroxidation, was significantly decreased only in animals receiving 7-NI injection. Taken together, the results of the present study provided evidence that the NO pathway contributed to oxidative stress after SE, and nNOS/NO pathway may underlie one of the potential mechanisms contributing to SE-induced spatial memory deficits.     

Antiamnesic and Antioxidants Effects of Ferulago angulata Essential Oil Against Scopolamine-Induced Memory Impairment in Laboratory Rats

Neurochemical Research - Ferulago angulata (Apiaceae) is a shrub indigenous to western Iran, Turkey and Iraq. In traditional medicine, F. angulata is recommended for treating digestive pains,...     

WY14643 Attenuates the Scopolamine-Induced Memory Impairments in Mice

WY14643 is a selective agonist of peroxisome proliferator-activated receptor-α (PPAR-α) with neuroprotective and neurotrophic effects. The aim of this study was to evaluate the effects of WY14643 on cognitive impairments induced by scopolamine, a muscarinic acetylcholine receptor antagonist. We conducted different behavior tests including the Y-maze, Morris water maze, and passive avoidance test to measure the cognitive functions of C57BL/6J mice after scopolamine and WY14643 treatment. It was found that WY14643 injection significantly attenuated the scopolamine-induced cognitive impairments in these behavioral tests. Moreover, WY14643 treatment significantly enhanced the expression of brain-derived neurotrophic factor (BDNF) signaling cascade in the hippocampus. The usage of both PPAR-α inhibitor GW6471 and BDNF system inhibitor K252a fully prevented the memory-enhancing effects of WY14643. Therefore, these findings suggest that WY14643 could improve the scopolamine-induced memory impairments, and these effects are mediated by the activation of PPAR-α and BDNF system, thereby exhibiting a cognition-enhancing potential.     

l-Deprenyl Prevents Lipid Peroxidation and Memory Deficits Produced by Cerebral Ischemia in Rats

1. The present work shows the results on behavior and on biochemical parameters of l-deprenyl (0.1, 5, and 10 mg/kg, p.o.) administered daily for 5 days to rats submitted to global cerebral ischemia. 2. The transient global ischemia was carried out by clamping the animals bilateral common carotid arteries for 20 min. The parameters studied were memory acquisition and memory retention, locomotor activity and thiobarbituric acid reactive substances, as an index of lipid peroxidation. 3. l-Deprenyl treatment significantly improved memory deficits as compared to the ischemic group as measured by the elevated T maze test. A similar result was observed on the passive avoidance test where l-deprenyl improved late but not early memory as compared to the ischemic group. Except for an increased locomotor activity observed in the group treated with 5 mg/kg, no other alteration was detected in this behavioral test. Rats submitted to transient global ischemia (and without l-deprenyl) showed an increase in MDA levels in the hippocampus and the treatment with l-deprenyl (5 or 10 mg/kg) significantly reversed this effect bringing values close to those of the sham-operated controls. A similar profile was observed with nitrite levels. 4. In conclusion, the work showed a significant protective effect of l-deprenyl on memory deficits and lipid hyperperoxidation observed after cerebral ischemia. Possibly, the drug is acting at least in part through its antioxidant activity.     

Physiological Slowing and Upregulation of Inhibition in Cortex Are Correlated with Behavioral Deficits in Protein Malnourished Rats

Protein malnutrition during early development has been correlated with cognitive and learning disabilities in children, but the neuronal deficits caused by long-term protein deficiency are not well understood. We exposed rats from gestation up to adulthood to a protein-deficient (PD) diet, to emulate chronic protein malnutrition in humans. The offspring exhibited significantly impaired performance on the ‘Gap-crossing’ (GC) task after reaching maturity, a behavior that has been shown to depend on normal functioning of the somatosensory cortex. The physiological state of the somatosensory cortex was examined to determine neuronal correlates of the deficits in behavior. Extracellular multi-unit recording from layer 4 (L4) neurons that receive direct thalamocortical inputs and layers 2/3 (L2/3) neurons that are dominated by intracortical connections in the whisker-barrel cortex of PD rats exhibited significantly low spontaneous activity and depressed responses to whisker stimulation. L4 neurons were more severely affected than L2/3 neurons. The response onset was significantly delayed in L4 cells. The peak response latency of L4 and L2/3 neurons was delayed significantly. In L2/3 and L4 of the barrel cortex there was a substantial increase in GAD65 (112% over controls) and much smaller increase in NMDAR1 (12-20%), suggesting enhanced inhibition in the PD cortex. These results show that chronic protein deficiency negatively affects both thalamo-cortical and cortico-cortical transmission during somatosensory information processing. The findings support the interpretation that sustained protein deficiency interferes with features of cortical sensory processing that are likely to underlie the cognitive impairments reported in humans who have suffered from prolonged protein deficiency.     

