Shea Lab Journal Club: SHANK3 controls maturation of social reward circuits in the VTA

SHANK3 controls maturation of social reward circuits in the VTA. Bariselli et al. (2016) Nature Neuroscience doi:10.1038/nn.4319

This is the latest installment of  an ongoing series of capsule summaries of the Shea Lab journal club meetings. We are doing this to actively provoke open discussion of papers we read that are either published in a traditional journal or BioRxiv.

This meeting was attended by members of the Shea and Tollkuhn labs.

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Autism spectrum disorders (ASD) are typically marked by disinterest in social engagement. It is widely accepted that mouse models of ASD also commonly show reduced interest in social partners. Neuroscientists who study ASD have a very limited understanding of the neural circuit basis for social disinterest. However, these authors speculate that social interaction may activate brain reward pathways overlapping with those that are activated by other types of reward such as sucrose or drugs abuse. Moreover, they suggest that mutations that cause ASD may alter social behavior by interfering with the function of these pathways. Specifically, this paper focuses on the role of dopamine releasing neurons in the ventral tegmental area (VTA). As someone who’s interested in this topic, I think this is a reasonable and interesting speculation worth investigating.

To test this idea, the authors use viral delivery of shRNA to knock down Shank3 expression in VTA neurons. Shank3 is a scaffolding protein that contributes to the organization of the postsynaptic membrane, and mutations of Shank3 cause Phelan-McDermid syndrome and other ASDs. By comparing properties of these manipulated neurons to neurons in control mice, they show altered synaptic properties and in vivo spontaneous activity. Mice with shank three knockdown in the VTA also show moderate but significant changes in their preference to approach an enclosure containing a social partner versus an empty enclosure. This behavior phenotype may be related to electrophysiological changes they see in VTA neurons, but it is unclear.

Importantly, in Figure 8 the authors attempt to restore preference for social interaction in Shank3 knockdown mice by optogenetically boosting activity in dopamine releasing VTA neurons. Ostensibly, this experiment makes a more direct link between VTA neuron function and sociability. Most of our journal club group was deeply confused by this experiment. According to the manuscript:

“In vivo, we stimulated VTA DA neurons35 during T2 when mice were in close proximity to the social stimulus (Fig. 8e). ShShank3 mice that did not receive optogenetic stimulation showed a reduction in social preference at T2 (Fig. 8f,g). However, phasic stimulation of VTA DA neurons increased social preference during T2 in both scrShank3 and shShank3 mice (Fig. 8f) and increased normalized social preference of shShank3 mice to the levels of the scrShank3 control group (Fig. 8g).”

So if I understand correctly, the experimenters gave the mice an extremely pleasurable blast of dopamine every time they approach the social partner. Perhaps not surprisingly,  all of the mice started hanging around the social partner, irrespective of whether they had Shank3 knockdown. Are we missing something? How is this different from intracranial self stimulation? Aren’t they just conditioning the mice with the reward signal? I’m curious whether this came up in review. For example, did anyone suggest they try stimulating dopamine release when the mouse approach the empty closure?

I welcome comments from readers and the authors. Maybe there’s something I don’t understand.

 

Fitter, Happier

“See if you can fit it on the paper
See if you can get it on the paper”

 

There were several discussions of scientific “productivity” on Twitter yesterday. It’s long been clear to me that people have wildly different ideas about what this means and how to measure it. Many times you find people talking about how many papers a scientist has published, but does anyone seriously think that that is a useful number? One major factor is that individual researchers and communities have dramatically different ideas about what constitutes a publication unit. I remember being very annoyed when my first grant, which was directly based on my postdoctoral work, was reviewed with a ding that it was based on “a single publication.” Setting aside the fact that I didn’t invent a whole field and there was long literature preceding me, why is that in and of itself a neg? That was four years of work done entirely by me. I probably could have portioned out some number of smaller nuggets and published them separately, but why is that a good thing?

