Effects of Early Life Stress on Neuroendocrine and Neurobehavior: Mechanisms and Implications

Response of the hypothalamus-pituitary-adrenal axis to stress and negative feedback. CRH is transported by means of the hypophyseal portal system to the pituitary gland, where it elicits the release of ACTH from the anterior lobe of the pituitary gland, which finally stimulates the secretion of glucocorticoids from the adrenal glands. In each of these steps, the original signal can not only be amplified but can also undergo modulation, e.g., feedback regulation. Glucocorticoids in turn act back on the hypothalamus and pituitary (to suppress CRH and ACTH production) in a negative feedback cycle. CRH = corticotrophin-releasing hormone; ACTH = adrenocorticotropic hormone.

Long-term effects of early life stress on neurobehavior. The early environment modifies the interplay between the limbic system and hypothalamic-pituitary-adrenal axis and influences long-term neurobehavioral development (modified from Fig. 1 in Ref. 65). LHPA = limbic-hypothalamic-pituitary-adrenal axis.

Model of glucocorticoid effects on excitotoxicity. Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system and activates both ionotropic receptors and G protein-coupled (mGlu) receptors. Activation of these receptors evokes cellular responses by means of increased iCa²⁺ and is responsible for basal excitatory synaptic transmission and many forms of synaptic plasticity such as LTP and LTD. The iCa²⁺ level varies with Ca²⁺ influx through both the glutamate-operated Ca²⁺ channel and VSCC and with the mGlu receptor-mediated calcium release from intracellular stores. However, high concentrations of glutamate cause cell death through the excessive activation of these receptors. Overactivation at NMDA receptors triggers an excessive entry of Ca²⁺, initiating a series of cytoplasmic and nuclear processes that promote neuronal cell death, such as activating NOS, lipases, proteases, and endonucleases. All these mechanisms, together with enhanced oxidative stress can induce cell death through necrosis as well as apoptosis. Glucocorticoids seem to enhance the postsynaptic response by inhibiting the glutamate uptake by glial cells and by preferentially stimulating the genomic expression of the NMDA receptor subunit, NR2B, that increases Ca²⁺ influx. Furthermore, glucocorticoid receptor activation increases Ca²⁺ current through VSCCs (modified from Fig. 2 in Ref. 65). VSCC = voltage-sensitive Ca²⁺ channel; NMDA = N-methyl-d-aspartic acid; AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; iCa²⁺ = intracellular Ca^2+; mGlu = metabotropic glutamate; LTP = long-term potentiation; LTD = long-term depression; NOS = nitric oxide synthase.