N-methyl-d-aspartate Receptors in the Prelimbic Cortex are Critical for the Maintenance of Neuropathic Pain

Neurochemical Research - The mechanisms underlying chronic and neuropathic pain pathology involve peripheral and central sensitisation. The medial prefrontal cortex (mPFC) seems to participate in...     

The Flavonoid Quercetin Reverses Pulmonary Hypertension in Rats

Quercetin is a dietary flavonoid which exerts vasodilator, antiplatelet and antiproliferative effects and reduces blood pressure, oxidative status and end-organ damage in humans and animal models of systemic hypertension. We hypothesized that oral quercetin treatment might be protective in a rat model of pulmonary arterial hypertension. Three weeks after injection of monocrotaline, quercetin (10 mg/kg/d per os) or vehicle was administered for 10 days to adult Wistar rats. Quercetin significantly reduced mortality. In surviving animals, quercetin decreased pulmonary arterial pressure, right ventricular hypertrophy and muscularization of small pulmonary arteries. Classic biomarkers of pulmonary arterial hypertension such as the downregulated expression of lung BMPR2, Kv1.5, Kv2.1, upregulated survivin, endothelial dysfunction and hyperresponsiveness to 5-HT were unaffected by quercetin. Quercetin significantly restored the decrease in Kv currents, the upregulation of 5-HT_2A receptors and reduced the Akt and S6 phosphorylation. In vitro, quercetin induced pulmonary artery vasodilator effects, inhibited pulmonary artery smooth muscle cell proliferation and induced apoptosis. In conclusion, quercetin is partially protective in this rat model of PAH. It delayed mortality by lowering PAP, RVH and vascular remodeling. Quercetin exerted effective vasodilator effects in isolated PA, inhibited cell proliferation and induced apoptosis in PASMCs. These effects were associated with decreased 5-HT_2A receptor expression and Akt and S6 phosphorylation and partially restored Kv currents. Therefore, quercetin could be useful in the treatment of PAH.     

Memory Consolidation in the Cerebellar Cortex

Several forms of learning, including classical conditioning of the eyeblink, depend upon the cerebellum. In examining mechanisms of eyeblink conditioning in rabbits, reversible inactivations of the control circuitry have begun to dissociate aspects of cerebellar cortical and nuclear function in memory consolidation. It was previously shown that post-training cerebellar cortical, but not nuclear, inactivations with the GABA_A agonist muscimol prevented consolidation but these findings left open the question as to how final memory storage was partitioned across cortical and nuclear levels. Memory consolidation might be essentially cortical and directly disturbed by actions of the muscimol, or it might be nuclear, and sensitive to the raised excitability of the nuclear neurons following the loss of cortical inhibition. To resolve this question, we simultaneously inactivated cerebellar cortical lobule HVI and the anterior interpositus nucleus of rabbits during the post-training period, so protecting the nuclei from disinhibitory effects of cortical inactivation. Consolidation was impaired by these simultaneous inactivations. Because direct application of muscimol to the nuclei alone has no impact upon consolidation, we can conclude that post-training, consolidation processes and memory storage for eyeblink conditioning have critical cerebellar cortical components. The findings are consistent with a recent model that suggests the distribution of learning-related plasticity across cortical and nuclear levels is task-dependent. There can be transfer to nuclear or brainstem levels for control of high-frequency responses but learning with lower frequency response components, such as in eyeblink conditioning, remains mainly dependent upon cortical memory storage.     

