Archive for the 'Neuroscience' category

Logothetis driven out of monkey research

May 04 2015 Published by under Animals in Research, Neuroscience, Science Politics

Neuroscientist Nikos Logothetis (PubMed) has informed his colleagues that he is stopping his long running nonhuman primate research program. An article in ScienceInsider by Gretchen Vogel details the issues:

Nikos Logothetis, a director at the Max Planck Institute for Biological Cybernetics in Tübingen, Germany, says he will conclude his current experiments on macaques “as quickly as possible” and then shift his research to rodent neural networks. In a letter last week to fellow primate researchers, Logothetis cites a lack of support from colleagues and the wider scientific community as key factors in his decision.

This is not the "start" as was alleged by a Twitter person today. This is a long running trend that has been going on for decades. Productive laboratories that use nonhuman primates have been closing one by one. The decision by Harvard to shutter the New England National Primate Research Center was shocking in the way it violated the trend for picking off research labs one by one, but it was otherwise simply part of a larger trend.

And why are Universities and Research Institutes like Max Planck divesting themselves of monkey labs as quickly as possible? The Vogel article suggests an answer.

Logothetis’s research on the neural mechanisms of perception and object recognition has used rhesus macaques with electrode probes implanted in their brains. The work was the subject of a broadcast on German national television in September that showed footage filmed by an undercover animal rights activist working at the institute. The video purported to show animals being mistreated.

Logothetis has said the footage is inaccurate, presenting a rare emergency situation following surgery as typical and showing stress behaviors deliberately prompted by the undercover caregiver. ... The broadcast triggered protests, however, and it prompted several investigations of animal care practices at the institute. Investigations by the Max Planck Society and animal protection authorities in the state of Baden-Württemberg found no serious violations of animal care rules.

Emphasis added. This is a typical scenario. In essence, animal rights terrorist fanatics are able to get Universities and Research Institutions to turn their backs on productive researchers simply because they don't want to deal with the headaches any longer. Or because they fear bad press. The accusations are almost always falsified. Baseless. But it doesn't matter. The Universities are running in absolute terror of the fanatics.

Of course it goes beyond that, which is why Logothetis called out his fellow scientists.

The [Max Planck] society is “one of the best scientific organizations worldwide,” Logothetis wrote, but it has failed to take concrete steps against the activists. “I am no longer willing or able to accept the never-ending stream of abuse from animal activists toward myself and my co-workers while seeing them encouraged to increase their aggressive activities by the tolerance and very slow reactions of scientific organizations. There is a clear lack of consequences for illegal actions such as infiltration, violation of privacy, theft of documents, and even intentionally caused distress to animals in order to film supposed animal torture or abnormal behavior,” the letter states.

Logothetis’s letter also faults his scientific colleagues in Tübingen for distancing themselves from the controversy. The neighboring Max Planck Institute for Developmental Biology posted a disclaimer on its website emphasizing that there are no monkeys at the institute, he notes, and colleagues at the nearby Hertie Institute for Clinical Brain Research refused to issue a declaration of support.

Pastor Niemöller once observed:

First they came for the Socialists, and I did not speak out—
Because I was not a Socialist.

Then they came for the Trade Unionists, and I did not speak out—
Because I was not a Trade Unionist.

Then they came for the Jews, and I did not speak out—
Because I was not a Jew.

Then they came for me—and there was no one left to speak for me.

There are certainly parallels. Biological scientists express a range of attitudes about many things and the use of animals in research is one of them. From fears of coming under assault themselves if they speak up, to discomfort with making an informed decision about the allegations against Professor Logothetis to frank antipathy to research in monkeys, we span the same range as many lay people.

We are easily able to delude ourselves that if we just let the most-detested targets of the terrorists get thrown under the bus, we can live our own lives in relative safety for another few years. Maybe run out the clock on our career before things get too bad.

Money is tight, after all, and gee, well lets not do anything to rile up the nice little old ladies who are poised to donate a few million to the University, eh? Let's not do anything to draw the attention of animal right's Congress Critters. That might make things awkward for the NIH.

