Imaging genetics and development: challenges and promises

Abstract

Excitement with the publication of the human genome has served as catalyst for scientists to uncover the functions of specific genes. The main avenues for understanding gene function have been in behavioral genetics on one end and on the other end, molecular mouse models. Attempts to bridge these approaches have used brain imaging to conveniently link anatomical abnormalities seen in knockout/transgenic mouse models and abnormal patterns of brain activity seen in humans. Although a convenient approach, this article provides examples of challenges for imaging genetics, its application to developmental questions, and promises for future directions. Attempts to link genes, brain, and behavior using behavioral genetics, imaging genetics, and mouse models of behavior are described. Each of these approaches alone, provide limited information on gene function in complex human behavior, but together, they are forming bridges between animal models and human psychiatric disorders.

Figure 1

Cumulative citations for neuroimaging genetic papers (in blue) and developmental neuroimaging genetic papers (in red) over the past decade.

Figure 2

Phenomenological (A) versus biological (B) approach to behavioral genetics [Casey et al., 2009].

Figure 3

Model of impact of BDNF across development. (A) The genetic variant BDNF Val66Met leads to an amino acid substitution in the BDNF prodomain (Val to Met at position 66) that results in decreased activity‐dependent secretion of BDNF from neurons. Thus, this trafficking defect leads to a decrease in the availability of biologically active BDNF. (B) This model predicts that BDNF levels will have different functional consequences across development. As the variant BDNF (Val66Met) has decreased secretion throughout this period, we anticipate that there will be functional deficits, evident even in childhood, but (C) these deficits will become diminished by adolescence when BDNF levels peak. In addition, BDNF levels will be modulated by environmental stressors. Carriers of the Met allele will have decreased secretion and less neurotrophic support for plasticity and change, whereas Val allele carries will show greater change, including both positive and negative effects on hippocampal structure and function, but potentially greater neurotrophic support for plasticity and resilience once a stressor is removed [Casey et al., 2009].

Figure 4

Altered behavior and neural circuitry underlying extinction in mice and humans with BDNF Val66Met. Impaired extinction in Met allele carriers (Val/Met and Met/Met) as a function of time in 68 mice (A) and 72 humans (B) as indexed by percent time freezing in mice and skin conductance response (SCR) in humans to the conditioned stimulus when it was no longer paired with the aversive stimulus. (C) Brain activity as indexed by percent change in MR signal during extinction in the ventromedial prefrontal cortex (vmPFC) by genotype (xyz = −4, 24, 3), with Met allele carriers having significantly less activity than Val/Val homozygotes [VM < VV = blue], image threshold P < 0.05, corrected. (D) Genotypic differences in left amygdala activity during extinction (xyz = −25, 2, −20) in 70 humans, with Met allele carriers having significantly greater activity than Val/Val homozygotes [VM > VV = orange], image threshold P < 0.05, corrected. *P < 0.05. **MM were included in the analysis with VM, but plotted separately to see dose response. All results are presented as a mean ± SEM. VV = Val/Val; VM = Val/Met; MM = Met/Met [Soliman et al., 2010].