What's really the deal with toxoplasma gondii and human behavior?

T. gondii  cyst in a mouse brain.

T. gondii cyst in a mouse brain.

For a simple protozoan, Toxoplasma gondii has experienced something of a meteoric rise in popularity over the past several years. Actually, to be fair T. gondii has garnered quite a bit of interest since the 1930s, when it was discovered the parasite could be transmitted from a mother to a fetus in the womb, sometimes resulting in severe congenital disorders. Curiosity about T. gondii grew significantly in the early 2000s, however, when it was found that T. gondii infection in mice and rats might influence the behavior of the rodents so as to make them less afraid of cats.

Recently, interest in T. gondii has been especially focused on the hypothesis that the microorganism might also be able to influence human behavior. Indeed, this idea has become a popular topic of discussion even outside the sphere of research. This notoriety, however, has led to a spectrum of opinions that range from the suggestion T. gondii is responsible for a variety of psychiatric symptoms to the viewpoint that there is no sound evidence at all to indicate such a thing. Is one of these perspectives more accurate than the other?

T. gondii and rodent behavior

Effects of T. gondii infection on rodent behavior have been recognized since the late 1970s when it was observed that infected mice displayed impaired performance on memory tasks. Various other studies over the next couple of decades noted effects on behavior and cognition in rodents, but widespread interest in the behavioral effects of T. gondii infection was triggered by the publication of a study that suggested T. gondii-infected rats exhibit a diminished aversion to cat urine---and that some infected rats may even display an attraction to it. This effect was eventually seen in mice as well.

This finding was compelling when placed in the context of something called the parasite manipulation hypothesis, which states that some parasites have evolved mechanisms to influence their hosts so as to promote the parasite's transmission. This hypothesis was thought to make sense when used to describe T. gondii because T. gondii is only capable of reproducing within the intestines of cats; felines thus play an essential role in the life cycle of the parasite. After reproduction, however, several million oocysts (sort of a protozoan parasite version of an embryo) are expelled from the feline intestines in the feces. Unfortunately for these oocysts, this causes them to be forced out of their preferred feline intestinal environment, seemingly without a clear path of return. That is where rodents come in.

Many animals who are exposed to the feces of an infected cat (e.g. through contaminated food or drinking water) can become infected with T. gondii. Rodent infection, however, might be especially useful to T. gondii due to the role of cats as natural predators of rodents. Some have suggested that the ability of T. gondii to reduce rodent fear of cat urine gives T. gondii a method by which to find its way back to its preferred environment. By making rodents less cautious around cat urine, which previously had acted as a distinct threat-identifying odorant, rodents may put themselves in harm's way and be more likely to be eaten by cats. If they are, T. gondii ends up right where it needs to be to reproduce and continue its life cycle.

Neuronal mechanisms for T. gondii action

In order to manipulate the behavior of rodents it would seem necessary for T. gondii to have a means by which it could influence neurobiology; of course, such a mechanism would also be necessary for the manipulation of human behavior. What exactly this mechanism might be is still under investigation, but one thing that's certain is that T. gondii does have a way of making it to the brain of its host, whether that host be a human or a rodent. Indeed, T. gondii invasion of the central nervous system is associated with the most severe complications of T. gondii infection in humans, and by some estimates T. gondii may cross the blood-brain barrier and enter the brain as quickly as 7 days after infection occurs.

Once T. gondii is in the brain, it can infect neurons directly. What happens as a result is still uncertain, but several hypotheses have been proposed to explain the ways T. gondii infection can disrupt neuronal function. One hypothesis is that T. gondii infection of neurons can alter dopamine metabolism to increase dopamine synthesis and release. Another hypothesis contends that T. gondii infection can influence calcium signaling in such a way as to make neurons either hypo- or hyper-responsive. A complete model of T. gondii's effects on neurons has not yet been elucidated, however, so the true mechanism may involve these processes or something different altogether.

When T. gondii enters the brain, it also infects glial cells like microglia and astrocytes; activation of these cells is associated with the production of a general inflammatory response in the brain. This neuroinflammation may have a variety of effects on neurobiology, including influences on neurotransmitter metabolism, changes in neurotransmitter receptor levels, and effects on synaptic morphology or connectivity. Thus, the repercussions of inflammation caused by T. gondii infection may also be extensive enough to modify the behavior of the host.

