Undernutrition and Overnutrition in the Neonatal Rat: Long-Term Effects on Noradrenergic Pathways in Brain Regions

Abstract

ABSTRACT. To determine whether neonatal nutrition influences development of CNS noradrenergic systems, litter sizes were manipulated at birth to produce undernutrition (16-17 pupsllitter) or overnutrition (five to six pups) and compared to rats reared in normal litter sizes (10-11 pups). Studies were conducted throughout the preweaning period in which nutrition was manipulated, as well as during postweaning nutritional rehabilitation. Sparing of brain growth occurred, evidenced by much smaller changes in brain region wt than in body wt. Similarly, neonatal malnutrition produced major deficits in norepinephrine levels in peripheral sympathetic pathways, but levels in the brain remained within normal limits. Development of 13H]norepinephrine synaptosomal uptake, a biochemical index for presynaptic terminals, was unimpaired by malnutrition; indeed, higher uptake values were seen than in the control population. Nevertheless, norepinephrine turnover was severely attenuated during nutritional restriction and the effect persisted into adulthood; the deficit was greater in the cerebral cortex than in the cerebellum, despite the fact that cerebellar growth showed less sparing. Development of binding capabilities of noradrenergic receptors, particularly the a.2-and @-subtypes, were also adversely affected in cerebral cortex, again suggestive of a deleterious effect on synaptic function. Animals exposed to neonatal overnutrition showed only slight effects on brain region wt or norepinephrine levels, but did display some suppression of [3H]norepinephrine synaptosomal uptake and enhancement of norepinephrine turnover; changes in receptor binding capabilities in the overnourished animals were attributable to the small alterations in brain region wt. These data indicate that neonatal nutrition alters presynaptic and postsynaptic markers of noradrenergic function that remain abnormal even when nutritional rehabilitation occurs. (Pediatr Res 27: 191-197, 1990) Abbreviation ANOVA, analysis of variance The role of prenatal and postnatal nutrition in maintenance of normal growth and development is an issue of intense interest. A variety of studies on animal models of early malnutrition has demonstrated the phenomenon of "brain sparing," wherein the CNS undergoes substantially less growth impairment and struc- Supported by USPHS HD-097 13.tural disruption than does the rest of the organism (1-3). However, studies of central catecholaminergic mechanisms suggest that abnormal nutritional status has a substantial deleterious effect on neuronal and synaptic function. During dietary restriction, norepinephrine levels and some indices of neuronal activity show moderate degrees of attenuation (4-8); although whole brain norepinephrine levels tend to be restored to normal in adulthood (9-1 I), there are at least two reports that deficits in receptor binding sites and synaptic activity may persist if malnutrition is maintained into adulthood (12, 13). Recent work on factors other than nutrition has demonptrated the existence of critical p...

Effects of litter size on sympathetic activity in young adult rats

“…Because SNS activity is under the direct control of centers in the hypothalamus and brain stem, it is likely that litter size affects the functional development of these regions as well. In support of this conjecture, Seidler and colleagues (24) showed that NE turnover within the cerebral cortex and cerebellum of the rat was affected by litter size in developing animals. More recently, Plagemann and colleagues (5,6,21,22) have demonstrated effects of litter size on the structure, neurochemistry, and responsiveness to leptin of neurons in the paraventricular, ventromedial, and arcuate nuclei of the hypothalamus.…”

“…Similarly, cardiac NE concentrations are inversely related to litter size at 15 days of age, although not at weaning (10). Finally, cardiac and renal NE levels are lower at 40 days of age in rats reared in large litters than in those reared in smaller litters (24). However, the consequences of litter size for sympathoadrenal function (in contrast to tissue NE levels) in adult animals has not been examined.…”

“…Because rearing male and female rats in large litters was previously shown to diminish NE levels in heart and kidney (24), our initial studies examined the impact of litter size on organ weight and NE content in tissues from male and female rats. The results are presented in Tables 1 and 2, respectively.…”

Pro-TRH and pro-CRF expression in paraventricular nucleus of small litter-reared fasted adult rats

“…Noradrenaline (NA) is an upregulator of hypophysiotropic proTRH expression (Uribe et al 1993, Perello et al 2007. Importantly, brain NA concentrations in early-overfed animals are low (Seidler et al 1990), and the binding of adrenergic receptors in PVN is reduced in diet-induced obese rats (Levin 1996). This is also indicated by the reduced catecholamine release in caffeine-stimulated adrenal cells of early-overfed adult rats produced by litter reduction, as well as by low expression of the b2-adrenergic receptor evaluated in liver homogenates, which may lead to decreased peripheral sensitivity to catecholamines and lipolysis rate (Conceicao et al 2013).…”

Developmental origins of obesity: a sympathoadrenal perspective

“…33 Finally, changes in fetal or neonatal nutrition owing to the presence of maternal diabetes or variations in litter size, respectively, also exert effects on SNS development. 34,35 The effects associated with exposure to these environmental factors are not uniform. As the SNS is composed of numerous function-specific subdivisions, 36 however, development of each subunit is likely influenced by its own set of environmental factors.…”