Understanding Social Behaviour in Research – Why we should remember RAT PARK

14 NOV 2016

One of the major aims of scientific investigation is to improve human lives, particularly our health. One of the best current tools for improving human health is the animal model, though there is a lot of ongoing work into alternative methods. An animal model is a representative living system that can be manipulated to reflect a particular condition or illness. Rodents are popularly used due to many factors including size, breeding rates, and the ease at which they can be altered in genetically meaningful ways. However, it is important to remember that rodents cannot be considered a tool in the same manner as a microscope as they are living organisms with their own set of behaviours. This may seem obvious or even silly to mention, but experiments that have not considered this important aspect of the animal model have affected our ability to improve human health.

    An excellent example of this is in the field of drug addiction studies which allowed animals to self administer recreational drugs which were common in the 1950’s and 60’s. These consisted of socially isolating each animal to prevent animals from damaging equipment and hindering each other’s surgical recovery. The results of such studies caused investigators to conclude that drug addiction was not only instant but impossible to stop. A research group from Simon Fraser University considered such experiments in the context of the human condition. Knowing that rats and humans are social animals, they considered the impact that social isolation may play in producing these results. After all, how would you respond to an endless supply of drugs and nothing else?

    To this end they built a free range environment they named ‘rat park’ and split the rats into two groups. One group lived in the free range rat park environment and the second group lived in classical single caged environments. Their results showed that not only were the rat park animals better at coping with addiction but they were also more resilient to becoming addicted in the first place. This is very important to understanding human addiction as it is clear that there is more to addiction than simply a supply of drugs.This example illustrates how animal models can be much more informative tools to medicine when their social behaviour is considered as an important factor.

For more information on Rat Park have a look at Prof Bruce Alexander’s website.

Or this comic by Stuart McMillan.

The header image was sourced from: http://www.stuartmcmillen.com/comics_en/rat-park/#page-1

A Step-by-Step Guide to convincing Mom it’s Dad’s fault–with Science!

(You do want to seem like the reasonable one here, right?)

Kira Rienecker | 30 AUG 2016

mrsfields-sandwich-product
Link to Image Source

Let’s say it’s a hot summer day (As an American, the chances of such a day seem slim in Britain, but let’s roll with the hypothetical here), and you have in your hand an exquisite ice cream sandwich–cool and sweet, with the mist of a sub-zero freezer still rising off it.

Now let’s say a pesky younger sibling didn’t think to get his own, and you now stand (ahem–fairly) accused of not sharing, under threat of dire punishment.

How do you convince Mom your behaviour is Dad’s fault?

(Preferably before this lovely ice cream sandwich melts away!)

STEP 1: Argue behaviour has some genetic roots

Behaviour is a difficult trait to pin to a genetic origin. It is a complex, emergent property of the brain, influenced by many other confounding factors, like culture, experience, and social context. However, we do have experimental models that demonstrate behaviour does have some genetic roots. For example, some knock-out models, in which we delete a gene from a model organism such as a rodent, demonstrate altered fundamental behaviours.

The behaviours we can measure in model organisms are simple compared to the behaviours Mom is paying that child psychologist to sort out. We need to focus on measures we can easily quantify. Research in behavioural genetics includes measures of dominance vs subordinance, ease of movement and levels of activity, time exploring novel environments, anxiety, sexual behaviour, satiety, impulsivity, and compulsivity, among others.

We also know that some of the genes or clusters of genes, when missing in humans, cause neurodevelopmental disorders with characteristic behavioural changes. For instance, Prader Willi Syndrome (PWS), in which the gene rich chromosome region 15q11-q13 (paternal origin) is disrupted, is associated with a distinct behavioral profile. This includes mild cognitive deficits, insensitivity to pain, tantrums, obsessive tendencies, a compulsive desire to eat, and in some cases psychosis [Davies 2007, Perez 2010].

But missing (or indeed extra) bits of chromosomes aren’t the only reason we might see behavioural variation in humans. Natural genetic variation may explain some (but not all) of the statistically normal range of human behaviours. Someone may have a higher or lower IQ, be more or less impulsive, seek more or less novelty, or be more or less anxious and still be within a range considered ‘typical’, and not pathological [Nuffield 2002, Plomin 2016]. Some might, conceivably, be more or less likely to share their ice cream with their younger sibling…

STEP 2: Point out that Mom’s & Dad’s genomes contribute differently to the brain.