While there is much to still be understood about the way or ways in which T. gondii can affect host behavior, there are at least plausible mechanisms identified by which such an effect might occur in mammalian hosts (including humans). And, when we are investigating the potential of an exposure like T. gondii infection to cause an effect on a host, biological plausibility can support the argument that the potential exists. In other words, if there were no plausible biological mechanism by which T. gondii could influence behavior, then we would be less confident it is actually affecting behavior (even when studies like those discussed below find some correlation between infection and behavioral changes). Just because there is a biologically plausible manner by which T. gondii can influence behavior, however, doesn't mean it actually does. To be confident about the relationship between T. gondii and human behavior we also need some strong evidence showing a relationship between infection and behavioral changes in human populations.

T. gondii and human behavior

The relationship between T. gondii infection and human behavior has been a subject of research for many years, and studies of the prevalence of T. gondii infection in psychiatric patients date back to the middle of the 20th century. However, the suggestion that T. gondii may be manipulating rodent behavior led to a resurgence of interest in T. gondii 's potential to affect people. Along with that increase in research-related interest came heightened interest from the popular press, which caused the potential influence of T. gondii on psychiatric symptoms to become a trendy---but often sensationalized---topic.

Regardless, legitimate research into this topic continues to be conducted; by now researchers have explored the potential association between T. gondii infection in humans and a wide range of behavioral and psychiatric outcomes. And, a number of studies have detected correlations between the presence of T. gondiii antibodies and behavioral or psychiatric abnormalities. For example, one study found T. gondii infection to be associated with increased aggression in women and increased impulsivity in younger men. Another study detected a correlation between homicide rates and rates of T. gondii infection in the population. Other findings include links to suicide rates and even traffic accidents (hypothetically due to the effect of the parasite on characteristics like reaction time).

By far, though, it seems the most frequently investigated relationship between T. gondii infection and psychiatric abnormalities is the association between T. gondii and schizophrenia. Over 40 studies examining the relationship between T. gondii infection and schizophrenia or psychotic symptoms have been published since the 1950s. In 2012, a group of researchers synthesized data from 38 of these studies to determine if there was a consistent association between T. gondii infection and schizophrenia. The results of this analysis suggested that, across all of the studies included, individuals who had been diagnosed with schizophrenia were about 2.73 times more likely to also be infected with T. gondii. In terms of how this increase in risk stacks up against other known risk factors for schizophrenia, it is similar in magnitude to the increase in risk of schizophrenia seen in those who grow up in an urban environment or in those who have a father who is age 55 or older at birth, but significantly lower than the increased risk imparted by having another immediate family member with schizophrenia.

Based on this information along with the biological plausibility of T. gondii's mechanism for affecting brain activity, it may sound to you like there is something to the idea that T. gondii infection can lead to psychiatric disorders (or schizophrenia in particular). However, there are some reasons to take all of these T. gondii findings regarding human behavior with a grain of salt. One is that the studies conducted up to this point generally have followed this methodology: get a sample of individuals, test them for antibodies to T. gondii (which would indicate an infection if present), and look for correlations between the presence of antibodies and schizophrenia (or some other psychiatric outcome). 

While a study like this can be informative, it leaves many questions unanswered. For example, even if this type of study finds a link between T. gondii and schizophrenia, because data was only collected at one point in time it is impossible to tell if the T. gondii infection preceded (and thus caused) schizophrenia. This allows for a number of other possible explanations for the relationship between infection and schizophrenia. For example, there is a possibility that the correlation between T. gondii infection and schizophrenia exists because infection becomes more likely after the onset of schizophrenia. What if, for instance, the onset of schizophrenia is associated with behavioral changes (e.g. eating and hygiene changes specifically) that increase exposure to sources of T. gondii contamination?

Alternatively, what if some common variable increases the risk of both T. gondii infection and schizophrenia? For example, what if something about one's neurobiology makes one more likely to own a cat (and thus be exposed to T. gondii through exposure to cat feces) and also predisposes one to schizophrenia? Or, what if T. gondii doesn't increase the risk of schizophrenia, but some other microorganism passed from a cat to a human does? In that case, owning a cat would make someone more likely to be infected with T. gondii and more likely to develop schizophrenia, but not due to a direct link between T. gondii and schizophrenia. Indeed, one study found no significant link between T. gondii infection and schizophrenia, but did find a significant association between having close contact with cats and schizophrenia. In the end, the problem is that observational studies that rely on data collected at only one point in time allow for too many other possibilities to let us have any confidence that there is a causal relationship between the variables we are interested in. Hence these studies can detect correlation, but not causation.

