One of the most intriguing genes highlighted by Charney (sect. 4.1.1) is that of brain-derived neurotrophic factor (BDNF), a growth factor implicated by numerous research studies as an important mediator of neuronal plasticity. Although Charney notes the impact of increased hippocampal BDNF expression on neurogenesis–via cell signaling that promotes neuronal survival, growth, and differentiation–it is valuable to recognize that BDNF is prevalently expressed not only in the hippocampus, but also in the cerebral cortex and other limbic structures. BDNF also functions in these regions as a biomolecular mediator of neural plasticity and in the corresponding development of neuroanatomical circuits and complex behavioral phenotypes. Exploring–more in-depth–the functions of BDNF provides insight into the phenotypic and behavioral significance of gene-environment interactions outlined by Charney (sect. 5.2).

Following transcription and translation of the BDNF gene, protein products are packaged into large vesicles within neurons and released following neuronal depolarization in an activity-dependent manner, comparable to neurotransmitter release (Mowla et al. Reference Mowla, Pareek, Farhadi, Petrecca, Fawcett, Seidah, Morris, Sossin and Murphy1999) and consistent with Hebbian theory. Deficiencies of BDNF can contribute to underdevelopment of neurons. Low levels of BDNF mediate age-related declines in hippocampal volume and memory function (Erickson et al. Reference Erickson, Prakash, Voss, Chaddock, Heo, McLaren, Pence, Martin, Vieira, Woods, McAuley and Kramer2010). Moreover, the environments in utero, during early life, and in adulthood can have long-lasting effects on the methylation patterns and chromatin modeling of the BDNF gene in cells across the brain, affecting how much or how little growth factor is available in different neuroanatomical regions.

BDNF contains at least eight distinct promoter regions that together with differential alternate splicing, polyadenylation, and promoter expression can generate over 18 different isoforms. The isoforms are selectively localized within neurons, contributing to highly specific regional, spatial, and temporal regulation of neural plasticity. Epigenetic modifications, including DNA methylation and histone acetylation, meticulously regulate the BDNF gene. The effect Charney notes of increased hippocampal plasticity following exercise (sect. 4.1.1) has indeed been demonstrated to be mediated by chromatin remodeling of BDNF, including histone acetylation and demethylation of promoter regions (Gomez-Pinilla et al. Reference Gomez-Pinilla, Zhuang, Feng, Ying and Fan2011). Interestingly, promoters I and III have been found to be transcriptionally upregulated in the amygdala during consolidation of fear learning (Rattiner et al. Reference Rattiner, Davis and Ressler2004), and BDNF has been shown to be necessary in the hippocampus for extinction of aversive memories (Heldt et al. Reference Heldt, Stanek, Chhatwal and Ressler2007).

Human clinical studies have found strong evidence that patients suffering from depression have lower levels of serum BDNF compared to healthy subjects, deficiencies that can be ameliorated with antidepressants (Sen et al. Reference Sen, Duman and Sanacora2008). Other pharmaceuticals and mood stabilizers have demonstrated effects as well: Lithium, valproic acid, and several other HDAC inhibitors have been shown to upregulate BDNF promoter IV expression (Yasuda et al. Reference Yasuda, Liang, Marinova, Yahyavi and Chuang2009). A study of postmortem suicide victims' brains revealed hypermethylation at CpG sites in the BDNF promoter IV, corresponding to lower BDNF mRNA levels in specific brain areas (Keller et al. Reference Keller, Sarchiapone, Zarrilli, Videtic, Ferraro, Carli, Sacchetti, Lembo, Angiolillo, Jovanovic, Pisanti, Tomaiuolo, Monticelli, Balazic, Roy, Marusic, Cocozza, Fusco, Bruni, Castaldo and Chiariotti2010). Using serum samples of patients living with major depression, another study recently found hypermethylation of CpG sites in BDNF promoter I (Fuchikami et al. Reference Fuchikami, Morinobu, Segawa, Okamoto, Yamawaki, Ozaki, Inoue, Kusumi, Koyama, Tsuchiyama and Terao2011). These findings highlight the potential of using an individual's BDNF methylation profile as an epigenetic biomarker of depression. Moreover, they add credence to Charney's supposition of a paradigm shift away from the prediction of complex phenotypes using the genetic code alone, and toward greater recognition of epigenetic/neogenetic effects (sect. 10).