Normally this is the point of my post where I exhort you to fight. To stand up and oppose this assault on scientific research. Where I point out to you that after the monkeys (and cats and dogs) comes the goats and the rabbits from which you get your antibodies. Where I tell you that all this pressure is doing is to move certain kinds of research to non-Western countries in which the animal research protections are, at best, at the lever of the US in 1950.

This is the point where I am supposed to be telling you to call your Congress Critter.

But I can't.

Logothetis is not the first and he will not be the last.

We have had ample opportunity for biological scientists to see and be motivated to do something about this situation.

They have not done so.

So I would be wasting my breath.

43 responses so far

Nature publishes overwhelmingly proven "NEW AMAZING FINDING" ....because optogenetics!

The PR headlines are breathless and consistent:

Researchers Identify Brain Circuit That Regulates Thirst

Brain’s On-Off Thirst Switch Identified

The paper is here.

Yuki Oka, Mingyu Ye & Charles S. Zuker Thirst driving and suppressing signals encoded by distinct neural populations in the brain Nature (2015) doi:10.1038/nature14108

The takeaway punch message from the Abstract:

These results reveal an innate brain circuit that can turn an animal’s water-drinking behaviour on and off, and probably functions as a centre for thirst control in the
mammalian brain.

Somebody like me immediately thinks to himself "subfornical neurons control drinking behavior? This is like the fifth lecture in Psych 105: Introduction to Physiological Psychology."

Let's do a little PubMed troll for "subfornical drinking". Yeah, we've known since at least the 1970s that the subfornical control of drinking behavior is essential, robust and mediated by angiotensin II signalling. We know how this area responds to blood volemia and natremia and how the positioning relative to the third ventricle and the function of the circumventricular organ vis a vis the blood-brain barrier permits this rapid-response. We know the signalling works through AT1 receptor subtype to excite subfornical neuronal activity via electrophysiological recording techniques and genetic deletions. Cholinergic mechanisms have likewise been identified as critical components via pharmacological experiments. Mapping of activated neurons has been used to identify related circuitry. The targets of subfornical neurons are known and their involvement in drinking behavior has likewise been characterized. Extensively. We know that electrical stimulation of these neuronal populations activates drinking in water sated rats, for goodness sake! We know there are at least three subpopulations of SFO neurons involved and something about the neurochemical signalling complexity.

There are review articles that you can read if you want to get up to speed.

The new work by Oka and colleagues simply repeats the above-mentioned electro-stimulation experiment from 1983 using optogenetic stimulation. Apart from this, maybe, we have an advance* in that they identified ETV-1 vs VGAT (GABA transporter) markers of two distinct subpopulations of neurons which have opposite effects on the motivation to consume water.

That's it.

This paper is best described as a very small, incremental advance in understanding of thirst and drinking behavior, albeit tarted up with the pizzaz of optogenetic techniques.

Yet it was published in Nature.

Someone really needs to introduce the editorial staff of Nature to PubMed.
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*BTW, a Nature editor confirms this microscopic incremental advance is what is new about this paper.

66 responses so far

Sometimes the good guys win

Sep 30 2014 Published by under Neuroscience, NIH

I've mentioned a time or two that I think the DREADD approach is infinitely more useful than optogenetics for anything that matters.

So congrats to the team for this new award.

DREADD2.0: AN ENHANCED CHEMOGENETIC TOOLKIT

DESCRIPTION (provided by applicant): The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has the ambitious goal of elucidating how neuronal ensembles interactively encode higher brain processes. To accomplish this goal, new and improved methods for both recording and manipulating neuronal activity will be needed. In this application, we focus on technologies for manipulating neuronal activity. The major significance of this application is that we will provide an enhanced chemogenetic toolbox that allows non-invasive, multiplexed spatiotemporal control of neuronal activity in domains ranging from single synapses to ensembles of neurons. To achieve this, we will provide: Chemical actuators with improved pharmacokinetics and pharmacodyamics suited for use with current DREADDs in eukaryotes ranging from Drosophila to primates (Specific Aim #1) Photo-caged CNO and other chemical actuators to provide millisecond-scale control (Specific Aim #1) Novel DREADDs and 'split-DREADDs' targeted to distinct neuronal pathways to enable multiplexed interrogation of neuronal circuits (Specific Aims #2 and 3) Chemogenetic platforms with minimized desensitization and down-regulation (Specific Aim #3)

I am excited to see where this leads.

