Deborah Suchecki

Maternal regulation of the hypothalamic-pituitary-adrenal axis in the infant rat: the roles of feeding and stroking.

Twenty-four hours of maternal separation results in increased secretion of ACTH and corticosterone (CORT), suggesting the hypothalamic-pituitary-adrenal (HPA) axis is regulated by some aspect of maternal behavior. Previous results indicate that feeding plays a role in maintaining low levels of CORT in 12-day-old pups. In Experiment 1 basal and stress levels of CORT and ACTH were measured in maternally-deprived pups either provided or not with milk to determine whether: (1) feeding maintains ACTH secretion at low levels, and/or (2) feeding maintains the adrenal insensitive to ACTH. The results showed that, although ACTH levels were markedly low (compared to previous values reported by this laboratory) for both groups, only non-fed pups showed a robust increase in basal and stress CORT levels. During the deprivation period in Experiment 1, all pups were manually stroked to induce urination and defecation, suggesting an effect of stroking on ACTH secretion. Experiment 2 examined this hypothesis. Stroking suppressed stress-induced elevations of ACTH secretion due to maternal deprivation. CORT levels, however, were elevated in all deprived pups. The results indicate that maternal regulation of the infants HPA axis occurs at multiple levels. Feeding appears to regulate adrenal sensitivity, whereas anogenital stroking inhibits the activation of centrally-controlled components of the axis.

Effects of Maternal Deprivation on the ACTH Stress Response in the Infant Rat

Prolonged maternal deprivation during early ontogeny results in increased basal and stress-induced corticosterone levels. In the following experiments we examined whether these increases were due, at least in part, to augmented ACTH secretion. Thus, ACTH levels were measured in 24-hour maternally deprived and nondeprived 6-, 9-, and 12-day-old pups exposed to a mild stressor (i.e. saline injection followed by placement in a novel environment at room temperature). The results showed: (1) nondeprived pups showed a small response to saline--the response of deprived pups, however, was greater than that of nondeprived pups; (2) the magnitude of the response increased with age; (3) ACTH levels remained elevated for at least 30 min. Subsequent experiments examined whether the continuous exposure to novelty and/or loss of body heat could explain the persistence of this response. Neither variable affected the ACTH response to saline. Our results indicate that factors of maternal origin are partly responsible for the regulation of the ACTH response to stress. Furthermore, the persistence of the response suggests that the negative feedback system in the infant is immature.

Activation and inhibition of the hypothalamic-pituitary-adrenal axis of the neonatal rat: Effects of maternal deprivation.

These studies investigated the activation and inhibition (negative feedback) of the neonatal rat. The ACTH response of maternally deprived pups is persistently elevated for 30 min, suggesting a deficiency in the negative feedback system. In Experiment 1, we examined the time-course of corticosterone (CORT) and ACTH responses to a saline injection over a 120-min period during development. In deprived pups, CORT and ACTH were persistently elevated throughout the testing period, whereas only 15-day-old nondeprived pups showed ACTH and CORT elevations. Further nondeprived and deprived pups were exposed twice to ether (Experiment 2) or saline injections (Experiment 3) separated by a 1-h interval. Nondeprived pups showed an augmented ACTH response to double exposure to ether, but not to saline. No CORT response to either stimulus was observed. In response to one exposure of each stimulus, deprived pups showed increased ACTH and CORT values and no further elevation to repeated exposure. These results suggest the negative feedback system of neonates is immature, but partially functional in deprived pups. Moreover, nondeprived pups show a stressor-specific response to stress, whereas deprived animals show a similar response to different stimuli.