Some behaviours, notably those which relate to mothering behaviour, and altruism (how likely you are to share your ice cream sandwich), may be more Dad’s fault than Mom’s.

But wait! Both Mom and Dad give you a copy of each gene… shouldn’t they contribute equally to how you turn out?

As it turns out, a subset of genes, called imprinted genes, will selectively express (use) only the copy from one parent! Remember Prader Willi Syndrome (PWS)? The particular set of symptoms for this disease only appear if the disrupted chromosome region was inherited from Dad. If this same disrupted region was instead inherited from Mom, it manifests as Angelman’s Syndrome (AS), which has a very different character. AS is characterized by mental retardation, ataxia, epilepsy, a ‘happy’ disposition and repetitive or stereotyped behaviours [Davies 2007, Perez 2010, Bird 2014].

These diseases each result from disruptions in the same DNA region, but the results differ depending on whether this disruption is in the copy of the region from Mom or Dad. This is because some genes in the region normally only express one parent’s version to make what the gene encodes. If the copy the gene normally doesn’t use is missing, no big deal! You weren’t using it anyway. BUT, if the copy the gene exclusively uses is missing, BIG DEAL. The other copy of the gene won’t get the cue to come up to bat, and you’ll use neither version.

Because some genes in the PWS/AS region of the DNA are only expressed from Mom’s copy and others are only expressed from Dad’s copy, problems with the region inherited from one parent will cause a different set of symptoms than problems with the region inherited from the other [McNamara 2013, Cassidy 2000].

Theoretically, then, this could distinguish the impact Mom and Dad each have on your failure to share that ice cream sandwich.

Evolutionarily speaking, imprinting would seem to be a disadvantage. Why would you limit yourself to using only one copy (haploid) when you could use two (diploid) and have a backup? That imprinted genes exist among many species implies a strong natural selection for this mechanism is present, overcoming the disadvantage of functional haploidy (when, for functional purposes, you appear to have only one copy) [Wilkins 2016]. If expression of a particular gene benefits the survival and reproductive success of those using Dad’s copy more than those using Mom’s, natural selection will favor silencing Mom’s and using Dad’s.

But remember, they’re the same gene! Why would Dad’s help you out more than Mom’s (or vice versa)? Often, this is because the same gene can help out the propagation of Dad’s genetic line more than Mom’s (or vice versa).

First of all, let’s look at the arms race going on in the placenta. Mom’s genome and Dad’s genome both want this kid to survive, but Mom has to use the same machinery to produce as many of her kids (with her genetics) as she can, whereas Dad can piggyback the machinery of multiple women to produce kids with his genetics (as much as Mom may disapprove). Therefore, Mom’s and Dad’s genomes have very different strategies during pregnancy. It’s in the best interests of Dad’s genes to suck as many resources out of Mom as possible, to ensure the survival and success of his kid during pregnancy. Mom’s genes, on the other hand, need to carefully parse out what resources she has, so she doesn’t spend it all on just one kid. If she only has one ice cream sandwich, she wants both kids to be happy, so she’s forcing you to share.

What results from the placental arms race is a method of imprinting referred to as intra-locus conflict, where one copy of a gene is active and the other silent. For example, the gene Ifg2 increases the ability of nutrients to passively diffuse across of the placenta. The more nutrients that pass from Mom, through the placenta, to the kid, the more the kid can grow [Sibley 2004]. This is great for Dad’s genes, but potentially damaging for Mom’s! Dad’s genes will be propagated best, according to the restrictions of natural selection, if it keeps this gene ‘on’, producing more protein product and getting as much out of Mom for this kid as possible. Mom’s genes, however, will be propagated best (by limiting the resources she doles out), if she doesn’t allow two copies of Igf2 to be running in the placenta at the same time. Dad’s is already on, so Mom shuts her copy down.

So Mom & Dad contribute copies of the same genes, but these contributions aren’t functionally equivalent–they are complementary. They also contribute differently to different tissues. Relevant to your ice-cream behavioural argument, Dad’s genes seem to contribute more in the brain! In the adult mouse brain, only 37% of the sum total of imprinted genes (whose use is biased towards only one parent’s copy) use Mom’s copy exclusively [Wilkins 2016]. The distribution of parental contribution within regions of the brain exaggerates this difference even more: Mom’s genome appears to contribute more towards the cerebral cortex (important for planning, executive decisions, and higher brain function), whereas Dad’s contributes more towards the hypothalamus and other deep midbrain structures (important for more ‘primitive’ behaviours such as reward-response, motivation, and homeostasis) [Keverne 1996].

