Wednesday Notes

On the agenda for today
8am, everywhere This morning I will mainly be bricking it prior to my poster presentation. Chase et al: Attentional set formation is vulnerable to deficits in reversal learning, but is not disrupted by orbital prefrontal cortex lesions (805.10, board JJJ36).

Morning Posters
Unfortunately, I’m not really going to get to see any posters this morning, but were that not the case, this is what I’d be seeing.
Green et al: Prenatal stress increases stress-reactivity and impairs fear extinction after adult stress: A model of PTSD (809.11, board LLL20)
Nieves-Martinez et al: Aged rats impaired in reversal learning and set shifting have reduced muscarinic receptor activation of G-proteins in dorsomedial striatum (805.3, board JJJ29)

13:00, Room 6F Control of Behaviour by Neurotransmitter Signalling

Afternoon Posters
Christen et al: Long-range integration of emotional prosody and spatial attentional processes is mediated by amygdalo-orbitofrontal synchronization (909.9, board LLL14)

Tags: SfN 2010 to-do

Wednesday Notes

On the agenda for today
8am, everywhere This morning I will mainly be bricking it prior to my poster presentation. Chase et al: Attentional set formation is vulnerable to deficits in reversal learning, but is not disrupted by orbital prefrontal cortex lesions (805.10, board JJJ36).

Morning Posters
Unfortunately, I’m not really going to get to see any posters this morning, but were that not the case, this is what I’d be seeing.
Green et al: Prenatal stress increases stress-reactivity and impairs fear extinction after adult stress: A model of PTSD (809.11, board LLL20)
Nieves-Martinez et al: Aged rats impaired in reversal learning and set shifting have reduced muscarinic receptor activation of G-proteins in dorsomedial striatum (805.3, board JJJ29)

13:00, Room 6F Control of Behaviour by Neurotransmitter Signalling

Afternoon Posters
Christen et al: Long-range integration of emotional prosody and spatial attentional processes is mediated by amygdalo-orbitofrontal synchronization (909.9, board LLL14)

Tags: SfN 2010 to-do

Is reversal learning a useful test of cognition?

Here’s the thing about reversal learning: it means different things to different people. I’ve blogged on that before. But even among those who, in my opinion, define it correctly, there’s disagreement over what cognitive processes underlie learning to respond to something that was previously negatively correlated with reward.

In quite an elegantly designed touchscreen experiment, James et al (512.6) attempted attempted to tease apart two component psychological processes of learning to reverse: perseveration - or habitual responding to the previously rewarded stimulus - and learned avoidance (though I prefer the term “learned non-reward”: I feel like “avoidance” implies they are being punished, which is often not the case) - or a reluctance to respond to a stimulus that was previously negatively correlated with reward.

Rats performed three types of three-choice reversals: classic reversal - where rats learn “A not B, C is irrelevant” and then reverse to “B not A, C is irrelevant” - perseverative reversal - where rats learn “A not B, C is irrelevant” then “D, not A or C” - and learned non-reward reversals - where rats learn “A not B, C is irrelevant” then reverse to “B, not C or D”. While it’s possible to detect which stimulus the rat is responding to based on where he touches the screen, by replacing either the previously rewarded or previously non-rewarded with a neutral novel stimulus, it is possible to more accurately measure what drives up the number of trials needed to learn a discrimination reversal. In the classic reversal condition rats made more perseverative errors than learned non-reward errors, however when the two component processes are separated in the other two conditions, accuracy improves overall. This suggests that, while perseveration may make up the bulk of the errors during reversals, learned non-reward is also important.

The tempting inference to draw from these data is that animals with reversal impairments follow the same pattern of responding as do James et al’s intact rats, but this is not always the case. Riceberg and Shapiro (404.17), for example, used a plus-maze to test reversal learning: first rats learned to always navigate to the North, and then they reverse to always go to South. When rats only have two choices to make, it is very difficult to make inferences regarding perseveration, so the authors transferred the experiment to an 8-arm radial maze. Rats with lesions to the orbital prefrontal cortex were impaired at reversing on both versions of the task, but in the radial maze they made no more perseverative errors than control rats: instead they made more incorrect entries to arms that were never correlated with reward.

