As a proverbial ‘watcher of the skies,’ I was delighted to come across a research study in plants that demonstrated the transgenerational transmission of defensive responses to threats to survival. Agarwal, Loforsch and Tollrian (1999) provided evidence that nature prepares offspring to cope with similar threats which confronted the mother without the offspring having been exposed to such threats (see their article “Transgenerational induction of defences in animals and plants” published in Nature, 401, 60). Herbivory resulted in the expression of inducible defenses in plants. In the radish plant, damage from caterpillars induces an increased production of mustard oil glycosides and a greater density of setose trichomes on newly formed leaves. These defenses protect the radish against subsequent predation. The seedlings derived from such plants showed significant changes in glycosinolate profiles and altered trichome expression: the number of trichomes per leaf was increased in the seedlings as a function of maternal herbivory. Only the mother radishes were exposed to herbivory in any form! Such changes are adaptive. Nature has a profound wisdom in which environment plays a highly significant role (a point I have been long emphasizing in relation to schizophrenia research). In this study, caterpillars gained significantly less weight, presumably from reduced consumption, when exposed to seedlings from damaged versus undamaged mothers.
This is only one example of this effect. Michael Meaney (2004) has commented on similar research in insects and reptiles: the helmet size of water fleas and the capacity for flight in grasshoppers are only a few examples of this natural phenomena (see Michael Meaney’s “The nature of nurture: maternal effects and chromatin remodeling” in Essays in Social Neuroscience edited in 2004 by John Cacioppo and Gary Berntson for The Massachusetts Institute of Technology Press). The fundamental principle here is that of maternal regulation of the development of rudimentary defensive responses to threat. Meaney, of the Douglas Hospital Research Centre, Montreal , Canada , notes:
“These are classic examples of epigenetic, or nongenomic, inheritance, where traits of the parents are transmitted to offspring in a manner not dependent on information encoded in the nuclear genes. Maternal effects in plants and insects alter the form and intensity of defensive responses to threat. The environmental experience of the mother is thus translated through an epigenetic mechanism of inheritance into phenotypic variation in the offspring. Indeed, maternal effects could result in the transmission of adaptive responses across generations” (p. 5).
Meaney and colleagues have demonstrated that similar effects occur in mammals. In the latter, there are highly stable individual differences in maternal licking and grooming (LG) of offspring. These naturally occurring variations in maternal care are associated with individual differences in LHPA (limbic-hypothalamic-pituitary-adrenal axis) responses to stress/challenge. As adults, offspring of mothers who display high LG and arched-back nursing (high-LG-ABN mothers) are behaviorally less fearful and show attenuated LHPA responses to stress/challenge than offspring of mothers that are low in LG-ABN. Cross-fostering research demonstrated that the biological offspring of low-LG-ABN reared by high-LG-ABN dams resemble the normal offspring of high-LG-ABN (and vice versa). This research has also been corroborated by research done by Stephen Suomi and colleagues at the Laboratory of Comparative Ethology, National Institute of Child health and Human development, NIH (see S. Suomi’s “Aggression, serotonin, gene-environment interactions in rhesus monkeys” also in Essays in Social Neuroscience edited in 2004 by John Cacioppo and Gary Berntson for The Massachusetts Institute of Technology Press).
Meaney noted that maternal behavior in the rat permanently alters the development of LHPA responses to threat through tissue-specific effects on gene expression. The magnitude of the LHPA response to threat is a function of the neuronal stimulation of hypothalamic corticotropin-releasing factor (CRF) release which then activates the pituitary-adrenal system, as well as modulatory influences, such as glucocorticoid (cortisol in humans) negative feedback that inhibits CRF synthesis and release and therefore attenuates LHPA responsiveness to threat. The adult offspring of high-LG-ABN compared with low-LG-ABN demonstrate increased hippocampal glucocorticoid receptor expression and enhanced glucocorticoid feedback sensitivity. The offspring of high-LG also demonstrate decreased hypothalmic CRF expression and attenuated LHPA responses to stress.
Transcription factors such as nerve growth factor-inducible factor A (NGFI-A) regulate gene expression, and thus provide a cellular bridge between genes and environmental factors. However, the relation is constrained because DNA operates within a chromatin context. The DNA sequences which form our ‘genetic code’ are wrapped around histone proteins and are only variably accessible to transcription factors. The positive charge of the histones and negatively charged DNA form bonds which preclude transcription factors from binding to DNA regulatory sites (promoter/enhancer). However, the histone acetyl transferases (HAT’s) that acetylate histone tails, thereby neutralizing the charge, relaxes the tightly-coupled histone-DNA packaging system to a state in which transcription factors can enter the fray and bind to DNA sites. There are structural changes to DNA that result in silencing of DNA transcription. DNA methylation (which I believe is really where the ‘genetic action’ lies in many of the disorders we label the schizophrenias, i.e., gene-environment interaction, and as underscored by psychoanalyst Peter Fonagy in his “The interpersonal interpretive mechanism: the confluence of genetics and attachment theory in development” in Emotional Development in Psychoanalysis, Attachment Theory and Neuroscience: Creating Connections edited in 2003 by Viviane Green for Brunner-Routledge, in humans it is the environment as actually experienced which counts) is a stable, epigenomic mark that occurs at cytosine nucleotides and it attracts a group of enzymes called “histone deacetylases” which prevent histone acetylation and thereby preserve the tightly-coupled histone-DNA relation. DNA methylation is therefore associated with a stable suppression in gene transcription and is the pathway in which genes are silenced. Importantly for those researchers attempting to challenge the neurogenetic and neurobiological reductionism endemic in much of scientific research and therefore in the popular press/media as well, this may be the process by which maternal care during postnatal life can program the expression of specific genes in the brain and body.
Meaney et al (2003) researched the methylation of the exon I7 glucocorticoid receptor promoter, which revealed significant differences as a function of maternal care. Significant differences in a single cytosine within the NGFI-A consensus sequence (the DNA sequence to which NGFI-A binds) were revealed in the offspring of high and low LG-ABN mothers. Methylation always occurred in the offspring of low-LG mothers and rarely so in the offspring of high-LG mothers. These differences emerged remarkably within the first week of life. In addition, cross-fostering resulted in changes associated with the rearing mother within 12 hours of birth. Meaney concluded:
“Thus DNA methylation does appear to be one mechanism for the enduring maternal effects on the development of defensive responses to threat in mammals...DNA methylation could serve as an intermediate process that imprints dynamic environmental experiences on the fixed genome resulting in stable alterations in phenotype” (p.11).
In relation to humans, anxiety could make the caregivers less sensitive to their offspring. Research in mammals demonstrates that stress appears to consistently decrease parental investment in their young, resulting in patterns of parental care that increase stress reactivity in the offspring. Environmental adversity is translated into patterns of maternal care which enhances the defensive responses of the offspring, much as John Bowlby suggested psychoanalytically: that offspring internalize the defenses of their parents. Depending on the actual environment confronting the offspring, transgenerational trauma can be either adaptive or non-adaptive (e.g., in Hitler’s Germany, hypervigilance might be very adaptive in the offspring of traumatized parents, whereas it would not be in an environment which is not as adverse).
Brian Koehler PhD
New York University
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brian_koehler@psychoanalysis.net