Disruptions of the mother-infant relationship and stress-related behaviours: Altered corticosterone secretion does not explain everything

The hypothalamic-pituitary-adrenal (HPA) axis is the main neuroendocrine system of response to stress, and an imbalance of this systems activity is believed to be at the core of numerous psychiatric pathologies. During the neonatal period, the glucocorticoid response to stress is maintained at low levels by specific maternal behaviours, which is essential for proper brain development. Effective evaluation of the impact of increased secretion of corticosterone during an essentially anabolic developmental period on adulthood behaviour involved separation of the neonate from its mother for periods ranging from 3 to 24h. It has been shown that disinhibition of the stress response is achieved by such procedures. The pioneering studies by Seymour Levine set the stage for a prolific and promising field of study that may help neuroscientists unveil the neurobiological underpinnings of stress-related disorders. Based on a series of studies, we propose that maternal separation and maternal deprivation change stress-related behaviours, but that corticosterone seem to be only partially involved in these changes in adulthood. It appears that extra-hypothalamic corticotrophin-releasing factor and neurotransmitter systems may be the primary mediators of these behavioural outcomes.

Pituitary-adrenal and interleukin-6 responses to recombinant interleukin-1 in neonatal rats

The cytokine interleukin-1 (IL-1) is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis. During postnatal development, the rat appears to be hyporesponsive to many stimuli which activate the HPA system in adulthood. Since hyporesponsiveness depends to a large extent on the stimulus, these experiments investigated the ontogeny of the HPA axis and interleukin-6 (IL-6) responses to IL-1 beta. Six-, 9-, and 18-day-old pups were injected with human recombinant IL-1 beta and plasma ACTH, corticosterone (CORT) and IL-6 levels were measured. IL-1 beta administration resulted in age-dependent endocrine and immune responses. The younger neonates secreted less ACTH and CORT and more IL-6. This was not due to a lowered capacity of the pituitary to synthesize and secrete ACTH since peptide levels following adrenalectomy did not reveal age differences. These data suggest that the diminished response to IL-1 beta is due to the immaturity of neural circuits which may be required to fully activate the HPA axis to immune signals.

Neuroendocrine Outcomes of Sleep Deprivation in Humans and Animals

Hormones can modulate and be modulated by sleep. This close relationship has been recognised for many decades. Sleep deprivation is an adverse condition that can alter the functioning of the neuroendocrine system, inasmuch as concentrations of hormones involved in anabolic processes, such as growth hormone (GH) are reduced, whilst levels of hormones involved in anabolic processes, such as glucocorticoids (GC) are increased. Therefore, prolonged periods of sleep deprivation, either internally or externally imposed, may lead to a wear and tear phenomenon, much similar to prolonged stressful conditions. In human beings, the vicious circle composed by sleep deprivation, stress and obesity has been claimed to be a major contributor to type II diabetes, cardiovascular diseases and ultimately, death

High corticosterone after olfactory social stimuli in a rodent model of traumatic stress.

Posttraumatic stress disorder (PTSD) is characterized by recurrent recollections and avoidance of the traumatic event and general hyperarousal that affect some victims of life-threatening events. In addition to the important application of animal fear conditioning paradigms in psychobiological studies of the mnemonic aspect of PTSD, special attention should be devoted to the exaggerated emotional and hormonal reactions to unconditioned stimuli, hallmarks of PTSD. Overreacting to harmless stimuli that do not bear resemblance to learned threats may be the result of a process of fear sensitization, which is vastly maladaptive and may interfere with daily life. It is argued that fear sensitization can possibly underpin the emergence of unconditioned behavioral disturbances seen in PTSD. Social withdrawal is also seen in PTSD, and physiological reactions may exacerbate behavioral avoidance to social situations. In this regard, we have evaluated fear conditioning and several behavioral indexes of fear sensitization, characteristic of posttraumatic stress in rats. We hypothesized that exposure to novel social stimuli might be associated with high hormonal levels in rats previously submitted to an unpredictable and inescapable highly intense electric footshock, a model of severe stress. We found that, in addition to a robust contextual fear conditioning and a consistent behavioral overreactive state, the hormonal responsiveness to a socioenvironmental stimulus was also exacerbated in rats exposed to the traumatic stress, compared with control rats. Our data corroborate previous studies showing affective sequalae in PTSD animal models and provide additional information on physiological reactions associated with traumatic stress in rats.