One problem with theories which start with genes and then go on to try to explain complex mental outcomes such as psychosis or autism in the way in which the imprinted brain theory does is that they leave you asking what, if anything, fills the explanatory gap between the two?  

The answer, of course, is the epigenesis of the central nervous system, which builds brains according to instructions written in DNA. One major way in which DNA does this is to code for neuro-transmitters, growth factors, and other agents that control and regulate the expression of genes in the development of the brain. A striking example of the latter is the subject of a recent paper by my colleague, Bernard Crespi. Writing with Peter Hurd, he shows that GTF2I, a gene which codes for General Transcription Factor IIi, is strongly expressed in the brain and that variations in its expression provide a neurogenetic basis for social communication and social anxiety, both among individuals in healthy populations and in Williams syndrome (where you find a striking lack of fear of strangers, coupled with indiscriminate friendliness and extreme volubility).

Hormones are another example of biological factors which bridge the DNA-to-behaviour gap, but are widely misunderstood. People think of them as magic potions, with intrinsic power to masculinize, for example, in the case of androgens such as testosterone, which has far-reaching effects on the body, brain, and behaviour. But testosterone is a very simple molecule that differs from its feminizing alternative, oestrogen, by only one atom. Could a single atom change the magic potion that much?

The truth is that hormones are chemical messages, which, like any message, need to be received to have any effect. The classic example of this is androgen insensitivity syndrome, which results in a person seeming to be female, but in fact being chromosomally male and having male levels of testosterone way above anything found in females, and all thanks to a complete lack of testosterone receptors. Such receptors, like the hormones to which they respond, are coded in DNA, and their number and characteristics are crucial to the way in which hormonal messages are received and interpreted. For example, variations in V1aR, a gene for a vasopressin hormone receptor, explain why prairie voles are life-long monogamists but meadow voles are promiscuous.

This means that natural selection gets two bites at the cherry, so to speak, where hormones are concerned. Selection can act on the genes involved in forming the hormone (several in the case of testosterone, for which there is no single gene as such but rather a number of enzymes that synthesize it from cholesterol). But selection can also act on the genes that code for receptors (in the case of the androgen receptor, the number of glutamine units specified inversely determines sensitivity to testosterone: rodents have 1, gorillas 6-17, chimps 8-14, humans are most insensitive with 11-31, averaging 21). 

Another important consideration that people overlook—especially where sex hormones such as testosterone are concerned—is that chemical messages, just like any other kind of message, can be mixed, or even conflicting. As Bernard Crespi points out in a paper soon to appear in Biological Reviews,* in humans, oxytocin—a hormone similar to vasopressin—“motivates, mediates and rewards the cognitive and behavioural processes that underlie the formation and dynamics of a more or less stable social group, and promotes a relationship between two or more individuals.”

Indeed, he notes that “oxytocin is also apparently represented culturally by specific words (e.g. ‘hygge’ in Danish and ‘gemütlichkeit’ in German) whose meanings correspond closely to its documented endocrine effects” (coziness/friendliness, according to Google Translate). Enhanced monitoring of gaze and increased empathy have been reported after oxytocin administration, and along with intensification of existing pro-social tendencies, oxytocin facilitates memory of faces. Variations in the oxytocin receptor gene, OXTR, are associated with measures of social recognition, co-operation and empathy.

Where brain development is concerned, three recent studies have demonstrated strong oxytocin-induced increases in activation of specific cortical brain areas, especially in regions of the medial prefrontal cortex that regulate processes related to mentalism (or theory of mind). Oxytocin administration also leads to increased functional connectivity between the amygdalas (key parts of the emotional or limbic brain) and the orbitofrontal cortex which, as Crespi puts it, “may serve to foster the controlled mentalization that leads to enhanced, more-deliberative social decision-making.”

Testosterone, on the other hand, “exhibits opposite effects from oxytocin on diverse aspects of cognition and behaviour, most generally by favouring self-oriented, asocial and antisocial behaviours.” By direct contrast to oxytocin, testosterone reduces connectivity between regions involved in mentalism “and is thereby expected to reduce controlled mentalization, in contexts where aggressive behaviour is favoured over affiliation or cooperation.”

As far as mental illness is concerned,

Reduced oxytocin and higher testosterone levels have been associated with under-developed social cognition, especially in autism. By contrast, some combination of oxytocin increased above normal levels, and lower testosterone, has been reported in a notable number of studies of schizophrenia, bipolar disorder and depression, and, in some cases, higher oxytocin involves maladaptively ‘hyper-developed’ social cognition in these conditions. This pattern of findings suggests that human social cognition and behaviour are structured, in part, by joint and opposing effects of oxytocin and testosterone, and that extremes of such joint effects partially mediate risks and phenotypes of autism and psychotic-affective conditions.

Crespi goes on to argue that the model illustrated in his diagrams (above and below) 

suggests in particular that higher oxytocin, and lower testosterone, should be associated with increased levels of hyper-developed, dysregulated, or affectively biased mentalistic cognition in schizophrenia and depression, as well as other psychotic-affective conditions. For example, a paradigmatic hyper-mentalistic symptom of schizophrenia, paranoia, explicitly involves an exaggerated ‘me and them’ social relationship, and so might be expected to involve unresolved, oxytocin-associated stress and anxiety given the central role of this hormone in mediating both positive, and negative, social connections, and its apparent role in shifting cognition from self to other orientation (…).

Finally, writing with Mikael Mokkonen in Evolutionary Applications, Crespi reviews the genetic and evolutionary basis of the testosterone v oxytocin model, specifically “two major forms of genomic conflicts, genomic imprinting, and sexual antagonism, with regard to their impacts on hormonally mediated, health-related human phenotypes.”** 

Clearly, where the imprinted brain theory is concerned, the gene-behaviour gap is beginning to be bridged!

* Crespi, Bernard, "Oxytocin, testosterone, and human social cognition," Biological Reviews, in press. 

** Mokkonen, Mikael, and Crespi, Bernard, "Genomic conflicts and sexual antagonism in human health: insights from oxytocin and testosterone," Evolutionary Applications, in press.

(With thanks and acknowledgement to Bernard Crespi for his help.)

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