Amantadine Ameliorates Dopamine-Releasing Deficits and Behavioral Deficits in Rats after Fluid Percussion Injury

Aims

To investigate the role of dopamine in cognitive and motor learning skill deficits after a traumatic brain injury (TBI), we investigated dopamine release and behavioral changes at a series of time points after fluid percussion injury, and explored the potential of amantadine hydrochloride as a chronic treatment to provide behavioral recovery.

Materials and Methods

In this study, we sequentially investigated dopamine release at the striatum and behavioral changes at 1, 2, 4, 6, and 8 weeks after fluid percussion injury. Rats subjected to 6-Pa cerebral cortical fluid percussion injury were treated by using subcutaneous infusion pumps filled with either saline (sham group) or amantadine hydrochloride, with a releasing rate of 3.6mg/kg/hour for 8 weeks. The dopamine-releasing conditions and metabolism were analyzed sequentially by fast scan cyclic voltammetry (FSCV) and high-pressure liquid chromatography (HPLC). Novel object recognition (NOR) and fixed-speed rotarod (FSRR) behavioral tests were used to determine treatment effects on cognitive and motor deficits after injury.

Results

Sequential dopamine-release deficits were revealed in 6-Pa-fluid-percussion cerebral cortical injured animals. The reuptake rate (tau value) of dopamine in injured animals was prolonged, but the tau value became close to the value for the control group after amantadine therapy. Cognitive and motor learning impairments were shown evidenced by the NOR and FSRR behavioral tests after injury. Chronic amantadine therapy reversed dopamine-release deficits, and behavioral impairment after fluid percussion injuries were ameliorated in the rats treated by using amantadine-pumping infusion.

Conclusion

Chronic treatment with amantadine hydrochloride can ameliorate dopamine-release deficits as well as cognitive and motor deficits caused by cerebral fluid-percussion injury.     

Neuropeptide S Facilitates Mice Olfactory Function through Activation of Cognate Receptor-Expressing Neurons in the Olfactory Cortex

Neuropeptide S (NPS) is a newly identified neuromodulator located in the brainstem and regulates various biological functions by selectively activating the NPS receptors (NPSR). High level expression of NPSR mRNA in the olfactory cortex suggests that NPS-NPSR system might be involved in the regulation of olfactory function. The present study was undertaken to investigate the effects of intracerebroventricular (i.c.v.) injection of NPS or co-injection of NPSR antagonist on the olfactory behaviors, food intake, and c-Fos expression in olfactory cortex in mice. In addition, dual-immunofluorescence was employed to identify NPS-induced Fos immunereactive (-ir) neurons that also bear NPSR. NPS (0.1–1 nmol) i.c.v. injection significantly reduced the latency to find the buried food, and increased olfactory differentiation of different odors and the total sniffing time spent in olfactory habituation/dishabituation tasks. NPS facilitated olfactory ability most at the dose of 0.5 nmol, which could be blocked by co-injection of 40 nmol NPSR antagonist [D-Val⁵]NPS. NPS administration dose-dependently inhibited food intake in fasted mice. Ex-vivo c-Fos and NPSR immunohistochemistry in the olfactory cortex revealed that, as compared with vehicle-treated mice, NPS markedly enhanced c-Fos expression in the anterior olfactory nucleus (AON), piriform cortex (Pir), ventral tenia tecta (VTT), the anterior cortical amygdaloid nucleus (ACo) and lateral entorhinal cortex (LEnt). The percentage of Fos-ir neurons that also express NPSR were 88.5% and 98.1% in the AON and Pir, respectively. The present findings demonstrated that NPS, via selective activation of the neurons bearing NPSR in the olfactory cortex, facilitates olfactory function in mice.     

