When Mouse plays Dice

RIKEN researchers working in the US with American colleagues have developed a technique for switching individual nerve circuits on and off, and employed it to determine the role of an important pathway used in forming memories. In specially bred mice, the international research team found the tri-synaptic pathway (TSP) in the hippocampal region of the brain is integral to rapid formation of functional memory, but not necessary for incremental learning. Decline of the TSP is thought to be associated with ageing and neurodegenerative conditions such as Alzheimer’s disease. The TSP is one of two parallel nerve circuits known to be involved in learning and memory. It carries information from the entorhinal cortex (EC) through the three major processing regions of the hippocampus—the dentate gyrus, CA3 and CA1—before returning to the EC (Fig. 1). The other circuit, the monosynaptic pathway (MSP), simply takes information from the EC to the CA1 and back again. Previously, researchers studied what happened when cells in each of these regions are destroyed, and when specific nerve receptors are blocked. But these methods can only provide partial understanding of the role of each pathway. In a recent paper in Science¹, the team of researchers from the RIKEN-MIT Neuroscience Research Center in Cambridge, Massachusetts, led by Susumu Tonegawa, outlines how they developed a technique to block and unblock the transmission of impulses across a specific nerve junction in the TSP by controlling the expression of the tetanus toxin gene using the antibiotic doxycycline. The team then used its technique—named DICE-K after a Japanese major league baseball pitcher—to study the ability of mice with or without a functional TSP to perform tasks involving different types of learning and memory. The researchers found that the MSP alone is sufficient for the incremental acquisition and recall of spatial learning and memory associated with the Morris water maze, where over repeated trials mice learn to associate the position of an escape platform hidden underwater with landmarks placed outside the tank. But the TSP is crucial to the more sophisticated acquisition of memory in tasks where rapid learning is required—in novel environments, for instance. “Using this technology, we can shut down communication between nerve cells whenever we want, during or after memory acquisition,” says team member Toshiaki Nakashiba. “We can also apply it to circuits other than the TSP. It provides a level of experimental accuracy never achieved before.”

Modafinil: a good cognitive enhancer ?

Modafinil: A Review of Neurochemical Actions and Effects on Cognition

Michael J Minzenberg¹ and Cameron S Carter¹

Neuropsychopharmacology (2008) 33, 1477–1502; doi:10.1038/sj.npp.1301534; published online 22 August 2007 http://www.nature.com/npp/journal/v33/n7/abs/1301534a.html Modafinil (2-[ (Diphenylmethyl) sulfinyl] acetamide, Provigil) is an FDA-approved medication with wake-promoting properties. Pre-clinical studies of modafinil suggest a complex profile of neurochemical and behavioral effects, distinct from those of amphetamine. In addition, modafinil shows initial promise for a variety of off-label indications in psychiatry, including treatment-resistant depression, attention-deficit/hyperactivity disorder, and schizophrenia. Cognitive dysfunction may be a particularly important emerging treatment target for modafinil, across these and other neuropsychiatric disorders. We aimed to comprehensively review the empirical literature on neurochemical actions of modafinil, and effects on cognition in animal models, healthy adult humans, and clinical populations. We searched PubMed with the search term 'modafinil' and reviewed all English-language articles for neurochemical, neurophysiological, cognitive, or information-processing experimental measures. We additionally summarized the pharmacokinetic profile of modafinil and clinical efficacy in psychiatric patients. Modafinil exhibits robust effects on catecholamines, serotonin, glutamate, gamma amino-butyric acid, orexin, and histamine systems in the brain. Many of these effects may be secondary to catecholamine effects, with some selectivity for cortical over subcortical sites of action. In addition, modafinil (at well-tolerated doses) improves function in several cognitive domains, including working memory and episodic memory, and other processes dependent on prefrontal cortex and cognitive control. These effects are observed in rodents, healthy adults, and across several psychiatric disorders. Furthermore, modafinil appears to be well-tolerated, with a low rate of adverse events and a low liability to abuse. Modafinil has a number of neurochemical actions in the brain, which may be related to primary effects on catecholaminergic systems. These effects are in general advantageous for cognitive processes. Overall, modafinil is an excellent candidate agent for remediation of cognitive dysfunction in neuropsychiatric disorders.