So I was interested in this exchange that came in a larger discussion of standards for review of NIH grants:

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In a strict sense, Drug Monkey is right because science is never complete, but his argument is really a straw man. We can’t pretend that all papers are anything close to equal in terms of scientific productivity. And to head off an inevitable response, I am not talking about Glam. I am also not talking about middle vs. first author papers. It is absolutely the case that first author papers can reflect a wide range of what we deem to be productivity. In my opinion, at the extreme that range may even plausibly span an order of magnitude.

My attitude is that it is more efficient and better for science to publish your data in larger chunks, but I understand that many people feel differently. I’m interested in hearing from people in the comments. Given the same data, what is the argument for splitting it up? How do you know when to stop and publish something?

 

We Jam Econo

In 1985, punk band The Minutemen released an album entitled Project: Mersh, which was a self-conscious, tongue-in-cheek attempt to make a record that was marketable without necessarily bothering to make it any good.

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The Minutemen were to say the least peculiarly idiosyncratic characters and their lyrics and interviews were peppered with their own insider lingo. For example, “jamming econo” referred to their preference to operate cheaply as a band, and their landmark record “Double Nickels on the Dime” was so titled in mockery of Sammy Hagar’s cheesy declaration “I Can’t Drive 55.” As I understand it, they felt Hagar sadly needed to prove he was wild somehow since he was too cowardly and/or lacking in imagination to be wild musically. Having no such hangups, The Minutemen proudly drove “Double Nickels on the Dime.”

“Mersh” was their term for “commercialism” in music: formulaic in approach, superficially alluring and ultimately hollow. In his wonderful book Our Band Could Be Your Life, author Michael Azerrad explains it this way:

“By mimicking the ‘mersh’ form and yet destined to sell few records, they were making a point about music  biz chicanery: Any band could sound like this if they had enough money, but that wouldn’t mean they were any good.”

I’m sure you’re wondering what the point of all this is.

I am inspired to tell this story about The Minutemen because of my increasing impression that there is a convergent formula for a segment of Glam neuroscience that fits well with my understanding of what it means to be mersh. I’m not going to single out examples, but feel free to do so in the comments! To me it is typified by the kind of study that has many authors from multiple labs, with each one contributing one or two panels. Such papers often do this apparently to create the illusion of a “comprehensive” and “mechanistic” “story.” Unfortunately, they also more than occasionally rely on a logical framework wherein putting two observations next to one another means they are related. Yet these papers have appeal and get lots of attention.

In my ongoing mission to port the logic and language of punk rock to science, I propose that these papers henceforth be derided as “mersh.” Neuroscience needs more Minutemen and less Sammy Hagar.

Shea Lab Journal Club: A distributed network for social cognition enriched for oxytocin receptors

A Distributed Network for Social Cognition Enriched for Oxytocin Receptors. Mitre et al. (2016) J Neurosci 26(8):2517

This is the first installment of what will be an ongoing series of capsule summaries of the Shea Lab journal club meetings. We are doing this to actively provoke open discussion of papers we read that are either published in a traditional journal or BioRxiv.

This meeting was attended by members of the Shea and Tollkuhn labs. Names have been changed to protect the opinionated🙂

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Dang, this is one big, hairy beast of a paper! It starts out with a pretty straightforward and very important goal: to develop a sensitive and selective antibody to the mouse receptor for the neuromodulator oxytocin and identify the pattern of expression at the regional circuit and sub cellular levels. The paper does that rather nicely and then goes on to incorporate EM, RNAseq, and in vitro and in vivo electrophysiology over the course of 13 figures.

Like I said, the first half of the paper is a tight and thorough execution of the goal as formulated above. The authors identify for the first time the network of brain regions that express this receptor, and they observe a provocative pattern of presynaptic expression that was (to me anyway) unexpected. They achieve this by bearing down on the formidable task of developing and validating an OXTR antibody

The second half of the paper runs through an series of exciting but somewhat preliminary observations primarily using in vitro and in vivo electrophysiology. Most of this stuff is super interesting, examining oxytocin’s acute neuromodulatory effects and its effects on synaptic plasticity. The down side is that many of these effects are not deeply explored, so I hope that they get followed up on. A little bird told me that a lot of these things were responses to reviewer comments, which is weird to me. It seems to me that the physiology would be better served in its own venue. Greedy reviewers!