More awards under The BRAIN Initiative.

27 responses so far

Hard truths for supposed neuroscientists

This is the truest and best thing I have read on the internet today.

12 responses so far

Guest Post: Gender Sensitivity in Neuroscience is a Work in Progress

This is a guest post from someone who wishes to remain anonymous.

 


 

This week, the Society for Neuroscience opened its website allowing attendees to book their hotels for their annual meeting. The timing was couldn’t have been worse for the Vanderbilt neuroscience community given that on Monday, a former graduate student of the program leveled a disturbing series of accusations against neuroscientist Aurelio Galli. At least 10 of the 60+ alleged events of harassment occurred at SfN meetings. The year before the defendant claims she was subject to harassment, The Society for Neuroscience named Vanderbilt their ‘Neuroscience Training Program of the Year’.

 

In a 20 million dollar harassment suit filled in Nashville, sordid details were laid out of alcohol fueled harassment both in the lab and at the Society for Neuroscience’s annual meetings in 2012 and 2013. The student, a recovering alcoholic, alleges she was subjected to unwelcome and embarrassing commentary from Galli about her perceived lesbianism, her sex life and her looks both in lab as well as in front of male professors.

 

Vanderbilt fired back saying they had investigated the claims and would vigorously defend themselves.  The medical center director and the chancellor were named as defendants, as were Mark Wallace, the head of the Vanderbilt Brain Institute and National Academy member and Chair of the Department of Molecular Biology and Physiology, Roger Cone. Wallace and Cone were included for their failure to act on the student’s claims and protect her career.

 

For those outside the field, the neuroscience community seems to be holding down opposite poles in gender and racial equality. The leadership of both the Journal of Neuroscience and the Society are enviably gender balanced in the last decade. SfN was one of the first national societies to initiate meaningful career-long mentorship for women and minorities. Thanks in part to this commitment, women constitute 50% of most neuroscience graduate training programs. The national attrition of women from academic science is also evident in Vanderbilt’s neuroscience program which has an all male leadership and > 30% of its training faculty as women. The vast majority of these female faculty members are assistant professors.

 

Sending a female graduate student from a heavily male influenced neuroscience graduate program to SfN would present many sources of potential conflict. The first SfN meeting the student claims she was harassed at was in New Orleans, a city proud of its tradition of asking women to show their breasts for beads.

 

The female graduate student alleges that at SfN, her PI required her to attend a cocktail party on a boat where senior male scientists “became intoxicated and were allowed to make romantic and sexual advances on the students”. <I’ll insert my editorial opinion that news does not surprise me especially in light of the report this week from Kate Clancy that the majority of women in her survey of field scientists say they have been harassed with more than 20% reporting that they have been assaulted.>

 

Why would anyone attend boat party or any other kind of party where alcohol is flowing freely and fun is a much more clear objective than science?   For many trainees, this is often the only chance they have to spend time talking to well-published PIs. Presumably, at a party like this, senior investigators would be amenable to laid back conversations with trainees providing a rare chance to judge the character of potential future mentors.

 

These parties are the products of the bygone era of much larger gatherings held a decade or more ago by men who were SfN officers and investigators. Hosts had ample institutional ‘slush’ funds and open bar was the norm. The fabled parties hosted by former Emory Psychiatry chairman Charlie Nemeroff were more or less the height of partying for many members.

 

While at Emory, Nemeroff managed to get millions in personal wealth by consulting for drug companies while also studying those drugs using funding for his lab from NIMH. This income presumably enabled him to host these lavish events. Nemeroff’s parties would often devolve into factions that went skinny-dipping, participated in drinking contests and unwelcome ass grabbing, and yes, accomplished some important networking.

