Nurture & Resilience

Section Temperament & Stress/Animal Models clearly conveys that there are inborn mechanisms that determine how organisms will respond to certain environmental stressors. Micheal J Meaney of McGill University has been leading animal research since the 1980s that monitors the impact of different types of nurture on nature and early nurture’s delayed effects into adulthood. Dr. Meaney and colleagues found that removing rat pups from their mother’s daily for 15 minutes during their first 21 postnatal days, forced mothers to lavish their pups with post-reunion attention that they normally would not do if the pups were left undisturbed in their respective nests. The experimental paradigm forced mothers to nurture more often and to be better mothers. “Mothers of handled litters have shorter but more frequent next bouts and spend significantly more time manipulating their pups, especially licking of pups than mothers of non-handled pups. This latter effect is likely due to the fact that mothers of handled litters are getting on and off their pups more frequently and licking is associated with termination of each bout. Handled pups show increased ultrasonic vocalization and such calls (further) elicit maternal care or retrieval…Handling (also) increases arched back nursing- non handled mothers more frequently adopt a blanket posture lying over the pups.” (Francis et al., 1996, p. 139-40.) Increased maternal care provides offspring with increased tactile and thermal stimulation that regulates and decreases the pup’s body temperature in response to stress (Meaney et al., 1991). Dr. Meaney and associates found that both handled (H) and non-handled (NH) rats into adulthood do not differ from one another in as far as their resting hormonal levels (Bhatnagar & Meaney, 1995). Nonhandled rats at postnatal day 21 experience significantly increased plasma CRH and ACTH levels at 20, 40, 120 minutes during cold and restraint stress and at 40 minutes post stress (Meaney et al., 1993; Bhatnagar & Meaney, 1995). Handled adult rats’ responses to persistent chronic stress are briefer (Meaney et al., 1993) and better regulated (Meaney et al., 1991) by corticolimbic structures as a result of enhanced neural development (Liu et al., 2000). This is evidenced in increased glucocorticoid receptor (GR) expression (Meaney et al., 1989) and serotonin (5-HT2) turnover (Mitchell et al., 1990) in the hippocampus. In addition previously handled adult rats demonstrate increased type II or GR mRNA in dorsal regions of the dentate gyrus, Cornu Amonnis (CA1) and CA2 of the hippocampus, with the largest effect in the CA1 region (O’Donnell et al., 1994; McCormick et al., 2000). In fact, handling’s effects on GR density are greatest if it occurs between postnatal days 1-7 rather than postnatal days 8-14 (Meaney & Aitken, 1985) suggesting a critical period for its occurrence. The increase in hippocampal neurons and GR binding impact the later adult well into senescence as evidenced in lower basal plasma glucocorticoid concentrations (Meaney et al., 1988), decreased ACTH stress responsivity and enhanced corticosterone diurnal variation in handled elderly (Meaney et al., 1992). The type I receptor, the mineralocorticoid receptor (MR), (which also carries corticosterone) shows broader expression, though less dense, throughout the hippocampus, with little effect in the dorsal region. (As will be discussed in section 1.5 of this web site, maternal separation during early ontogenetic development tends to impair MR mRNA expression in this region as well. Therefore a relationship exists between early enrichment and GR expression and early deprivation and MR developmental alterations. The significance of needs further analysis.) Previously handled rat adults at 4-6 months secrete less ACTH and need less glucocorticoid corticosterone to return hormonal activity back to resting states (Meaney et al., 1989; Liu et al., 1997; Tejedor-Real et al., 1998). In other words handled rats’ stress systems are more responsive to cooling down from the stressed state. In addition, the rate of neural death in the hippocampus of handled rats is slower at 22 months of age when compared with non-handled counterparts (Meaney et al., 1988,1991, 1992). Handled rats seem to maintain their mental acuity well into their senior years. Aged non-handled rats exhibit higher evening plasma ACTH and corticosterone levels (Meaney et al., 1992) which is reflective of heightened sustained stimulation of stress circuitry.

