Effects of prenatal protein malnutrition and neonatal stress on CNS responsiveness.

Maturation of the nervous system and consequent behavior depends in part on prenatal nutritional factors and postnatal environmental stimulation. In particular, the hypothalamus and the hippocampus are two important CNS areas that are vulnerable to such pre- and postnatal manipulations. Therefore, the present study was undertaken to explore the effects of both prenatal protein malnutrition and neonatal isolation stress on hypothalamic and hippocampal functioning in infant rats. Specifically, we assessed the levels of plasma corticosterone, as well as dopamine, serotonin and their metabolites in both the hypothalamus and hippocampus in rat pups that had been prenatally malnourished (6% casein diet) and isolated from nest, dam, and siblings for 1 h daily during postnatal days (PND) 2 through 8. We found that on PND 9 malnourished pups weighed less, had smaller hypothalami and a suppressed corticosterone response to acute and chronic isolation stress. However, their dopamine metabolism in the hypothalamus was increased following acute isolation on PND 9 as seen in isolated controls. Prenatal protein malnutrition also resulted in a significant elevation in serotonin in both brain areas, increased 5HIAA in the hypothalamus, and decreased dopamine in the hippocampus. Repeated isolation caused a reduction in 5HIAA in both brain parts, but only in control pups. These pre- and postnatal challenges may each cause a specific pattern of modifications in the CNS and, in combination, may be additive, particularly in the hypothalamic-pituitary-adrenal (HPA) stress response and the serotonergic functioning in both the hypothalamus and hippocampus, a finding with important clinical implications.

Increased extracellular release of hippocampal NE is associated with tetanization of the medial perforant pathway in the freely moving adult male rat.

The induction of long-term potentiation (LTP) within the dentate gyrus of the hippocampal formation is modulated by many afferent influences from a number of subcortical structures known to be intimately involved in hippocampal-dependent learning and memory. It has been demonstrated in slice and anesthetized preparations that norepinephrine (NE) is one of these major neuromodulators involved in the induction of LTP. However, the majority of these studies have not been conducted in the freely moving animal. Recently, we developed surgical procedures and instrumentation techniques to simultaneously record electrophysiological and neurochemical data from the hippocampal formation. The present study uses these techniques to examine the underlying neurochemical changes in the hippocampus associated with the induction of hippocampal dentate LTP in the freely moving adult rat. These findings establish baseline levels of NE that can be used to evaluate the impact of various tetanization paradigms as well as the effect of a variety of insults on hippocampal plasticity.

Postnatal stress selectively upregulates striatal N-methyl-D-aspartate receptors in male rats.

Early life events have been thought to contribute towards vulnerability to drug addiction later in life. In the present investigation, the effect of daily neonatal maternal isolation stress on NMDA channel activity was studied. [3H]MK-801 binding was measured in several brain regions from neonatally isolated (ISO) and nonhandled (NH) adult male and female rats. Maximal [3H]MK-801 binding in the caudate-putamen of male ISO rats was 58% higher compared to same sex NH rats. Unlike male rats, maximal [3H]MK-801 binding in the caudate-putamen of female ISO rats was lower than female NH rats. No other brain region showed any significant difference in maximal [3H]MK-801 binding between ISO and NH male and female rats, respectively. There was no effect of pup isolation on the binding affinity (K(d) value) in either sex. Repeated maternal isolation is associated with alterations in the NMDA channel activity in the caudate-putamen of adult rats, and may be responsible for the augmentation in the addictive behavior reported.

The effect of cholinergic stimulation on rat pup ultrasonic vocalizations.

As cholinergic stimulation increases vocalizations in adult rats, the present study investigated the effects of systemic oxotremorine, a cholinergic agonist, on the production of separation calls in rat pups of different ages and whether these effects are in response to central versus peripheral stimulation. The first experiment examined the dose-response effects of oxotremorine on the number of vocalizations and acoustic parameters of 10-, 15-, and 17-day-old rat pups. In contrast to other studies on adult rats, pup vocalizations were decreased while marginally changing acoustic parameters. The second experiment, using muscarinic antagonists, showed that pretreatment with atropine sulfate, which can cross the blood-brain barrier (BBB), reversed the call-reducing effect of oxotremorine whereas pretreatment with atropine methyl nitrate, which does not cross BBB, did not. Suppression of vocalizations by oxotremorine may be explained by central activation and not the peripheral effects of the drug. Dissimilar effects of cholinergic stimulation of infant and adult rat brains may be attributed to a differential role of the cholinergic system during development and maturity.

Central allopregnanolone is increased in rat pups in response to repeated, short episodes of neonatal isolation.

This experiment investigated whether neonatal isolation stress alters central concentrations of progestins. Whole brain progesterone (P), dihydroprogesterone (DHP), and allopregnanolone (3alpha, 5alpha-THP) were measured in pups that were isolated from the nest, dam, and siblings for 1 h on postnatal days (PND) 2-9 and were compared to control litters of pups that were not isolated. Isolated 2-day-old pups had significantly lower central P and higher P to DHP and 3alpha, 5alpha-THP metabolism ratios. On PND 9, pups that had been repeatedly isolated (PND 2-8), had significantly lower whole brain DHP and significantly greater whole brain 3alpha, 5alpha-THP compared to controls. Thus, the biosocial stress of isolation in neonatal rats alters central pregnane steroids.