 

From the Venderbuilt lawsuit, “networking” was the reported benefit Galli touted as a reason for the trainee to attend the boat party. Indeed, Galli trained at Emory from 1993-1995 while Nemeroff was there, so these kinds of parties probably did help him advance his career. The expectation that a female recovering alcoholic would likewise benefit underscores a clear cultural clash that needs to be addressed by both the Vanderbilt community and the Society for Neuroscience.

31 responses so far

A chance to support research on Parkinson's Disease

Apr 23 2014 Published by under CrowdFund, LinkLove, Neuroscience, Public Health

The scientist known as @parklifensci (Parklife blog) on the Internet will be walking in the Parkinson's Unity Walk. The donation page says:

Why I'm walking:
Every walker and donor makes a difference by taking the Walk one step closer to finding the cause and cure for Parkinson’s. By joining together with thousands of others, we'll be empowering those who are living with the disease, and honoring those who lived with Parkinson’s.

Who I’m walking for:
Over 1 million people in the United States have Parkinson’s. 60,000 people are newly diagnosed every year – one person, every nine minutes. Walking and raising funds and awareness for research is my chance to help.

Why I'm supporting the Parkinson’s Unity Walk:
100% of donations go to research. The Parkinson’s Unity Walk is the largest grassroots event in the U.S., raising funds and awareness for research.

Ways to support my fundraising efforts:
There's strength in numbers so please join me. Donate, register to walk, and fundraise.

I encourage you to donate if you can or join the walk if you are nearby.

No responses yet

Faces of Neuroscience: Jean A. King, Ph.D.

JeanKing Dr. Jean A. King [webpage] is Vice-Chair of Research and Professor in the Department of Psychiatry at the University of Massachusetts Medical School [PubMed; CV]. She completed her PhD in 1988 at NYU in Neurophysiology and conducted postdoctoral training at Emory. Dr. King's research record is diverse but can be characterized as focusing on neuroendocrine systems, stress, aggression, fear and substance abuse. Her work has also focused on advancing noninvasive imaging techniques in animal models using magnetic resonance imaging, in addition to the papers she has credit on three patents for neuroimaging advances. Professor King is the Director of the Center for Comparative Neuroimaging within the UMass Medical School. A recent paper from her laboratory (open access) applies imaging techniques to investigate white matter structural integrity in the brains of nicotine addicted human subjects that are associated with measures of physical dependence.

Over the years Dr. King's work has been funded by the National Science Foundation and the National Institutes of Health (a RePORTER search illustrates her NIH funding history as a Principal Investigator).

As you would expect for a scientist of this caliber, her expertise has been sought by an array of journals to provide peer review of manuscripts and by the NIH to serve on many grant review panels. I can confirm that Professor King is an excellent and insightful reviewer of grant applications with a persuasive and often humorous demeanor. Her comments were invariable informative, particularly for noob-ish grant reviewers (ahem). Similarly, Dr. King has supervised numerous trainees, participated on many service committees for her University, for the NIH and for multiple academic societies or entities. She has additional service in nonacademic settings. In this record there is a strong addition of service on issues important to women in science and in careers, generally.

I thank you, Professor Jean A King, for your long commitment to advancing our understanding of the brain and of affective disorder.

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Disclaimer: I am professionally acquainted with Dr. King.

picture borrowed from http://www.umassmed.edu/Content.aspx?id=96786

Series Note: The Diversity in Science Blog Carnival was created by D.N. Lee of the Urban Science Adventures! blog. In early 2009 she issued a call for a new blog carnival celebrating diversity in science and hosted the inaugural edition. The Diversity in Science Carnival #2 was hosted at Thus Spake Zuska under the theme Women Achievers in STEM - Past and Present. Prior entries from me have focused on Laura O'Dell, Carl Hart, Chana Akins, Percy Julian, Jean Lud Cadet,  and Yasmin Hurd.

One response so far

The Society for Neuroscience is launching a new Open Access journal

Jan 15 2014 Published by under Neuroscience, Open Access, Society for Neuroscience

An email from current president of the Society for Neuroscience announced the intent of the society to launch a new Open Access journal. They are seeking an Editor in Chief, so if you know any likely candidates nominate them.