This finding fits in quite well with my poster (805.10), which I’m presenting tomorrow morning. Much as Riceberg and Shapiro’s rats responded to irrelevant arms during reversal rather than perseverate, my lesioned rats have difficulty forming an attentional set, which may be due to an impaired ability to recognise the relationship between relevant and irrelevant stimuli.

But OPFC lesions are only a small part of the story. At this year’s meeting I’ve seen reversal deficits reported after chronic stressful exposure to cold temperatures (Furr et al, 697.10), acute ketamine challenges (Gastambide et al, 665.10), microinjections of corticotropin-releasing factor (Snyder et al, 697.6), chronic THC exposure (Stenson et al, 363.17)… The list goes on. If the causes are different, then the precise cognitive explanation for the behaviour may also be different.

Reversal learning will always be a useful test of cognition for translational neuroscience due to the long history of reliably produced reversal deficits in human diseases. However, without better answers to the questions “why are your reversals impaired?” and “what are your animals actually learning/doing?” we aren’t getting all the information that we can from this measure.

Tags: SFN 2010

Neuroscientists make good targets

Between 1997 and 2007 the number of law schools offering courses focussed on animals went from ostensibly zero to over one hundred, law journals offering essays and reports on animal cases have steadily increased, and suits on behalf of animal owners - and sometimes even the animals themselves - have become more common.

In “Conferring Legal Rights to Animals: Research in the Crosshairs”, a distinguished panel of lawyers, law professors and neuroscientists presented an often overlooked facet of the animal rights movement: some extremists have traded bullhorns and violence for gavels and lawsuits.

Joyce Tischler, founder of the Animal Legal Defence Fund, likens the legal struggle for animal rights to that undertaken by the NAACP throughout the Civil Rights Era: the rights of the oppressed minority (in this case animals instead of African Americans) can be expanded and enshrined in law by exposing the injustices they suffer to sympathetic judges. The important thing to note about this philosophy is that Tischler, and others like her, recognise that the Civil Rights Era was not started and finished by Brown vs Board of Education; but rather by a long campaign of smaller court cases - some won and many lost - to achieve the larger goal by small, incremental change.

If a vet killed your pet through negligence should you be able to sue for emotional damages? This is one of the major issues currently facing animal law: for many of us pets are real members of the family, and losing them - particularly through veterinary malpractice - would be horrifying. Phrasing the issue like this is makes it difficult to disagree with, however the hidden consequence to granting pet owners the right to sue vets for emotional damages is that it further establishes the legal standing of animals as being similar to people (at least in US law, animals are literally property). This is an increment of change towards the end goal of granting true “personhood” to all animals: pet ownership would be akin to slavery, eating meat akin to cannibalism, and scientific research akin to torture and murder.

In Europe, this legal battle is already taking some casualties. Recently a revised EU directive governing animal research was ratified (2010/63 EU), and it contains several clauses which are dangerously open to interpretation. Take Article 8 section 1a, for example, which limits the use of non-human primates:

[N]on-human primates shall not be used in procedures, with the exception of those procedures meeting the following conditions: [the procedure is] undertaken with a view to the avoidance, prevention, diagnosis or treatment of debilitating or potentially life-threatening clinical conditions in human beings…

Now consider these posters from yesterday’s sessions:

Ikeda et al (506.23) examined marmosets’ performance on an object retrieval with detours task to test the effects of several antipsychotics. This task requires executive control to plan an appropriate course of action to retrieve a food reward by reaching into a box with only one opening. Lurasidone, a second-generation antipsychotic with antagonistic properties at the dopamine D4 receptor, improved marmosets’ ability to plan while other common antipsychotics like olanzapine and haloperidol did not. I’d say it’s fairly clear that was undertaken with a mind towards finding treatments for the “debilitating and potentially life-threatening” condition of schizophrenia.

