Treating the Developing versus Developed Brain: Translating Preclinical Mouse and Human Studies

Abstract

Behaviors and underlying brain circuits show characteristic changes across the lifespan that produce sensitive windows of vulnerability and resilience to psychopathology. Understanding the developmental course of these changes may inform which treatments are best at what ages. Focusing on behavioral domains and neurobiological substrates conserved from mouse to human supports reciprocal hypothesis generation and testing that leverages the strengths of each system in understanding their development. Introducing human genetic variants into mice can further define effects of individual variation on normative development, how they contribute to risk and resilience for mental illness, and inform personalized treatment opportunities. This article emphasizes the period of adolescence, when there is a peak in the emergence of mental illness, anxiety disorders in particular. We present cross-species studies relating fear learning to anxiety across development and discuss how clinical treatments can be optimized for individuals and targeted to the biological states of the developing brain.

Figure 1. Developmental emergence of mental disorders

Based on data from (Kessler et al., 2005; Kessler and Wang, 2008)

Figure 2. Development of cued fear extinction parallels clinical response to cognitive behavioral therapy in anxiety disorders

(A) Reduced fear extinction learning in both mice and human during adolescence (Pattwell et al., 2012b). (B) Diminished treatment response during adolescence based on data from the Child/Adolescent Anxiety Multimodal Study (CAMS) (Walkup et al., 2008) subdivided by developmental stage (A) adolescents show nonsignificant decrease in responsiveness to cognitive behavioral therapy (Drysdale et al., 2014). *Adolescent extinction is significantly lower than childhood and adulthood.

Figure 3. Cross-species approach to individual variation in behavior

Introducing common genetic polymorphisms into the mouse genome supports parallel studies of brain structure and function using species-specific techniques across levels of biology. Polymorphic effects on conserved behaviors cross-validate and refine results from each species. Analysis of gene x development interactions can be identified in mice and specific hypotheses tested in humans.

Figure 4. Developmental expression of (A) BDNF and (B) components of the endocannabinoid system in the brain

Both systems peak in adolescence and may contribute to unique attributes of fear learning during this stage. Effects of BDNF Val66Met and FAAH C385A across development are presented in dotted lines.

Figure 5. Individual variation in cued-fear extinction learning

Extinction learning is attenuated in (A) humans with the BNDF Met (M) allele relative to non-Met allele (V) as measured by change in galvanic skin response **P<0.01. (B) This finding is paralleled in the BDNF SNP knock-in mice measured by less change in freezing behavior with repeated presentation of the conditioned stimulus alone during extinction trials *P<0.05 (VV vs. VM/MM). Adapted with permission from (Soliman et al., 2010). Extinction learning is enhanced in (C) humans with the FAAH A allele relative to C allele as measured by greater change in galvanic skin response. *P<0.05 (D) This finding is paralleled in the FAAH SNP knock-in mice measured by decreased freezing behavior with repeated presentation of the conditioned stimulus alone during extinction trials. **P < 0.01 homozygous knock-in mice vs wild-type controls; P<0.05 heterozygotes vs wild type. Adapted with permission from (Dincheva et al., 2015).

Figure 6. Leveraging behavioral sub-domains to overcome developmental liabilities

In adolescence acquisition of cued-fear associations is intact (A) relative to adults (*P<0.05 early vs late trials) but (B) extinction (difference in early vs late extinction trials reduced *P<0.05) contributing to risk for anxiety disorders and response to treatment. (C) Reconsolidation of fear associations is intact in adolescents and can reduce fear memories as well as in adults (difference in fear response with vs without reminder cue P<0.05) between suggesting that adding reconsolidation to exposure-based therapy for adolescents would improve clinical response. Adapted with permission from (Johnson and Casey, 2015).