With this in mind, one way to get closer to some answers to these questions about T. gondii and psychiatric symptoms is to conduct more studies using longitudinal designs. A longitudinal study design, for example, would begin with a sample of overtly healthy people---some people who were infected with T. gondii and some who were not; these individuals would then be followed up with over a period of years to see if those with T. gondii infection were more likely to subsequently develop psychiatric disorders. This approach can provide more convincing evidence of a causal relationship, in part because it can provide insight into whether T. gondii infection precedes the onset of the symptoms (since at the start of the study the symptoms were not present).

Because of the paucity of studies that have the ability to detect causal links between T. gondii and human psychiatry, there are researchers who argue that some are inferring a causal relationship when the evidence for that causal relationship doesn't exist. For example, a recent study looked at the association between T. gondii infection and a number of psychiatric measures ranging from IQ to schizophrenia diagnosis. The authors found no link between T. gondii infection and shizophrenia or most other psychiatric measures, and in the concluding paragraphs they suggest that "earlier reports of links between T. gondii infection and behavioral impairments are exaggerated," due in part to the intrigue both researchers and the public have with the idea of T. gondii being able to manipulate human behavior. Interestingly, the study in question did actually detect a link between T. gondii infection and recent suicide attempts, suggesting that perhaps the idea the pathogen is influencing behavior is not entirely unreasonable.

Regardless, although there are some titillating findings concerning T. gondii infection and psychiatric disorders, at this point it is not a relationship we can be very confident in. This is not to say that there is no ground for the hypothesis to stand on, but instead that more research is needed before we can decide if the microorganism is really having some influence on human behavior. Despite the lack of strong evidence, however, there is likely a reason that infectious origins of psychiatric disorders has been such a popular topic in recent years. It's mind-boggling for most of us to imagine that this complex, highly-evolved organ we call the human brain can be manipulated and turned dysfunctional by organisms that have a diameter on the scale of micrometers. It creates for us a strangely wonderful sense of impotence that causes us to step back and reassess the position of superiority we generally give ourselves over other organisms. And that reminder of our own helplessness to control some aspects of the natural world can be both frightening and fascinating at the same time. Thus, the idea is inherently captivating, and it is likely to continue to attract speculation and exaggeration until we come to a more definite conclusion on its accuracy.

Parlog A, Schlüter D, & Dunay IR (2015). Toxoplasma gondii-induced neuronal alterations. Parasite immunology, 37 (3), 159-70 PMID: 25376390

Limitations of the consensus: How widely-accepted hypotheses can sometimes hinder understanding

To those of us who believe strongly in the scientific method, it really is the only approach to understanding the relationship between two events or variables that allows us to make assertions about such relationships with any confidence. Due to the inherent flaws in human reasoning, our non-scientific conclusions are frequently riddled with bias, misunderstanding, and misattribution. Thus, it seems there is little that can be trusted if it hasn't been scientifically verified.

The scientific method, however, is a human creation as well, and therefore it is less than perfect; at the very least our use of it is flawed due to the fact that human foibles inevitably creep into the process of innovation. One example of this can be seen when we mix our enticement to make scientific discoveries with financial incentives. When this occurs it makes the likelihood of malfeasance much higher, and causes tainted results to be a more distinct possibility. But there are many other examples of flaws in the scientific process that are a bit more subtle--and certainly less heinous--than fiscally-influenced dishonesty. Another pitfall, for instance, stems from the natural human bias toward favoring the familiar, understandable, and available ways of explaining a phenomenon over those that are less so.

This cognitive bias is generally most detrimental to the understanding of phenomena that are, as of yet, not well understood. For, when we gain some insight that we believe helps us to illuminate the mechanism underlying a poorly-understood phenomenon, we tend to build off of that insight. It serves as the foundation for many closely-related hypotheses and experiments to test those hypotheses. If these experiments are generally supportive of the new perspective, then our understanding of the phenomenon begins to form around that viewpoint. The new perspective then becomes the widely-accepted way of thinking about the phenomenon.

This may be fine if the newly-devised hypothesis ends up being indisputably accurate, as there is nothing wrong with building off of previous ideas to further overall understanding--indeed, this is the way the growth of human knowledge generally works. The problem occurs, however, when a sense of unanimity develops around the new hypothesis. This widespread agreement then can tend to limit the creative exploration of other mechanisms: it may make us quicker to disregard a competing hypothesis, less capable of obtaining grant funding to explore one, and sometimes less likely to pay attention to shortcomings in the consensus hypothesis itself. Thus, if a consensus hypothesis does not tell the full story (which often they do not), its acceptance may actually hinder scientific progress.