The Society for Neuroscience Council has appointed a Search Committee to recommend candidates to serve as editors-in-chief for two Society-published journals:

The Editor-in-Chief of The Journal of Neuroscience, to be appointed for a 5-year term beginning Jan. 1, 2015, after a period of transition with the current editor; and
The first Editor-in-Chief of a new online, open access neuroscience journal, expected to launch in late 2014, and temporarily referred to herein as “New Journal.” Please see the announcement here for more information about New Journal. This 5-year appointment will commence in the spring of 2014, to allow the new editor to be involved in decisions connected with the start-up of New Journal and the organizing of an initial editorial board.

The members of the Search Committee are: Moses Chao, Chair; Holly Cline; Barry Everitt; David Fitzpatrick; and Eve Marder.

The list of evaluation criteria may help you to think about who you should nominate.

In evaluating candidates for the editor-in-chief positions, the Search Committee will consider the following criteria:

  • previous editorial experience

  • adequate time flexibility to take on the responsibilities of editor-in-chief

  • a distinguished record of research in neuroscience

  • familiarity with online submission, peer review and manuscript tracking systems

  • ideas about novel approaches and receptivity to innovation during a time of great change in the scientific publishing field

  • service to and leadership in the neuroscience community (e.g., SfN committees)

  • evidence of good management skills and the ability to lead colleagues on an editorial board

  • for New Journal: the capacity to proactively engage on a start-up venture, and to innovate and lead in the creation of a high quality open access neuroscience journal, and guide it on a path to success

  • for The Journal of Neuroscience: the capacity to build on an established record of success, while continuing to evolve a leading journal in the field and take it to the next level

Interesting next step for the SfN. Obviously reflects some thinking that they may be left behind (even further, see diminishing reputation after the launch of Nature Neuroscience and Neuron) in the glorious New World Order of Open Access publication. Might just be a recognition that Open Access fees for a new journal when all the infrastructure is already there is going to be a cash cow for the Society from the beginning.

What I will be fascinated to see is where they pitch the New Journal* in terms of impact. Are they just trying to match JNeuro? Will they deliberately go a little lower down the feeding chain to avoid undercutting the flagship journal?

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*my suggestion of Penfield must have been too esoteric a reference.....

13 responses so far

BRAIN Initiative

I just watched part of a live stream [current link] of some meeting to brainstorm about what the $100M BRAIN Initiative should be.

What at a disaster.

Bunch of reinforcement that this is all about a bunch of senior dudes (mostly male dewds too) in neuron-recording neuroscience who used to make out like bandits from NIMH support. Now that we've undergone a long slide in funding levels and Insel's push to translational-ize the NIMH portfolio has gained the upper hand...these folks are struggling to get grants. JUST. LIKE. THE. REST. OF. US.

and they can't come up with anything amazing by themselves so they need $100M cash money to build some new recording tools to....you guessed it, record some more neurons.

Outside of the regular grant process because they find it hard to compete these days. JUST. LIKE. THE. REST. OF. US.

I have a proposal. Let's throw down, what, maybe $1M to record symposia and meetings of these people for the next year. Maybe have a few more of these summits. And after all that, if they've come up with some thing that is ACTUALLY NEW AND INTERESTING then and only then do we give them the $99M.

UPDATE: Permalink

35 responses so far

Failure to Replicate

I should have put that in quotes because it actually appears in the title of this new paper published in Neuropsychopharmacology:

Hart AB, de Wit H, Palmer AA. Candidate gene studies of a promising intermediate phenotype: failure to replicate. Neuropsychopharmacology. 2013 Apr;38(5):802-16. doi: 10.1038/npp.2012.245. Epub 2012 Dec 3. [PubMed]

ResearchBlogging.orgfrom the Abstract alone you can get a sense

We previously conducted a series of 12 candidate gene analyses of acute subjective and physiological responses to amphetamine in 99-162 healthy human volunteers (ADORA2A, SLC6A3, BDNF, SLC6A4, CSNK1E, SLC6A2, DRD2, FAAH, COMT, OPRM1). Here, we report our attempt to replicate these findings in over 200 additional participants ascertained using identical methodology. We were unable to replicate any of our previous findings.