Rasagiline Ameliorates Olfactory Deficits in an Alpha-Synuclein Mouse Model of Parkinson's Disease

Impaired olfaction is an early pre-motor symptom of Parkinson''s disease. The neuropathology underlying olfactory dysfunction in Parkinson''s disease is unknown, however α-synuclein accumulation/aggregation and altered neurogenesis might play a role. We characterized olfactory deficits in a transgenic mouse model of Parkinson''s disease expressing human wild-type α-synuclein under the control of the mouse α-synuclein promoter. Preliminary clinical observations suggest that rasagiline, a monoamine oxidase-B inhibitor, improves olfaction in Parkinson''s disease. We therefore examined whether rasagiline ameliorates olfactory deficits in this Parkinson''s disease model and investigated the role of olfactory bulb neurogenesis. α-Synuclein mice were progressively impaired in their ability to detect odors, to discriminate between odors, and exhibited alterations in short-term olfactory memory. Rasagiline treatment rescued odor detection and odor discrimination abilities. However, rasagiline did not affect short-term olfactory memory. Finally, olfactory changes were not coupled to alterations in olfactory bulb neurogenesis. We conclude that rasagiline reverses select olfactory deficits in a transgenic mouse model of Parkinson''s disease. The findings correlate with preliminary clinical observations suggesting that rasagiline ameliorates olfactory deficits in Parkinson''s disease.     

Olfactory Deficits in Niemann-Pick Type C1 (NPC1) Disease

Background

Niemann-Pick type C disease (NPC) is a rare autosomal recessive lipid storage disease characterized by progressive neurodegeneration. As only a few studies have been conducted on the impact of NPC on sensory systems, we used a mutant mouse model (NPC1^−/−) to examine the effects of this disorder to morphologically distinct regions of the olfactory system, namely the olfactory epithelium (OE) and olfactory bulb (OB).

Methodology/Principal findings

For structural and functional analysis immunohistochemistry, electron microscopy, western blotting, and electrophysiology have been applied. For histochemistry and western blotting, we used antibodies against a series of neuronal and glia marker proteins, as well as macrophage markers.NPC1^−/− animals present myelin-like lysosomal deposits in virtually all types of cells of the peripheral and central olfactory system. Especially supporting cells of the OE and central glia cells are affected, resulting in pronounced astrocytosis and microgliosis in the OB and other olfactory cortices. Up-regulation of Galectin-3, Cathepsin D and GFAP in the cortical layers of the OB underlines the critical role and location of the OB as a possible entrance gate for noxious substances. Unmyelinated olfactory afferents of the lamina propria seem less affected than ensheathing cells. Supporting the structural findings, electro-olfactometry of the olfactory mucosa suggests that NPC1^−/− animals exhibit olfactory and trigeminal deficits.

Conclusions/Significance

Our data demonstrate a pronounced neurodegeneration and glia activation in the olfactory system of NPC1^−/−, which is accompanied by sensory deficits.     

Awareness of Memory Deficits in Early Stage Huntington's Disease

Patients with Huntington''s disease (HD) are often described as unaware of their motor symptoms, their behavioral disorders or their cognitive deficits, including memory. Nevertheless, because patients with Parkinson''s disease (PD) remain aware of their memory deficits despite striatal dysfunction, we hypothesize that early stage HD patients in whom degeneration predominates in the striatum can accurately judge their own memory disorders whereas more advanced patients cannot. In order to test our hypothesis, we compared subjective questionnaires of memory deficits (in HD patients and in their proxies) and objective measures of memory dysfunction in patients. Forty-six patients with manifest HD attending the out-patient department of the French National Reference Center for HD and thirty-three proxies were enrolled. We found that HD patients at an early stage of the disease (Stage 1) were more accurate than their proxies at evaluating their own memory deficits, independently from their depression level. The proxies were more influenced by patients'' functional decline rather than by patients'' memory deficits. Patients with moderate disease (Stage 2) misestimated their memory deficits compared to their proxies, whose judgment was nonetheless influenced by the severity of both functional decline and depression. Contrasting subjective memory ratings from the patients and their objective memory performance, we demonstrate that although HD patients are often reported to be unaware of their neurological, cognitive and behavioral symptoms, it is not the case for memory deficits at an early stage. Loss of awareness of memory deficits in HD is associated with the severity of the disease in terms of CAG repeats, functional decline, motor dysfunction and cognitive impairment, including memory deficits and executive dysfunction.