Dr. Meaney and research associates observed many different strains of rats. They discovered (Anisman et al., 1998; Francis et al., 1999abc) one strain, the Long-Evans strain, that has two types of female rats who mother in two different ways. One type of naturally occurring style of mothering in the Long-Evans rat has a more anxious temperament. This type of mother tends to be more reactive to stressors. These types of mothers (low LG-ABN), low licking, grooming arched-back nursing type, exhibit greater hormonal sensitivity (evidenced in greater CRH, ACTH, and corticosterone secretion), behavioral disturbances to stressors and impaired learning, evidenced in increased symptoms of anxiety and difficulties in learning strategies to navigate a spatial water-maze. Low LG-ABN mothers (Liu et al., 1999) naturally tend to engage in blanket nursing postures, provide fewer licks to their pups if left undisturbed, and produce offspring who into adulthood themselves share similar responses to stress and limitations in learning. Another Long-Evans rat with a different maternal style, high licking, grooming arched-back nursing mother (high LG-ABN), (Francis et al., 1999ab) is less vulnerable to stress, secretes fewer stress hormones in response to stress, recovers more quickly from stress, is more responsive and better able to manage and learn new strategies to navigate a spatial water-maze task, has less hippocampal cell loss related with aging, and produces offspring who are more resilient to the effects of stress into adulthood. These mothers more spontaneously and frequently lick their pups and engage in arched back nursing positions that tended to wrap mother’s body around their pups to stimulate touch during each nursing bout (Francis et al., 1996) without experimenter manipulation. The naturally occurring high LG-ABN mother parented in a way that was more similar to mothers in the experimenters’ handling paradigms noted above.

Dr. Meaney and associates (Francis et al., 1999ab) switched litters and mothers so the stress responsive low LG-ABN mothers raised the more resilient biological offspring of high LG-ABN mothers. High LG-ABN raised the more stress responsive offspring of the low LG-ABN mothers. This has been called a “cross fostering” design (Frances et al., 1999bc). Low LG-ABN pups raised by high LG-ABN as adults have been found to be more resilient in their responses to stress, secrete less stress hormones in response to stress, are better able to learn the spatial water maze task and suffer far less hippocampal cell loss with aging, than those siblings who had been raised by their natural low LG-ABN mothers. These strengths are mediated by increased GR mRNA expression in the hippocampus and enhanced glucocorticoid negative feedback sensitivity by decreasing hypothalamic CRH mRNA levels (Frances et al., 1999a). It is not the maternal time devoted to raising offspring as both high and low LG-ABN spent equivalent time parenting, but rather the nature of the interaction between maternal figure and offspring that influences offspring neural development. In addition, as biologically low LG-ABN offspring of high LG-ABN mothers parented their own offspring, they tend to lick their own pups more frequently and nurse them arched back as their adopted mothers who had parented them. Interestingly they nurture their own offspring using the models presented by their high LG-ABN mothers into adulthood despite their low LG-ABN genetic predisposition. Offspring born to resilient high LG-ABN who were raised by adopted low LG-ABN mothers respond to stress in behavioral and neurohormonal equivalence as low LG-ABN pups who had been raised by high LG-ABN mothers. Stress responsive pups born to low LG-ABN mothers need optimal, preferred nurturing that modulates the pup’s stress response to help to overcome the expression of genetically programmed behaviors. Resilient pups born to high LG-ABN demonstrated increased resiliency even when maternal care was merely good enough.

Francis and associates (2000, 2002a) demonstrated that oxytocin receptor levels in the central nucleus of the amygdala, medial preoptic area (MPO) of the hypothalamus, and bed nucleus of the stria terminalis (BNST) are significantly higher in high LG-ABN mothers than low LG-ABN mothers. This finding suggests that nurturing behaviors stimulate oxytocin expression in these regions. Central administration of oxytocin regulates maternal behaviors of pup-licking and arched back nursing and its antagonism decreases these behaviors (Pedersen & Boccia, 2002). Maternal separation (Francis et al., 2002b) for 3 hours per day from postnatal day (pnd) 1-14 increases stress induced fearfulness and corticosterone secretion at postnatal day 70. Environmental enrichment (providing a complex burrow system filled with toys from pnd 22-70 to maternally separated rats from pnd 1-14) was unable to reverse the effects of earlier separation on CRH gene expression in the paraventricular nucleus of the hypothalamus and glucocorticoid receptor mRNA in the hippocampus. However, exposure to later enriching environments was able to decrease pnd 70 plasma corticosterone secretion in response to stress and to increase exploration in new environments, reflecting decreased anxiety to novelty in this strain.

In summary, infant rats with inborn vulnerable temperaments respond positively to their adopted nurturing mothers and later reproduce their mother’s parenting styles as they parent their own offspring. This was in part mediated by limbic oxytocin receptor activity. Infant rats with genetically predisposed resilient temperaments respond with resiliency to less than optimal parenting models; their biological resiliency allows them to later nurture their own offspring in their own genetically prescribed manner. This resiliency may also be mediated by genetically predisposed expression of limbic oxytocin receptors. These studies suggest that maternal behaviors and temperament can be transmitted from one generation to another (Francis et al., 1999a). Later enrichment programs can modify the impact of deficits in maternal behaviors, but enhanced hippocampal GR expression and ability to contain the stress response is lost after the window of opportunity elapses.

References

Anisman H; Zaharia MD, Meaney MJ, Merali Z (1998): Do early-life events permanently alter behavioral and hormonal response to stressors? Int J Dev Neurosci, 16(3-4): 149-64.

