Overexpression of Rab1 prevents Parkinson-like cell death

{alpha}-Synuclein Blocks ER-Golgi Traffic and Rab1 Rescues Neuron Loss in Parkinson’s Models — Cooper et al., Science

Fascinating evidence pointing toward a treatment for parkinson’s. Basically, Lindquist’s group finds that overexpression of a trafficking protein Rab1 that moves folded proteins from the ER to the Golgi can prevent alpha-synuclein accumulation-triggered death of rat neurons.

Of course, in vitro is not in vivo. And, for all we know, Parkinson’s could be a complex, multi-mechanism disease. But this looks promising!

Abstract:

Alpha-synuclein misfolding is associated with several devastating neurodegenerative disorders including Parkinson’s Disease (PD). In yeast cells and in neurons {alpha}Syn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following {alpha}Syn expression in yeast was a block in endoplasmic reticulum (ER) to Golgi vesicular trafficking. In a genome-wide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab GTPase Ypt1p, which associated with cytoplasmic {alpha}Syn inclusions. Elevated expression of Rab1, the mammalian YPT1 homolog, protected against {alpha}Syn-induced dopaminergic neuron loss in animal models of PD. Thus synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable.

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NYT on pharmacological advances in addiction treatment

An Anti-Addiction Pill? – New York Times

Lots of interesting stuff here on new treatments for addiction, including: A methadone (heroin-substitute) replacement called buprenorphine with less dependency and less of a high; an injectible version of alcoholism treatment naltrexone called Vivitrol, which is injectable and lasts one month; some medications that increase GABA production; and, perhaps most innovative is a vaccine against nicotine that allows antibodies to bind nicotine and prevent crossing through the blood-brain barrier.

Excerpts with some of the neat experiments involving dopamine receptors and environmental factors in addiction are after the jump.
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Softmax rule for exploration-exploitation

A very nice neuroecon expt. in the newest Nature:

Daw et al. find that humans choose between multiple slot machines (with different payoff probabilities) based on expected value (versus just going with the highest probability one most of the time and then randomly choosing another one every so often). Then, with fMRI, they find brain areas correlated with different value predictions.

News & Views (Daeyol Lee)

Cortical substrates for exploratory decisions in humans (Daw, Dayan)

Abstract:

Decision making in an uncertain environment poses a conflict between the opposing demands of gathering and exploiting information. In a classic illustration of this ‘exploration-exploitation’ dilemma, a gambler choosing between multiple slot machines balances the desire to select what seems, on the basis of accumulated experience, the richest option, against the desire to choose a less familiar option that might turn out more advantageous (and thereby provide information for improving future decisions). Far from representing idle curiosity, such exploration is often critical for organisms to discover how best to harvest resources such as food and water. In appetitive choice, substantial experimental evidence, underpinned by computational reinforcement learning (RL) theory, indicates that a dopaminergic, striatal and medial prefrontal network mediates learning to exploit. In contrast, although exploration has been well studied from both theoretical and ethological perspectives, its neural substrates are much less clear. Here we show, in a gambling task, that human subjects’ choices can be characterized by a computationally well-regarded strategy for addressing the explore/exploit dilemma. Furthermore, using this characterization to classify decisions as exploratory or exploitative, we employ functional magnetic resonance imaging to show that the frontopolar cortex and intraparietal sulcus are preferentially active during exploratory decisions. In contrast, regions of striatum and ventromedial prefrontal cortex exhibit activity characteristic of an involvement in value-based exploitative decision making. The results suggest a model of action selection under uncertainty that involves switching between exploratory and exploitative behavioural modes, and provide a computationally precise characterization of the contribution of key decision-related brain systems to each of these functions.

Backs to the Future

Backs to the Future

Cool stuff:

New analysis of the language and gesture of South America’s indigenous Aymara people indicates a reverse concept of time.

Contrary to what had been thought a cognitive universal among humans – a spatial metaphor for chronology, based partly on our bodies’ orientation and locomotion, that places the future ahead of oneself and the past behind – the Amerindian group locates this imaginary abstraction the other way around: with the past ahead and the future behind.

Appearing in the current issue of the journal Cognitive Science, the study is coauthored, with Berkeley linguistics professor Eve Sweetser, by Rafael Nunez, associate professor of cognitive Science and director of the Embodied Cognition Laboratory at the University of California, San Diego.

J Physiol. archive now online

The Journal of Physiology announced in the editorial in their recent issue that they have completed digitizing their archive all the way back to 1878, and that it’s now open-accessible from PubMed Central here. (Though I note that the PMC archive, contrary to the statements of the editorial, only goes back to 1904 at the moment.

This is great news, as a lot of classic neuroscience papers were published J Physiol in the 50s and 60s, and previously their online archive had only gone back to 1997 or so. See for example, the Hodgkin and Huxley 1952 papers (1, 2, 3, 4) and Hubel and Wiesel 1962.

-John O’Leary

Presynaptic somatic membrane potential can influence EPSPs

Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential : Nature

Very interesting work. Modulation of the somatic potential seems to influence the EPSP, as measured by paired patch recordings of two layer 5 cells in cortical slice. Somatic depolarization from resting potential to near threshold results in an increase in evoked EPSPs.

In synaptic physiology, we often make a point of distinguishing intrinsic changes (eg. membrane potential) from synaptic conductance changes. Now it looks like the line between those might be a bit blurry!

Here’s a N&V by Eve Marder too.