The dopamine hypothesis of schizophrenia

The dopamine hypothesis of schizophrenia is arguably a good example of this conundrum. Schizophrenia is a complex disorder that affects over 21 million people worldwide, but it can manifest in a drastically different way from patient to patient. It is characterized by a diverse group of symptoms that generally involve some detachment from reality, disordered thought processes, and/or impaired social interaction or withdrawal. The symptoms are commonly grouped as negative symptoms, which involve the absence of typical behaviors (e.g. limited speech, lack of affect), and positive symptoms, which involve the presence of unusual behaviors (e.g. hallucinations, delusions). Adding to the byzantine nature of the disorder, there are at least five subtypes of schizophrenia that distinguish schizophrenics by general trends in symptomatology. For example, paranoid schizophrenics often experience delusions of persecution along with hallucinations, while catatonic schizophrenics display a predominance of negative symptoms that include lack of movement, motivation, and emotion. Generally, the first clear symptoms of schizophrenia emerge in adolescence or adulthood in the form of an initial break with reality called a psychotic episode. The course of the disorder, however, is variable; some patients experience recurring psychotic episodes followed by remission of symptoms, while others suffer from constant symptoms that severely impact cognition and functioning on a daily basis.

The dopamine hypothesis of schizophrenia was formulated in the 1960s when it was discovered that drugs that can be used to treat schizophrenia also act as dopamine receptor antagonists. Because these drugs--which as a class are referred to as antipsychotics or neuroleptics--help to alleviate the positive symptoms of schizophrenia, it was assumed that the mechanism underlying schizophrenia must involve an increased level of dopamine neurotransmission. In other words, if antipsychotic drugs block dopamine activity and improve schizophrenic symptoms, then those symptoms must be caused by too much dopamine activity. Dozens of dopamine antagonist antipsychotic drugs have been developed since the 1960s with this reasoning in mind.

Further support for the dopamine hypothesis of schizophrenia was inferred from a phenomenon known as stimulant-induced psychosis. In some individuals who don’t have a history of psychosis, when high doses of stimulant drugs like amphetamine are taken (or even when normal doses are administered over long periods of time), the effects of the drugs appear similar in some ways to a psychotic episode. Because the drugs that can have this effect include as one of their primary mechanisms of action the increasing of dopamine levels, researchers suggested this strengthened the hypothesis that high dopamine levels are associated with schizophrenia. That is, if increasing dopamine levels through drug use can cause something that resembles a psychotic episode then it is likely psychotic episodes that occur naturally are also due to high dopamine levels.

Bolstered by these pieces of evidence, the dopamine hypothesis has guided schizophrenia research and drug development until the present day--and continues to do so. Over that time, additional research that supports the hypothesis has accumulated. For example, when amphetamine is administered to schizophrenic patients, the patients display greater increases in dopamine levels in response to the drug than healthy controls do. This supports the hypothesis that dopamine neurotransmission is dysregulated in schizophrenic patients, and suggests it may be elevated at baseline. Schizophrenic patients have also been found to have altered presynaptic dopamine function, including an increased capacity for dopamine synthesis and increased dopamine release from presynaptic neurons. The number of studies that have supported the hypothesis that dopamine signaling in schizophrenic patients is abnormal is actually quite extensive.

Regardless, serious questions about the role of dopamine in schizophrenia remain. Some still argue it isn't clear that there are dopaminergic abnormalities in the brains of schizophrenic patients, but even if we accept the premise that there are it remains undetermined if these differences in dopamine activity are the primary cause of the symptoms of schizophrenia. Despite the fact that antipsychotic drugs reduce activity at dopamine receptors, approximately 1/3 of schizophrenic patients don't respond to most antipsychotics. This suggests that some other mechanism must be at play in at least a significant minority of patients. Also, dopaminergic abnormalities alone don't seem to explain the negative symptoms of schizophrenia, as these are more resistant to the therapeutic effects of antipsychotic drugs than positive symptoms are. Indeed, some evidence even suggests negative symptoms may be improved by increasing dopamine levels. Furthermore, antipsychotics vary significantly in their affinity for the dopamine receptor, and that affinity doesn't always predict the clinical effectiveness of the drugs. Some antipsychotics have an affinity for serotonin receptors as well, and in some cases serotonin receptor affinity can predict clinical effectiveness, which suggests a role for the serotonin system in the mechanism underlying schizophrenia. And direct evidence for the hypothesis is lacking; when brains have been studied post-mortem or cerebrospinal fluid has been sampled to test for excessive dopamine activity, the results have been inconsistent.