Bhatnagar S & Meaney MJ (1995): Hypothalamic-pituitary-adrenal function in chronic intermittently cold-stressed neonatally handled and non-handled rats. J Neuroendocrinol, 7(2): 97-108.

Francis DD, Diorio J, LaPlante P, Weaver S, Seckl JR, Meaney MJ (1996): The role of early environmental events in regulating neuroendocrine development. Moms, pups, stress, and glucocorticoid receptors. Ann N Y Aca Sci, 794: 136-52.

Francis DD, Champagne FA, Liu D, Meaney MJ (1999a): Maternal care, gene expression, and the development of individual differences in stress reactivity. Ann N Y Aca Sci, 896: 66-84.

Francis D, Diorio J, Liu D, Meaney MJ (1999b): Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science, 266(5442): 155-8.

Francis DD & Meaney MJ (1999c): Maternal care and the development of stress responses. Curr Opin Neurobio, 9(1): 128-34.

Francis DD, Chapagne FC, Meaney MJ (2000): Variations in maternal behavior are associated with differences in oxytocin receptor levels in the rat. J Neuroendocrinol, 12(12): 1145-8.

Francis DD, Young LJ, Meaney MJ, Insel TR (2002a): Naturally occurring differences in maternal care are associated with the expression of oxytocin and vasopressin (V1a) receptors: gender differences. J Neuroendocrinol, 14(5): 349-53.

Francis DD, Diorio J, Plotsky PM, Meaney MJ (2002b): Environmental enrichment reverses the effects of maternal separation on stress reactivity. J Neurosci, 22(18): 7840-3.

Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A, Sharma S, Pearson D, Plotsky PM, Meaney M (1997): Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science, 277(5332): 1659-62.

Liu D, Diorio J, Day JC, Francis DD, Meaney MJ (2000): Maternal care, hippocampal synaptogenesis and cognitive development in rats. Nat Neurosci, 3(8): 799-806.

McCormick JA, Lyons V, Jocobson MD, Noble J, Diorio J, Nyirenda M, Weaver S, Ester W, Yau JL, Meaney MJ, Seckl JR, Chapman KE (2000): 5’-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific: differential regulation of variant transcripts by early-life events. Mol Endocrinol, 14(4): 506-17.

Meaney MJ, Aitken DH (1985): The effects of early postnatal handling on the development of hippocampal GRs: Temporal parameters. Dev Brain Res, 22: 301-04.

Meaney MJ, Aitken DH, van Berkel C, Bhatnagar S, Sapolsky RM (1988): Effect of neonatal handling on age-related impairments associated with the hippocampus. Science, 239(4841): 766-68.

Meaney MJ, Aitken DH, Viau V, Sharma S, Sarrieau A (1989): Neonatal handling alters adrencortical negative feedback sensitivity and hippocampal type II glucocorticoid receptor binding in the rat. Neuroendocrinology, 50(5): 597-604.

Meaney MJ, Mitchell JB, Aitken DH, Bhatnagar S, Bodnoff SR, Iny LJ, Sarrieau A (1991): The effects of neonatal handling on the development of the adrenocortical response to stress: implications for neuropathology and cognitive deficits in later life. Psychoneuroendocrinology, 16(1-3): 85-103.

Meaney MJ, Aitken DH, Sharma S, Viau V (1992): Basal ACTH, corticosterone-binding globulin levels over the diurnal cycle, and age-related changes in hippocampal type I and type II corticosteroid receptor binding capacity in young and aged, handled and non-handled rats. Neuroendocrinology, 55(2): 204-13.

Meaney MJ, Bhatnagar S, Larocque S, McCormick C, Shanks N, Sharma S, Smythe J, Viau V, Plotsky PM (1993): Individual differences in the hypothalamic-pituitary-adrenal stress response and the hypothalamic CRF system. Ann N Y Acad Sci, 697: 70-85.

Mitchell JB, Iny LJ, Meaney MJ (1990): The role of serotonin in the development and environmental regulation of type II corticosteroid receptor binding in rat hippocampus. Brain Res Dev Brain Res, 55(2): 231-5.

O’Donnell D, Larocque S, Seckl JR, Meaney MJ (1994): Post-natal handling alters glucocorticoid, but not mineralocorticoid messenger RNA expression in the hippocampus of adult rats. Brain Res-Mol Brain Res, 26(1-2): 242-8.

Pedersen CA, Boccia ML (2002): Oxytocin links mothering received, mothering bestowed and adult stress responses. Stress, 5(4): 259-67.

Tejedor-Real P, Costela C, Giber-Rahola J (1998): Neonatal handling reduces emotional reactivity and susceptibility to learned helplessness. Involvement of catecholaminergic system. Life Sci, 62(1): 37-50.