But how about Porter et al (506.92)? This poster reported data from rhesus macaques who had previously been given self-administration access to cocaine for 11 months. Even after several months of abstinence from the drug, cognitive deficits were seen in these animals: for example cocaine-experienced animals committed more premature responses on a six-choice serial reaction time task - which the authors argue may indicate an orbitofrontal-linked impairment in inhibiting behavioural responses. This experiment certainly has implications for addiction, but it could definitely be argued that this experiment was not conducted with curing addiction in mind. Would it have been allowed under the new EU directive?

Finally, consider Hecht et al’s (513.6) diffusion tensor imaging study of rhesus macaques, chimpanzees, and humans. The authors were able to trace the neuroanatomical connections of the mirror neuron systems in these three species. Their results demonstrate that the macaque system lies more ventrally than the chimp and human systems, with humans being the most dorsal. The conclusion offered from these data is that the macaque mirror neuron system mostly occupies those areas previously associated with goal representation, whereas the chimp and (especially) human systems occupy areas associated with the representation and generation of bodily movements. This has absolutely nothing to do with human disease, but it provides an invaluable neuroanatomical hypothesis for why only humans and chimpanzees can learn by imitating the actions of others: the best other non-human primates can do is “emulate”, or learn by focussing on other’s results.

I’ll close with a thought offered yesterday by Dr Michael Conn, associate director of the Oregon National Primate Research Centre: neuroscientists get targeted by animal rights extremists because pictures of our research can look horrifying when taken out of context or given a false explanation. We owe it ourselves, our colleagues and the public to explain what we do, how we do it and why it is right. That means explaining these “horrifying” images for what they really are, but it also means standing up for basic research. It’s easy to win the public’s hearts and minds by highlighting the work that directly leads to curing human disease, but through this we run the risk of tacitly implying that research which does not directly focus on human disease is worthless, or at least “less right”. This is patently untrue.

The vagueness surrounding the definition of “not directly focussed” will be the next legal battle facing animal research, and if neuroscientists don’t write that law, the animal rights movement will. If we don’t protect basic research, we may lose our ability to do everything else.

Tuesday Notes

The satellite symposium on “my hangover” is currently taking place in Panera. I blame the good people at #sfn10banter and @sfnposterface. Grumble grumble grumble.

On the agenda for today

Morning Posters
Homberg and Nonkes: Improved cognitive flexibility in the serotonin transporter knockout rat is not affected by chronic cocaine self-administration (574.19, board LL1)
Turchi et al: Effects of orbitofrontal and rhinal cortex lesions on relearning the rule for win-stay/lose shift, a prerequisite for performing one-trial stimulus-reward association (606.2, board LLL32)

Afternoon Posters
Whitt et al: Impaired reality testing in an animal model of schizophrenia (707.10, board MMM12)
Ainge et al: Lateral entorhinal cortex is activated by memory for object-context associations (708.9, board MMM37)

17:15, Ballroom 20 Tuning Depression Circuits Using Deep-Brain Stimulation

Tags: SfN 2010 to-do

Monday Notes

*Fun fact: this post has been ready to go since 8:30, but my computer just didn’t feel like going on the internet this morning, so it had to wait. Apologies*

You know you’ve been busy when 8am is a solid lie-in. Incidentally, have you tried the beers at Rock Bottom Brewery and Restaurant? I tried several last night…

On the agenda for today
9am, Room 11 While “Conferring Legal Rights to Animals: Research in the Crosshairs” sounds like something that I need to read in the ‘movie trailer voiceover voice’, I’m sure this will actually be a fascinating discussion about the animal welfare debate. Welfare is a topic that neuroscientists (quite rightly) talk about a lot, but this is the first time I’ve seen one of these talks from a legal/litigation perspective. This abstract also contained that most beautiful of phrases: “breakfast will be served”.

Morning Posters
Haney et al: Neural activity in orbitofrontal cortex reflects a real-time estimate of rats’ expectations for reward (404.18, board MMM19)
Crockett et al: Serotonin modulates human moral judgment and behaviour (403.2, board LLL58)

Afternoon Posters
Maclaren et al: Investigating the effects of lesions of the cholinergic mesopontine tegmentum on the locomotor response to nicotine (491.13, board CCC14)
Enomoto et al: Reducing prefrontal cortical GABA activity induces cognitive, behavioral and dopaminergic abnormalities that resemble those observed in schizophrenia (507.10, board MMM7)

Rest of the Evening
Bloggers and Neuro-Tweeps Engaging Recreationally: B.A.N.T.E.R. BOOM!

