STRESS AND THE DEVELOPING
LIMBIC–HYPOTHALAMIC–PITUITARY–ADRENAL (LHPA) AXIS

Introduction

Numerous behavioral, endocrine and clinical studies have shown that various stressors, which occur early in life, can produce profound alterations in growth and development. The endocrine stress response system in mammals is called limbic-hypothalamic-pituitary-adrenal axis (LHPA). It helps the body remain stable under physiological and psychological stress. Both rapid activation and rapid inhibition of the stress response are necessary in maintaining stress responsiveness. Failure to activate the stress response places the organism in a very fragile state. Failure to inhibit the stress response once initiated, increases the vulnerability to diseases and results in permanent effects on growth and differentiation of a number of developing systems, including the central nervous system.

The rodent is a good model to study the repercussion of early life adverse environment. However, the developmental time frame of the brain development and LHPA physiological function needs to be considered when relating animal studies to human development. In humans, excluding the cerebellum and hippocampus, neuronal proliferation is essentially completed before 24 weeks gestation. Beyond 24 weeks, glia continues to proliferate and oligodendroglia maintain ongoing myelination, with a peak in brain growth occurring near term. In contrast to humans, rodents experience their brain growth spurt after birth. It is estimated that on postnatal day 10 the rodent brain is roughly equivalent to that of the full term human brain of 38 to 40 weeks post-conception. Extrapolating from this model, the brain of a rodent pup at birth (P1) corresponds to that of a human fetal brain at or near 19–21 weeks gestation. The P2 animals approximates that of a 22-23 week human in terms of neurodevelopment, the P3 corresponds with that of a 24-26 week human, and the P6 pup to that of a 30-32 week human. Given these parallels, the neonatal rodent pup provides an ideal model in which to investigate effects of stress and of prolonged, tapering course of neonatal corticoid exposure on the developing brain.

An important consideration is that the ability to respond to stressful events develops after birth in the rodent. Animal studies suggest that early life events can alter the developmental trajectory of brain circuits including those that are critical for behavioral and hormonal responses elicited by changes in the environment that can be construed as stressful. Epidemiological studies in the human suggest that there is a link between adverse early life experiences and psychopathology (e.g. depression, anxiety, drug use). Simply being touched and held during the first few years of childhood may set up positive stress-response patterns that last a lifetime.

Rodent Studies: Inducing Long-Term Changes in the LHPA Axis

Because the development of hypothalamic-pituitary-adrenal (HPA) responses to stress can be modified by early environmental events, we utilize several paradigms in our laboratory to study the development of brain circuits. Handling is one of these paradigms. As adults, animals exposed to brief periods of handling daily for the first weeks of life show reduced ACTH and adrenal corticosterone level and enhanced glucocorticoid negative-feedback sensitivity compared with nonhandled animals. These differences are apparent as late as 24 to 26 months of age indicating that the handling effect on HPA function persists throughout life. Other laboratories have explored the neurobiology of 'handling'. We take advantage of the 'handling' manipulation to investigate the repercussion of prenatal and postnatal adverse stimuli. We can also begin to elucidate the contribution of the specific hormones and neurotransmitters involved in the long term anxiogenic phenotype induced by early life experiences.

Animal models of early life stress utilized in the Vazquez Lab

Clinical Studies: Exploring the Intrauterine and Post-natal Environment of Women at Risk for Depression and Their Offspring