The team, with de Wit's lab expert on the human phenotyping and drug-response side and Palmer's lab expert on the genetics, has been after genetic differences that mediate differential response to amphetamine for some time. There's a human end and a mouse end to the overall program which has been fairly prolific.

In terms of human results, they have previously reported effects as varied as:
-association of an adenosine receptor gene polymorphism with degree of anxiety in response to amphetamine
-association of a dopamine transporter gene promotor polymorphism with feeling the drug effect and diastolic blood pressure
-association of casein-kinase I epsilon gene polymophisms with feeling the drug effect
-association with fatty acid amide hydrolase (FAAH) with Arousal and Fatigue responses to amphetamine
-association of mu 1 opioid receptor gene polymorphisms with Amphetamine scale subjective report in response to amphetamine

There were a dozen in total and for the most part the replication attempt with a new group of subjects failed to confirm the prior observation. The Discussion is almost plaintive at the start:

This study is striking because we were attempting to replicate apparently robust findings related to well-studied candidate genes. We used a relatively large number of new participants for the replication, and their data were collected and analyzed using identical procedures. Thus, our study did not suffer from the heterogeneity in phenotyping procedures implicated in previous failures to replicate other candidate gene studies (Ho et al, 2010; Mathieson et al, 2012). The failure of our associations to replicate suggests that most or all of our original results were false positives.

The authors then go on to discuss a number of obvious issues that may have led to the prior "false positives".

-variation in the ethnic makeup of various samples- one reanalysis using ancestry as covariate didn't change their prior results.

-power in Genome-Wide association studies is low because effect sizes / contribution to variance by rare alleles is small. they point out that candidate gene studies continue to report large effect sizes that are probably very unlikely in the broad scheme of things...and therefore comparatively likely to be false positives.

-multiple comparisons. They point out that not even all of their prior papers applied multiple comparisons corrections against the inflation of alpha (the false positive rate, in essence) and certainly they did no such thing for the 12 findings that were reported in a number of independent publications. As they note, the adjusted p value for the "322 primary tests performed in this study" (i.e., the same number included in the several papers which they were trying to replicate) would be 0.00015.

-publication bias. This discussion covers the usual (ignoring all the negative outcomes) but the interesting thing is the confession on something many of us (yes me) do that isn't really addressed in the formal correction procedures for multiple comparisons.

Similarly, we sometimes considered several alternative methods for calculating phenotypes (eg, peak change score summarization vs area under the curve, which tend to be highly but incompletely correlated). It seems very likely that the candidate gene literature frequently reflects this sort of publication bias, which represents a special case of uncorrected multiple testing.

This is a fascinating read. The authors make no bones about the fact that they've found that no less than 12 papers that they have published were the result of false positives. Not wrong...not fraudulent. Let us be clear. We must assume they were published with peer review, analysis techniques and samples sizes that were (and are?) standard for the field.

But they are not true.

The authors offer up solutions of larger sample sizes, better corrections for multiple comparisons and a need for replication. Of these, the last one seems the best and most likely solution. Like it or not, research funding is limited and there will always be a sliding scale. At first we have pilot experiments or even anecdotal observations to put us on the track. We do one study, limited by the available resources. Positive outcomes justify throwing more resources at the question. Interesting findings can stimulate other labs to join the party. Over time, the essential features of the original observation or finding are either confirmed or consigned to the bin of "likely false alarm".

This is how science progresses. So while we can use experiences like this to define what is a target sample size and scope for a real experiment, I'm not sure that we can ever overcome the problems of publication bias and cherry picking results from amongst multiple analyses of a dataset. At first, anyway. The way to overcome it is for the lab or field to hold a result in mind as tentatively true and then proceed to replicate it in different ways.

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UPDATE: I originally forgot to put in my standard disclaimer that I'm professionally acquainted with one or more of the authors of this work.

Hart, A., de Wit, H., & Palmer, A. (2012). Candidate Gene Studies of a Promising Intermediate Phenotype: Failure to Replicate Neuropsychopharmacology, 38 (5), 802-816 DOI: 10.1038/npp.2012.245

19 responses so far

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