Tags: SfN 2010 to-do

Sunday Notes

On the agenda for today

8am, Room 2
Starting out today at the Neural Bases of Reward nano (centi? pico? deci?) symposium. Looks like we’re going to get a little serotonin transporter gene, a little risk-based decision making, some cheeky interpersonal attraction and then round it all off with some chat on obesity. Hearing about how rewarding food can be is just what I need after skipping breakfast.

Morning Posters
Dahlgren et al: Marijuana use and age of onset impacts performance on the Wisconsin Card Sorting Task (165.9, board AA6)
Greening et al: Dissecting the neural architecture of reversal learning: overcoming avoidance versus inhibiting responding (198.8, board III32)

Afternoon Posters
Padmala and Pessoa: Reward reduces conflict by enhancing executive function and suppressing task-irrelevant information (301.1, board KKK40 - really, SfN, we have 70 “KKK” boards?)
Walsh et al: 6 hours REM sleep restriction does not affect concurrent spatial and reversal learning in the Morris Water Maze (300.16, board KKK24)

Tags: SFN 2010 to-do

The Point of Conferences

While I was making my way through the Parkinson’s disease posters today, I bumped into a friend whom I hadn’t realised was at the conference. Her presence shouldn’t really have surprised me - I actually added her poster to my to-do list just a few short days ago - but it still (pleasantly) caught me off guard. After she rightly pointed out that Theme C was a bit of a detour for me, we started chatting about what has become my favourite thing about poster sessions: as much as I love finding posters presented by people who do similar work to mine, my favourite posters are the ones from completely different areas which have - almost coincidentally - produced data that affect how I think about my work.

I didn’t get much time on the poster floor today, but most of the time I did have I spent taking notes on Ko and colleagues’ poster (51.15) which, for most people, was about prefrontal dopamine transmission in Parkinson’s disease. The authors used PET scanning to measure D2 receptor occupancy - a proxy measure of dopamine activity - in Parkinson’s patients (n=8) and controls (n=6) performing two tasks derived from the Montreal Card Sort Task. The first, or “active” task required participants to sort the cards by a different rule on every stage: for example first by shape, then by colour, then by number. The second, or “control” task required participants to always sort cards by one rule only.

When I spoke with Ko, he seemed excited to report that DA activity in the orbital prefrontal cortex (OPFC) didn’t change between the two tasks in the PD group, and that global DA activity - as you might expect - was reduced in PD patients. But I was much more excited to see that OPFC DA activity did change between the two tasks in his control group. You see, for me, this poster wasn’t about PD at all, but rather about the role of the OPFC in the formation of attentional-set (which, as some of you may have already noticed, is what my poster - 805.10, board JJJ36 - is about on Wednesday).

On the face of it, Ko et al’s ‘active’ task employs executive function by requiring participants to shift between sorting rules on every stage, while the ‘control’ task requires no rule-shifting, and therefore isn’t mediated by executive function. However, this is not actually the case, and both tasks will employ some degree of executive control*. By requiring participants to only ever sort the cards by one rule in the ‘control’ task (e.g. by colour), the participants will gradually start to ignore the other aspects of the card stimuli (e.g. shape and number). We refer to this as the formation of attentional-set: a predisposition to attend only to the relevant features when discriminating between complex stimuli. Ko et al’s data suggest that DA levels in the OPFC are higher during attentional-set formation than when every stage has a new rule. As I’ll discuss in more detail on Wednesday, this fits in well with my data that rats with lesions to the OPFC are poorer at forming attentional-set than controls.

Two posters, from two different themes, on seemingly unrelated topics, fitting together in some bigger-picture neuroscience. Is there anything better?