Highly variable levels of BDNF expression–across brain regions and between individuals–have implications for behavioral phenotypes. BDNF serves as a model system that exemplifies the significance of epigenetic modifications in neurodevelopment and behavioral plasticity, which Charney posits (sect. 5.2). The resemblance between high licking and grooming rat mothers and their biological or fostered pups in regard to stress-related behavioral phenotypes and subsequent rearing behavior (sect. 5.2.1) has been further studied in relation to BDNF; findings corroborate the importance of the perinatal environment. Mice experiencing higher levels of perinatal care have demonstrated a propensity for greater social interactions in adulthood, correlated with increased hippocampal BDNF levels (Branchi Reference Branchi2009). Conversely, infant isolation has been associated with reduced levels of BDNF mRNA in the prefrontal cortex, hippocampus, and amygdala. Epigenetic studies of BDNF in rats have demonstrated an association between early life adversity and hypermethylation of BDNF promoter IV in the prefrontal cortex and hippocampus (Roth & Sweatt Reference Roth and Sweatt2011). The methylation effects have been found to not only persist into adulthood, but also to be intergenerational, with significant behavioral implications.

In human studies, prenatal exposure to maternal cigarette smoking has been associated with higher rates of BDNF promoter VI methylation in adolescent blood samples, and these adolescents showed an increase in drug experimentation (Toledo-Rodriguez et al. Reference Toledo-Rodriguez, Lotfipour, Leonard, Perron, Richer, Veillette, Pausova and Paus2010), a finding potentially consistent with “developmental programming” (sect. 7). Although intriguing, additional human studies are necessary to validate the numerous findings in animal models, despite the logistical challenges of robust epigenetic human studies.

Biological or statistical epistasis has been reported between BDNF and the serotonin transporter (SLC6A4) (Grabe et al. Reference Grabe, Schwahn, Mahler, Appel, Schulz, Spitzer, Fenske, Barnow, Freyberger, Teumer, Petersmann, Biffar, Rosskopf, John and Volzke2012), the dopamine receptor (DRD2) (Montag et al. Reference Montag, Markett, Basten, Stelzel, Fiebach, Canli and Reuter2010), and more recently the glucocorticoid receptor (Jeanneteau et al. Reference Jeanneteau, Lambert, Ismaili, Bath, Lee, Garabedian and Chao2012). In the latter case, BDNF expression was shown to regulate the release of corticotrophin-releasing hormone in the hypothalamic-pituitary-adrenal (HPA)-axis.

In essence, BDNF functions as a primary biomolecular substrate for encoding environmental experiences into neurons. The growth factor mediates the formation of neural engrams that derive from negative or positive life experiences–engrams in neural circuits and the HPA-axis that later direct adulthood stress responses and behavioral phenotypes. The epistatic and pleotropic effects of BDNF expression have implications for mood, temperament, behavior, and development of neuropsychiatric conditions (Boulle et al. Reference Boulle, van den Hove, Jakob, Rutten, Hamon, van Os, Lesch, Lanfumey, Steinbusch and Kenis2012). Stress, adversity, physical activity, early environment, enrichment, aging, and trauma can all change levels of gene expression, which can subsequently mediate neurodevelopmental and behavioral changes. In Charney's postgenomic paradigm, additional human subjects research with BDNF is necessary to better elucidate the functional trajectory from biomolecular science (genetics and neogenetics) to neurodevelopment (neuroanatomical structures/circuits) to behavioral phenotypes (normal and pathologic). This understanding will illuminate better therapeutic targets and facilitate the prevention of pathologic neurodevelopment.