Let’s say Mom invites you to proceed with your argument.

STEP 3: Illustrate which behaviours are Dad’s fault.

Let’s also consider sex-biased dispersal patterns in populations [Wilkins 2016, Ubeda 2010]. Mom’s and Dad’s genomes might also have different success rates if a population is more likely to share one parent than the other. A pride of lions, for example, is made up of many females and one male. The cubs in the pride all share genes through their Dad’s side, so most of the genetic differences between them come from Mom’s side. In this case, once the cubs are born (after Dad’s genes demand as much from Mom’s resources as possible), Dad’s genes will be propagated best if the cubs behave cooperatively. Cooperation tends to increase the group’s overall survival rate, and because the group shares Dad’s genes, Dad’s genes do well if the group does well. Mom’s genes, on the other hand, are competing with those of all the other Moms in the group. This competition means Mom’s genes have the best chance of being passed on to the next generation if they give the individual cub an advantage over the other cubs in the pride.

Lion_Pride_leader
Sex biased dispersal in a pride of lions means you are more likely to share dad than mom. Link to Source.

This difference between group and individual success creates a battle between Mom’s and Dad’s genomes. One way they can battle is through aspects of behaviour. In this pride of lions, Dad’s genes will promote altruism–the sharing of resources among the group to promote the survival of paternal siblings–and Mom’s genes will promote more selfish behaviour–benefiting the individual [Wilkins 2016].


This is where you can see your argument starting to fall apart in Mom’s eyes…

STEP 4: While grounded, sans-ice cream sandwich, consider where you went wrong.

First, consider that humans do not display the particularly female-biased dispersal pattern of a pride of lions, and this train of thought may have been influenced by your recent viewing of “The Lion King”.

Not only might this comparison to a patriarchal system offend your mother’s feminist sensibilities (female lions do most of the work in the pride anyway), but such a suggestion implies you are arguing is your selfish behaviour is really her fault (Though Úbeda et al 2010 do predict this is the case for hominids).

Alternatively. you could have tried the reverse argument, that Dad’s genes cause your selfish behaviour and Mom’s your altruistic behaviour. In the case of multiple paternity, it is in the interest of Mom’s genes to keep the siblings working together while Dad’s genes help them compete [Wilkins 2016, Haig 1992] . Unfortunately this could also have landed you in trouble, because you would then have suggested that you and your sibling don’t share the same Dad, which may or may not disturb your family dynamic.

Secondly, while these genes appear to contribute to some of the basic fundamentals of behaviour, human behaviour is ultimately complex, and we are unlikely to be able to use biology to predict its intricacies at the social level.

Piecing out the genetic contribution to behaviour is tough: one gene may contribute to many behaviours, and multiple genes may contribute to the same behaviour (polygenic). It is highly unlikely we will find “a gene for X”, where “X” is criminality, mothering, or hyperactivity etc. Even where different variants of a gene (alleles) can be shown to impact behaviour, factors such as environmental context, including early life stress, training, social environment, and culture can mediate this impact. Your genes may predispose you to a certain range in the spectrum of normal behaviours, but your outcome is alterable, and this predisposition will not dictate your fate [Nuffield 2002].

Imprinted genes introduce even more complexity. Sometimes the imprinting mark doesn’t result in simply the whole gene being singularly maternally or paternally expressed. Genes can produce several different messages, called transcripts, from the same sequence of code. Imagine this as a recipe for ice cream with optional ingredients (chocolate syrup, strawberries, peppermint dust). Including or excluding different combinations of those ingredients generates slightly different products from the same recipe. Transcripts can have their own imprinting sub-status, which manipulates the relative abundance of the different output versions. Depending on how the marks themselves change, the ratios of these different messages can change dynamically throughout development and between different tissue types [Wilkins et al 2016].

Step-By-Step Guide to Convincing Mom it's Dad's fault Ice Cream Diagrams 21-8-16 250 jpeg
While the original recipe calls for four ingredients, like a gene lays out all of its exons, you can get different products at the end by leaving out some items. Original Image.

Finally, the human genome and the human brain are quite robust systems.