Strengths/Praise: All present agreed that the paper’s greatest contribution was the development of a high quality antibody for oxytocin and the visualization of the brain-wide expression pattern. The apparent rigor with which this was done is a major strength. These resources provide an important substrate for future work.

Secondary, but also important, is the fact that this paper avoids the media glam image of oxytocin as a “love molecule” and takes it seriously as a modulator of neuronal activity and plasticity.

There were other nuggets of interest. The motif of presynaptic expression suggests some interesting unexpected functions for oxytocin. Also, the fact that OXT+ fibers overlapped the OXTR+ cells in certain hypothalamic regions but not elsewhere suggested to me distinct, circuit-specific modes of point-to-point and volume transmission. But that’s probably speculative of me.

Weaknesses/Criticism: Our major criticism was that the paper could have ended after 7 or 8 figures and started a new paper. But like I said, I subsequently learned that these were things the reviewers asked about, so maybe we shouldn’t fault the authors.

One other minor critique that came up was that the authors may have been a bit chauvinistic in choosing the regions they focused on. The auditory cortex is not one of the top expressing regions based on raw cell count, The counter argument I suppose is that with this kind of staining, sparse does not always imply weak. Also, looking at the  auditory cortex is well motivated by a recent high profile study by this group.

Coordination of brain wide activity dynamics by dopaminergic neurons

http://biorxiv.org/content/early/2016/03/02/042168

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Several neuropsychiatric conditions, such as addiction, schizophrenia, and depression may arise in part from dysregulated activity of ventral tegmental area dopaminergic (THVTA) neurons, as well as from more global maladaptation in neurocircuit function. However, whether THVTA activity affects large-scale brain-wide function remains unknown. Here, we selectively activated THVTA neurons in transgenic rats and measured resulting changes in whole-brain activity using stimulus-evoked functional magnetic resonance imaging (fMRI). Selective optogenetic stimulation of THVTA neurons not only enhanced cerebral blood volume (CBV) signals in striatal target regions in a dopamine receptor dependent fashion, but also engaged many additional anatomically defined regions throughout the brain. In addition, repeated pairing of THVTA neuronal activity with forepaw stimulation, produced an expanded brain-wide sensory representation. These data suggest that modulation of THVTA neurons can impact brain dynamics across many distributed anatomically distinct regions, even those that receive little to no direct THVTA input.

Evidence for selective attention in the insect brain

http://biorxiv.org/content/early/2016/02/29/041889

Benjamin L de Bivort, Bruno van Swinderen
The capacity for selective attention appears to be required for any animal responding to an environment containing multiple objects, although this has been difficult to study in smaller animals such as insects. Clear operational characteristics of attention however make study of this crucial brain function accessible to any animal model. Whereas earlier approaches have relied on freely behaving paradigms placed in an ecologically relevant context, recent tethered preparations have focused on brain imaging and electrophysiology in virtual reality environments. Insight into brain activity during attention-like behavior has revealed key elements of attention in the insect brain. Surprisingly, a variety of brain structures appear to be involved, suggesting that even in the smallest brains attention might involve widespread coordination of neural activity.

Sensitive red protein calcium indicators for imaging neural activity

http://biorxiv.org/content/early/2016/02/29/041780

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Genetically encoded calcium indicators (GECIs) allow measurement of activity in large populations of neurons and in small neuronal compartments, over times of milliseconds to months. Although GFP-based GECIs are widely used for in vivo neurophysiology, GECIs with red-shifted excitation and emission spectra have advantages for in vivo imaging because of reduced scattering and absorption in tissue, and a consequent reduction in phototoxicity. However, current red GECIs are inferior to the state-of-the-art GFP-based GCaMP6 indicators for detecting and quantifying neural activity. Here we present improved red GECIs based on mRuby (jRCaMP1a, b) and mApple (jRGECO1a), with sensitivity comparable to GCaMP6. We characterized the performance of the new red GECIs in cultured neurons and in mouse, Drosophila, zebrafish and C. elegans in vivo. Red GECIs facilitate deep-tissue imaging, dual-color imaging together with GFP-based reporters, and the use of optogenetics in combination with calcium imaging.