*I think Ko and his colleagues were made aware of this prior to the meeting, because in their abstract the tasks are described as “executive” vs “control”, while the poster named them “active” vs “control”

Saturday Notes

Precariously positioned puh-puh-puh-puh-poster-puh-puh-poster tubes have become the norm in downtown San Diego. The number of dinner-goers and bar-hoppers wandering the Gaslamp District with their badges still around their necks for no good reason has been steadily increasing. The #sfn10banter is approaching ‘Platinum’ status.

It’s finally Saturday, folks: time to get involved.

I poked my head in the convention centre yesterday to pick up the traditional cheap-as-chips tote bag and the daily books. There was something vaguely unsettling about the relative lifelessness of the corridors: were it not for the odd vendor in panicky-setup mode (or SfN employee in calm-before-the-storm mode), my friend and I would have been the only ones roaming the halls. The conference wants its delegates…

On the agenda for today

11am: Ballroom 20 
As if I needed to tell you, Glenn Close is giving the keynote speech on her mental health advocacy this morning. Changing the publics’ misconceptions about mental illness is one of the most important - and difficult - issues we face. I’ll be front-row-centre for this, attempting to pay attention and not just sing Dr John’s “Cruella De Vil” in my head throughout.

Afternoon Posters
Ilieva et al: Adderall’s perceived and actual effects on healthy people’s executive function (95.11, board III19)
Rygula et al: Serotonin depletions within the amygdala and orbitofrontal cortex impair probabilistic discrimination learning in marmosets (103.11, board LLL29)

I’m having a quiet start to the conference, actually. I might have to fill out my time by browsing the Exhibit Guide and finding some choice freebies; or by exploring the surrounding area. I noticed that there’s a Nobu right across the street: I wonder if I can find a way to write that off as a business expense…

Awesome: Viagra may increase anti-psychotic efficacy

Sildenafil adjunctive therapy to risperidone in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled trial Akhondzadeh et al (2010). Psychopharmacology (Online First)

Ok, ok. Let’s get the lolz at of the way right at the start. This is a study looking at the potential for sildenafil - yes, the erectile dysfunction drug better known as ‘Viagra’ - to work as a viable adjunctive therapy for schizophrenia.

[Insert your favourite Viagra joke here].

Ok, now let’s get serious. Broadly speaking, current anti-psychotic medications aren’t great at ameliorating the negative symptoms of schizophrenia: positive symptoms like delusions and hallucinations appear to be much easier to treat than, for example, disorganised thoughts and poor executive control. Recently, some second-generation antipsychotics have been shown to be cognitively enhancing in rats (like here and here), but unfortunately most antipsychotics do not appear to help cognition in schizophrenia.

The most obvious solution to this is to find better antipsychotics, and the end goal will always be to find one drug that improves both the positive and negative symptoms in schizophrenics, whilst causing minimal side-effects. For the time being, however, much focus has been given to adjunctive therapies: combining one medication for the positive symptoms with a separate medication for the negative symptoms, and then measuring the combination’s efficacy and tolerability.

This article presents the hypothesis that PDE5 inhibitors may serve to ameliorate NMDA receptor hypofunction, which is associated with negative symptoms in schizophrenia. Given that the PDE5 inhibitor sildenafil is already FDA approved and easily obtainable, it represents an obvious choice for a clinical trial. Thirty-six men and four women with chronic schizophrenia were given either once-daily tablets of sildenafil slightly higher than those prescribed for erectile dysfunction, or a placebo, in addition to their normal risperidone treatment.

Over the course of 8 weeks, the positive symptoms seen in both groups did not differ, but the group receiving sildenafil showed a significant reduction in the severity of negative symptoms. Seriously cool.

Viagra combination therapy probably isn’t going to become a treatment norm for schizophrenia: besides the obvious side-effect of - ahem - vasodilation in the corpus cavernosum, it is not entirely clear that the PDE5 inhibitors currently approved as erectile dysfunction drugs are completely safe and effective when added to antipsychotics. For this we would need larger clinical trials lasting for longer periods of time, and the inclusion of common antipsychotics besides risperidone. Nevertheless, this is an interesting proof-of-concept that PDE5 inhibition can improve cognitive deficits in schizophrenia.