AND THE DEVELOPING
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
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
Long term changes in the LHPA axis
Hormone Relationship in LHPA Axis
The limbic–hypothalamic–pituitary–adrenal axis.
The structures involved in this system include: the hippocampus, periventricular nucleus (PVN) of the hypothalamus, the anterior pituitary and the adrenal gland. Inhibition of the stress response is accomplished by three mechanisms: rate sensitive feedback, intermediate feedback and delayed feedback.GR, glucocorticoid receptor; MR, mineralocorticoid receptor;
CRH, corticotropin releasing hormone; AVP, vasopressin;
POMC, proopiomelanocortin; ACTH, adrenocorticotropin;
hnmRNA, heteronuclear mRNA; pm, posterior magnocellular PVN;
mp, medial parvocellular PVN; ME, median eminence;
al, anterior lobe; il, intermediate lobe;
nl, neural lobe; ctx, cortex; med, medulla.
Clinical Studies: Exploring the Intrauterine and Post-natal Environment of Women at Risk for Depression and Their Offspring
Maternal Depression Risk, Infant Attachment and Cortisol
Maternal Child Interaction is important