The law treats one’s actions as autonomous and willed. Any criminal defense (including charges of failure to share ice cream) relying upon behavioural genetics must demonstrate the force of a genetic deficiency or variant to be greater than one’s autonomy [Nuffield 2002].  Your genome (the collection of all genes in your DNA) and your brain have many redundant systems in place to compensate for things that may go wrong–they are robust to minor variations and disruptions. Unless you have a clear neurodevelopmental or mental health disorder with distinct behavioural differences demonstrated across other patients, you are likely within the normal range of human behaviour, and therefore can’t use this argument as an excuse. Under the fundamental assumptions of the criminal justice system, you have adequate knowledge of right and wrong as well as control of your own actions and thus responsibility for your decisions. Your melted ice cream is the result of your long winded argument; Mom’s not going to clean up this sticky mess you’ve found yourself in, as it is entirely your own doing.

Regardless of your inability to use this science to argue your way out of trouble, the field of Behavioural Genetics is invaluable. It helps us further our understanding of the brain and contributes to the wealth of knowledge we draw on to address issues such as neurodevelopmental disorders. With this research, we can get closer to genetic, pharmaceutical, and environmental interventions for diseases affecting behaviour outside the statistically normal range–an area of medicine with a history of murky understanding, social stigma, and emotional turmoil. This field is sensitive and important because it helps us connect our biology to our understanding of our identity as humans. We should take care to use this field to nurture a healthy identity and social sphere, rather than distort it to subvert responsibility.

STEP 5:  Realize arguing to Mom that she is responsible for your selfish behaviours is clearly not a way to win the argument and keep your ice cream. Try this argument on Dad next time.

References:

  • BIOETHICS NC. Genetics and human behaviour: The ethical context. Nuffield Council on Bioethics, London. 2002.
  • Bird LM. Angelman syndrome: review of clinical and molecular aspects. Application of Clinical Genetics. 2014 Jan 1;7.
  • Cassidy SB, Dykens E, Williams CA. Prader‐Willi and Angelman syndromes: Sister imprinted disorders. American journal of medical genetics. 2000 Jun 1;97(2):136-46.
  • Haig D. Genomic imprinting and the theory of parent-offspring conflict. Semin. Dev. Biol. 1992 Jan;3:153-60.
  • Keverne EB, Martel FL, Nevison CM. Primate brain evolution: genetic and functional considerations. Proceedings of the Royal Society of London B: Biological Sciences. 1996 Jun 22;263(1371):689-96.
  • Sibley CP, Coan PM, Ferguson-Smith AC, Dean W, Hughes J, Smith P, Reik W, Burton GJ, Fowden AL, Constancia M. Placental-specific insulin-like growth factor 2 (Igf2) regulates the diffusional exchange characteristics of the mouse placenta. Proceedings of the National Academy of Sciences of the United States of America. 2004 May 25;101(21):8204-8.
  • Úbeda F, Gardner A. A model for genomic imprinting in the social brain: juveniles. Evolution. 2010 Sep 1;64(9):2587-600.
  • Wilkins JF, Ubeda F, Van Cleve J. The evolving landscape of imprinted genes in humans and mice: Conflict among alleles, genes, tissues, and kin. Bioessays. 2016 May 1;38(5):482-9.

Your cat is trying to control your mind! (Inadvertently).

Rae Pass | 19 JUL 2016

Cats or dogs? An eternal debate, with passionate advocates on both sides. Those in the pro dog camp have an unusual argument they could lobby: cats can infect you with mind controlling parasites.

Toxoplasma gondii is a single celled obligate parasite, which means it is unable to complete its life cycle without a suitable host. In this case, that would be members of the Felidae family (cats).  Other warm blooded animals (including humans) can also be infected, but the parasite is unable to mature and reproduce. Eggs are excreted in cat faeces, but Toxoplasma can also be transmitted through undercooked meat, soil and from mother to baby if contracted during pregnancy (hence why pregnant women are told to avoid cat litter). Worldwide infection rates vary, but in some countries up to 95% of the population may be infected (CDC, 2015) . In the UK it is estimated up to a third of people will be infected at some point in their life. Someone you know may well be infected, and wouldn’t that just explain their odd behaviour?