Free poster on Alzheimer

Alzheimer's disease (AD) is a devastating neurodegenerative disorder with a relentless progression. AD pathogenesis is believed to be triggered by the accumulation of the amyloid-β peptide (Aβ), which is due to overproduction of Aβ and/or the failure of clearance mechanisms. Aβ self-aggregates into oligomers, which can be of various sizes, and forms diffuse and neuritic plaques in the parenchyma and blood vessels. Aβ oligomers and plaques are potent synaptotoxins, block proteasome function, inhibit mitochondrial activity, alter intracellular Ca²⁺ levels and stimulate inflammatory processes. Loss of the normal physiological functions of Aβ is also thought to contribute to neuronal dysfunction. Aβ interacts with the signalling pathways that regulate the phosphorylation of the microtubule-associated protein tau. Hyperphosphorylation of tau disrupts its normal function in regulating axonal transport and leads to the accumulation of neurofibrillary tangles and toxic species of soluble tau. Furthermore, degradation of hyperphosphorylated tau by the proteasome is inhibited by the actions of Aβ. These two proteins and their associated signalling pathways therefore represent important therapeutic targets for AD.

The Poster is freely available thanks to support from Elan and Wyeth.

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Amyloid-β and tau in Alzheimer's disease

Trembling sleep

SpringerLink - Journal Issue

A collection of (free) articles on sleep disturbances in parkinson's disease.

A nice overview on REM sleep behavior disorder both idiopathic and symptomatic.

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Tik tak

LWZ

LZW Data Compression

the protesasome: a trashcan for memories

Synaptic Protein Degradation Underlies Destabilization of Retrieved Fear Memory -- Lee et al. 319 (5867): 1253 -- Science

Reports
Synaptic Protein Degradation Underlies Destabilization of Retrieved Fear Memory
Sue-Hyun Lee, Jun-Hyeok Choi, Nuribalhae Lee, Hye-Ryeon Lee, Jae-Ick Kim, Nam-Kyung Yu, Sun-Lim Choi, Seung-Hee Lee, Hyoung Kim, Bong-Kiun Kaang*

Reactivated memory undergoes a rebuilding process that depends on de novo protein synthesis. This suggests that retrieval is dynamic and serves to incorporate new information into preexisting memories. However, little is known about whether or not protein degradation is involved in the reorganization of retrieved memory. We found that postsynaptic proteins were degraded in the hippocampus by polyubiquitination after retrieval of contextual fear memory. Moreover, the infusion of proteasome inhibitor into the CA1 region immediately after retrieval prevented anisomycin-induced memory impairment, as well as the extinction of fear memory. This suggests that ubiquitin- and proteasome-dependent protein degradation underlies destabilization processes after fear memory retrieval. It also provides strong evidence for the existence of reorganization processes whereby preexisting memory is disrupted by protein degradation, and updated memory is reconsolidated by protein synthesis.

Absynth Minded ?

Perhaps van Gogh, Toulouse-Lautrec and Picasso were all just faking it. Not their art, of course, but the purported effects of absinthe, a potent green-coloured liquor rumoured to cause hallucination and even drive indulgers to madness. Now a team of German and English chemists has found that turn-of-the-century absinthes boasted only low amounts of a chemical thought to induce insanity, thujone, which comes from the wormwood used to brew absinthe. The chemical's levels in vintage absinthes were comparable to the drink now legally sipped by nostalgia-craving hipsters in Europe and the United States. Artistes like van Gogh drank absinthe freely until 1915, when the French banned production. Fortunately, some collectors stocked up on absinthe, and many pre-ban vintages survive to this day, particularly bottles of Pernod Fils, the largest producer of the day. A team led by Dirk Lachenmeier, of the Chemical and Veterinary Investigation Office in Karlsruhe, Germany, analysed 13 pre-ban absinthes for their levels of thujone and several other chemicals that might cause drinkers to see the green fairy. Their investigation found that previous measures of the thujone content of pre-ban absinthes had been overestimated by nearly a factor of 10. Lachenmeier's team found low levels of other potential hallucinogens. But cheaper absinthes that no one bothered to collect might have contained methanol, an alcohol that can cause blindness. But it seems that Toulouse-Lautrec's swill caused little more madness than the $65 bottles now sold in the US.