The adaptive brain in mental health: overcoming inherited risk factors.

A primary function of the brain is to drive adaptation of the organism to its environment: learning, memory, attachment, fear, aggression, etc., are all manifestations of how the brain directs adaptation to the environment. One touch of a flame in youth is sufficient to engrain a learned behaviour that lasts a lifetime despite the memory of the specific event having long dissipated. To mediate these behaviours, the brain itself must adapt its transcriptional, structural and neurotransmission functions. This type of imprinted memory has been modelled in young Caenorhabditis elegans, where aversive memory is retained throughout the lifetime, while it is forgotten when adults are exposed.1 This persistent memory retention requires recruitment of new neurons that alone do not mediate memory retrieval, but that must be activated to permit memory retrieval via other neuronal circuits. Similarly, shocking mice in a given context generates a fear memory by recruiting a sparse subset of hippocampal neurons that can be reactivated to recruit the memory of the context. When these neurons are optogenetically inactivated, the fear memory is extinguished; when activated in a different context, this elicits an inappropriate fear response.2,3 Conversely, activating hippocampal cells that respond to a positive memory can reverse stress-induced depression-like behaviours.4 Thus, one mechanism of brain adaptation involves cellular adaptation, with recruitment of new sets of neurons. Despite its potential for adaptation, the greatest risk factor for mental illness remains family history,5 implicating genes, environment or both, and suggesting a limited capacity of the brain to adapt to these early and lifelong risk factors. The hypothesis that genetic makeup modifies the trajectory of adaptive behaviours underlies current efforts to identify specific genetic changes associated with mental illness. For example, genes associated with schizophrenia, such as NRG1, DISC1, or DTNBP1, undergo positive selection, suggesting that these genes drive a behavioural phenotype that may confer an evolutionary advantage in certain environments.6 The question is whether potentially harmful inherited traits provoke homeostatic compensatory responses and whether these responses can be augmented through early interventions.