Toxoplasma gondii has been dubbed the ‘zombie parasite’. Infection can persist throughout life in the central nervous system, modifying the structure and function of neurons from within, by such as silencing neurons and hindering apoptosis (Flegr, 2013). Over time this can lead to behavioural changes in the host, and gender differences have been shown on self-reported personality factor questionnaires (Lindova et al., 2006). Whilst infected people generally do not display obvious symptoms, they are 2.5x more likely to have a car accident (Flegr et al., 2002). This is potentially explained by long term infection leading to a prolonged reaction time to stimuli (Flegr, 2013).

1150934_10153321275855092_1469034815_n

(Yes this is me. Why do you think I hide in my lab all day?!)

Various studies have been conducted to unpick how this infection alters the host’s behaviour. In rodents, decreases have been seen in neophobia (fear of novelty), learning capability and motor performance (Flegr, 2013). One study found that rats infected with Toxoplasama gondii lost their innate fear of cats, even over the longer term, suggesting it may result in permanent structural changes in the brain (Berdoy, Webster & Macdonald, 2000). Although infection occurs throughout the brain, high concentrations of infection has been found in the amygdala, a region that plays a key role in emotional processing, memory and decision making.

Additionally, infected rodents appear to display a “fatal attraction phenomenon”, essentially the conversion of the fear response to feline urine to something akin to attraction. Ordinarily rodents may fixate on the odour, the associated danger focusing their attention, but in the absence of fear that fixation may cause them to react in an abnormal way. This fear reduction may result from the parasite’s need to find their natural host, a cat, to complete their life cycle. Prey that lose fear of their predators are more likely to be eaten, transmitting the parasite from rat to cat. This demonstrates the “manipulation hypothesis”, which postulates that some parasites alter their host’s behaviour in a manner beneficial to themselves. This phenomenon has been studied in infected humans, again finding a gender difference, with infected men rating cat urine as more ‘attractive’, whilst infected women displayed a decreased rating (Flegr et al., 2011).

There is also a proposed link between Toxoplasama gondii infection and schizophrenia. Those diagnosed with schizophrenia are more likely than the general population to have been infected with Toxoplasama gondii (Torrey et al., 2007), although it is important to stress schizophrenia is an incredibly complicated disease with many factors increasing its risk. A proposed mechanism in schizophrenia is the slow growth of microscopic cysts in neurons, as persistent infection can increase the cell’s production of dopamine, potentially altering their function (Prandovsky et al., 2011; Stanley Medical Research Institute, 2014). Alongside several other neurotransmitters, dopamine functioning appears to be abnormal in schizophrenia.

If you want to read more about ‘scientific zombies’ you should check out How to make a zombie, which covers Toxoplasama gondii, re-animation and all sorts of other interesting and disturbing scientific examples of ‘zombies’. If you’d rather read a more fictional version of a mind controlling parasite the Parasitology series by Mira Grant is also fantastic.

Undoubtedly cat lovers have not changed their minds after reading this, but then you wouldn’t would you? Your cat would not approve.

References:

  • Berdoy, M., Webster, J., & Macdonald, D. (2000). Fatal attraction in rats infected with Toxoplasma gondii. Proc Biol Sci, 267.
  • CDC (2015). Toxoplasma gondii Epidemiology & Risk Factors
  • Flegr, J. (2013).  Influence of latent Toxoplasma infection on human personality, physiology and morphology: pros and cons of the Toxoplasma–human model in studying the manipulation hypothesis. Journal of Experimental Biology, 216. 
  • Flegr, J., et al (2002). Increased risk of traffic accidents in subjects with latent toxoplasmosis: a retrospective case-control study. BMC Infect Dis, 2.
  • Flegr, J., et al (2011). Fatal attraction phenomenon in humans: cat odour attractiveness increased for toxoplasma-infected men while decreased for infected women. PLoS Negl Trop Dis, 5. 
  • Lindova, J., et al (2006). Gender differences in behavioural changes induced by latent toxoplasmosis. International Journal for Parasitology, 36.  
  • Prandovsky, E., et al (2011). The Neurotropic Parasite Toxoplasma Gondii Increases Dopamine Metabolism. PLoS ONE, 6. 
  • Stanley Medical Research Institute (2014). http://www.stanleyresearch.org/patient-and-provider-resources/toxoplasmosis-schizophrenia-research/neurotransmitters-and-t-gondii/
  • Torrey, E, et al (2007). Antibodies to Toxoplasma gondii in patients with schizophrenia: a meta-analysis. Schizophr. Bull. 33.