These shortcomings have prompted a number of revisions of the dopamine hypothesis. For example, it has now been suggested that schizophrenia is characterized by both excessive dopamine transmission and low dopamine activity in different areas of the brain. According to this perspective, dopamine underactivity is associated with negative symptoms and overactivity with positive symptoms. Some researchers, however, have begun to consider other neurotransmitter systems as playing a central role in schizophrenia. One hypothesis that is gaining considerable support suggests that there is reduced glutamate activity in the brains of schizophrenics. This glutamate hypothesis doesn't argue that dopamine activity is normal in schizophrenia, but rather that glutamate dysfunction may play an equally important role.

Thus, after 40 years or so of the dopamine hypothesis guiding schizophrenia research, more and more investigators are now considering it to be unlikely dopamine dysfunction fully explains schizophrenia. Of course, it would make sense that such a complex disorder cannot be explained by fluctuations in the levels of just one neurotransmitter. In fact, if the dopamine hypothesis had been devised today, it may have had a more difficult time gaining such widespread support, as the field of neuroscience is now much more wary than it was a few decades ago of explanations for complex disorders that focus primarily on one neurotransmitter (or one gene, brain region, etc.); we have learned from experience that these explanations often end up being gross oversimplifications.

But has the dopamine hypothesis hindered our understanding of schizophrenia? It's really impossible to know for sure. When one hypothesis dominates an area of research for a prolonged period of time, however, it usually does have a significant influence on that research. Widespread acceptance of the hypothesis can create a situation where challenges to it become less frequent, and competing hypotheses are often not given as much attention. Researchers may even find it easier to get grants funded when those grants involve an investigation of some aspect of the well-known hypothesis than when they involve venturing out into less familiar territory. This can have a restrictive effect on research, causing it to be more difficult to explore alternative hypotheses and thus actually making the consensus hypothesis more popular by default (because there are no viable alternatives). Thus, perhaps if the dopamine hypothesis hadn't had such extensive support, we would have seen competing perspectives like the glutamate hypothesis garner attention earlier on.

Additionally, when there is a consensus hypothesis, investigators may be more likely to disregard research results that disagree with it. After all, if everyone knows high dopamine levels cause schizophrenia, then there must be something wrong with the methods of an experiment that indicates otherwise. This type of thinking can contribute to publication bias, a tendency to only publish favorable results and discard findings that don’t support one’s hypothesis. This type of bias can serve to further propagate a consensus hypothesis as potentially contradictory research results are considered quirky aberrations instead of leads worth following. Schizophrenia research doesn't display clear evidence of a large influence of publication bias, but it doesn't seem to be completely clear of its influence, either.

Regardless, one could argue that a concentrated focus on one hypothesis is an important part of scientific investigation. It allows for the organization of our thoughts, and through the reduction of a complicated process into its component parts, helps us to make sense of at least a portion of what is going on. Successful experiments supporting a consensus hypothesis may also inspire increased experimentation in and attention to an area of research, which in and of itself may speed up the process of coming to understand a phenomenon more fully.

However, even if there are benefits to this increased focus, it may be best to still maintain that focus with the caveat in mind that just because a hypothesis is widely accepted does not mean it is correct. It may be useful to constantly remind ourselves that we still know very little about neuroscience, and that in most cases the simpler the hypothesis seems to be, the more likely it is to be lacking. Continuing to seek out greater complexity instead of focusing all our efforts on finding support for an easy-to-explain mechanism may allow us to avoid falling into the trap of the consensus hypothesis, which can in some ways limit the ability of our understanding to grow.

Moncrieff, J. (2009). A Critique of the Dopamine Hypothesis of Schizophrenia and Psychosis Harvard Review of Psychiatry, 17 (3), 214-225 DOI: 10.1080/10673220902979896

Early brain development and heat shock proteins

Early nervous system development.

Early nervous system development.

The brain development of a fetus is really an amazing thing. The first sign of an incipient nervous system emerges during the third week of development; it is simply a thickened layer of tissue called the neural plate. After about 5 more days, the neural plate has formed an indentation called the neural groove, and the sides of the neural groove have curled up and begun to fuse together (see pic to the right). This will form the neural tube, which will eventually become the brain and spinal cord. By around 10 weeks, all of the major structures of the brain are discernible, even if they are not yet fully mature. So, in a matter of two months, the framework for the human brain is built from scratch. If that doesn't put you in awe of nature, nothing will.

