Biomedical subjects
Publications and source records attributed to Joram Feldon.
Rat, monkey, and human infants have evolved to expect certain patterns of care. Spontaneous or experimental deviations of care from the norm result in infant stress responses. Hyperactivity of immature stress systems such as the limbic-hypothalamic-pituitary-adrenal axis and the limbic-sympatho-adrenomedullary axis can alter their subsequent reactivity across the life span.
Early life stress, involving activation of the hypothalamic-pituitary-adrenal (HPA) system, is associated with altered functioning of stress-related systems in adulthood. In the rat, postnatal development is characterized by low basal HPA activity and stress hyporesponsiveness, and infant exposure to atypical glucocorticoid levels leads to chronic alteration of HPA function and HPA-dependent peripheral and central processes. There have been few studies of primate HPA ontogeny, and here we report a study of changes in pituitary-adrenal function between birth and adulthood in the common marmoset monkey. In this simian primate, basal plasma ACTH and cortisol levels were actually elevated in neonates (ACTH, 141 +/- 28 pg/ml; cortisol, 1903 +/- 326 microg/dl) and wk 4 infants (ACTH, 114 +/- 9 pg/ml; cortisol, 290 +/- 8 microg/dl) relative to month 2 infants, juveniles (month 6), subadults (month 12), and adults (>2 yr; ACTH, 37 +/- 4 to 61 +/- 8 pg/ml; cortisol, 101 +/- 2 to 195 +/- 4 microg/dl). In contrast to older life stages, neonates lacked circadian change in their plasma cortisol levels, and this state of consistently high cortisol was associated with large adrenal glands in addition to high ACTH levels. Cerebrospinal fluid cortisol levels were, in accord with plasma levels, higher in wk 4 infants than in juveniles and subadults. In terms of stress response, month 2 infants demonstrated ACTH and cortisol peak stress responses similar to those at older life stages (infant stress cortisol, 185 +/- 36% of basal; subadult stress cortisol, 174 +/- 6% of basal); whereas infant ACTH recovery was also similar to that in older subjects, their cortisol poststress recovery was retarded. This primate, it is proposed, provides an excellent complementary model in which to test hypotheses derived from the rat model relating to HPA system ontogeny and the chronic effects and biomedical implications of hypercorticoidism during early life.
Latent inhibition (LI) refers to retarded conditioning to a stimulus as a consequence of its non-reinforced pre- exposure. LI is impaired in some subsets of schizophrenic patients and in rats treated with amphetamine. Antipsychotic drugs (APDs) potentiate LI under conditions that are insufficient to produce LI in control animals, namely, low number of pre-exposures or high number of conditioning trials. The present experiments tested the proposition that LI potentiation under both conditions stems from the action of APDs in the conditioning stage. Experiments 1-3 used 10 pre-exposures and 2 conditioning trials, and tested the effects of 2.5, 5, and 10 mg/kg clozapine, respectively. Experiments 4-6 used 40 pre-exposures and 5 conditioning trials, with clozapine doses as above. Clozapine was administered in either the pre-exposure, the conditioning stage, or in both. In all the experiments, vehicle controls did not show LI. Overall, clozapine administration in conditioning, irrespective of drug condition in pre-exposure, produced LI. The implications of these results for the mechanism of action of antipsychotic drugs are discussed.
The major characteristics of the postnatal environment of the rat pup are its mother and littermates. The pup, which is poorly developed at birth, matures rapidly in this environment, and regulates the behaviour and physiology of the dam and littermates, as well as vice versa. The study of the impact of the rat's postnatal environment on its long-term neurobehavioural development is of fundamental importance. In fact, it is one of the major examples--at the interface of the biological, social and medical sciences--of animal models for the study of the interaction between the environment and the genome in both the acute and chronic regulation of the phenotype. Specific experimental manipulations of the rat postnatal environment have been demonstrated to exert robust and marked effects on neurobiological, physiological and behavioural phenotypes in adulthood. In the present review we present some of the major findings, including some original data, and discuss what these existing data can tell us about the long-term neurobehavioural effects of the postnatal environment in rats, the external and internal mechanisms that mediate these effects, and the most appropriate directions for future basic and applied research in this area.
In the rat, relative to pup nonhandling (NH), early handling (EH) leads to old-adult offspring with a hyporesponsive HPA axis, superior spatial cognition, and greater hippocampal (HIPP) neuronal density. The present study compared the effects of EH and repeated maternal separation (MS), in the form of 6-hr separation on each of 4 days beginning at day 12, on spatial cognition, corticosterone (CORT) levels, and HIPP characteristics, in aged rats. Male Wistar rat pups were exposed to EH, MS, NH or our normal in-house husbandry (CON) and tested at 18-20 months. Relative to NH and CON, EH demonstrated superior spatial cognition, reduced CORT stress response, reduced CA-field volume and no change in HIPP neuronal number. MS demonstrated a trend to superior spatial cognition, an unaffected CORT stress response, reduced CA-field volume and no change in HIPP neuronal number. These findings are important in terms of the life-span mechanisms via which postnatal manipulations induce neurobehavioral effects, and the mechanisms via which CORT and HIPP structure relate to HIPP function.