Although the process of neural development is amazing, it is also very sensitive. There are indications that a number of environmental exposures during prenatal development may increase the risk of disorders like autism, schizophrenia, and epilepsy. Some of these dangerous environmental exposures are well known (e.g. alcohol consumption during pregnancy increasing the risk of developing fetal alcohol syndrome). However, there are a number of other factors whose detrimental effects on fetal neural development are still debated or have not yet been fully elucidated. For example, the effects on a fetus of substances like phthalates (plasticizers that are likely found in a number of products throughout your home), bisphenol A (another substance used in the production of plastics - found frequently in food and drink containers), and even tobacco smoke, are still being investigated. But a pregnancy free from exposure to any potentially harmful substances doesn't guarantee normal neural development. Even factors that are natural and more difficult to control, like maternal infection during pregnancy, are suspected of being detrimental in some cases.

To complicate the issue even further, it is difficult to predict who will be affected by these environmental insults and who will not. It seems that there may be a genetic susceptibility to neurodevelopmental damage that causes a particular exposure to be detrimental to one fetus, while it may not have a major impact on another with a different genetic makeup. This complication, however, also provides an opportunity to learn more about the etiology of neurodevelopmental disorders. For, if we can learn what mechanism is failing in the fetus who is affected, but functioning in the fetus who is not, then our understanding of the origin of these disorders will be drastically improved.

In a paper published last week in Neuron, Hashimoto-Torii et al. approached the problem from this angle and examined the role of heat shock proteins in neurodevelopmental problems. Heat shock proteins are peptides whose expression is increased during times of stress. They earned their name when it was discovered in the early 1960s that high levels of heat increased their expression in Drosophila (fruit flies). Since, it has been learned that heat shock protein expression is increased during all sorts of stress, including infection, starvation, hypoxia (lack of oxygen), and exposure to toxins like alcohol. Thus, some also refer to heat shock proteins as stress proteins.

To investigate the role of heat shock proteins in neurodevelopmental disorders, Hashimoto-Torii et al. exposed mouse embryos to three different types of environmental insults. They injected pregnant mice with either alcohol, methylmercury, or a seizure-inducing drug. Then, they looked to see how the brains of the embryos reacted. As they hypothesized, they saw a significant increase in the expression of a transcription factor (heat shock factor 1 or HSF1) that promotes the production of heat shock proteins.

When the researchers investigated the effects of prenatal exposure to the insults listed above in mice who lacked an HSF1 gene (HSF1 knockout mice), they saw that the exposed moms had smaller litters than control mice. The mice that were born, however, also displayed malformations consistent with neurodevelopmental damage, greater susceptibility to seizures after birth, and reduced brain size. The reduction in brain volume seemed to be due to decreased neurogenesis after the insult.

To make a clearer connection between heat shock protein activation and human disease, the researchers exposed stem cells derived from schizophrenic patients to methylmercury and alcohol, and compared the response of the "schizophrenic cells" to the response of cells from non-schizophrenic (control) patients. They didn't see an overall difference in heat shock protein expression between the two types of cells, but they did see significant variability in expression among the schizophrenic cells. In other words, both schizophrenic and control cells increased expression of heat shock protein after an insult, but some of the schizophrenic cells appeared to increase expression more or less than others. The control cells all displayed a relatively similar increase in expression. This suggests that there may be an abnormal response involving heat shock proteins in individuals with a certain genetic predisposition; perhaps this abnormal response makes the individual more susceptible to disrupted neurodevelopment.

Thus, the study by Hashimoto-Torii et al. points to heat shock proteins as a potential culprit behind what goes wrong in early brain development to lead to psychiatric disorders like schizophrenia and autism. More research will need to be done, however, to verify this role for heat shock proteins. And, even if future research supports this finding, it is likely that heat shock proteins are still only part of the puzzle. But the puzzle is complex, and so we will need to add many of these little pieces before we can begin to comprehend the whole picture.


Hashimoto-Torii, K., Torii, M., Fujimoto, M., Nakai, A., El Fatimy, R., Mezger, V., Ju, M., Ishii, S., Chao, S., Brennand, K., Gage, F., & Rakic, P. (2014). Roles of Heat Shock Factor 1 in Neuronal Response to Fetal Environmental Risks and Its Relevance to Brain Disorders Neuron DOI: 10.1016/j.neuron.2014.03.002