Mild prenatal protein malnutrition, induced by reduction of the casein content of the maternal diet from 25 to 8%, calorically compensated by the addition of excess carbohydrates, leads to so-called "hidden" malnutrition in the rat. This form of malnutrition results in normal body and brain weights of pups at birth, but in significant alterations of their central nervous system neurochemical profiles. Since severe forms of prenatal malnutrition induce morpho-functional deficits on callosal interhemispheric communication together with brain neurochemical disturbances, we evaluated, in rats born from mothers submitted to an 8% casein diet, the potassium-induced release of [3H]-noradrenaline in visual cortex slices, as well as functional properties of callosal-cortical synapses by determining cerebral cortical excitability to callosal inputs and fatigability and temporal summation of transcallosal evoked responses. Rats born from mothers submitted to a 25% casein diet served as controls. At birth prenatally malnourished pups had significantly higher cortical percent net noradrenaline release (14.79 +/- 1.11) than controls (9.14 +/- 1.26). At 45-50 days of age, rehabilitated previously malnourished rats showed, when compared to controls; (i) significantly reduced percent net noradrenaline release in the visual cortex (4.50 +/- 0.52 vs 11.31 +/- 1.14); (ii) decreased cortical excitability to callosal inputs as revealed by significantly increased chronaxie (607.2 +/- 82.8 microseconds vs 351.3 +/- 47.7 microseconds); (iii) enhanced fatigability of transcallosal evoked responses as revealed by significantly decreased stimulus frequency required to fatigate the responses (4.9 +/- 0.8 Hz vs 9.2 +/- 1.3 Hz); and (iv) decreased ability of callosal-cortical synapses to perform temporal summation, as revealed by significantly reduced percent response increment to double-shock (54.2 +/- 6.2 vs 83.0 +/- 11.0, for a 3.2-ms interstimulus time interval). These changes, resulting from mild prenatal protein restriction, are discussed in relationship to developmental processes leading to the formation of synaptic contacts between callosal axons and their appropriate cortical target during perinatal age.

Prenatal malnutrition results in increased concentration and release of central noradrenaline, a neurotransmitter that is an important regulator of normal regressive events such as axonal pruning and synaptic elimination. This suggests that some of the functional disturbances in brain induced by prenatal malnutrition could be due at least in part to increased noradrenaline activity that may enhance regressive events during early stages of development. To test this hypothesis we studied whether chronic administration of alpha-methyl-p-tyrosine, an inhibitor of tyrosine hydroxylase, to rats during gestation might prevent long-term deleterious effects of prenatal malnutrition on functional properties of interhemispheric connections of the visual cortex, and on asymmetry of visual evoked responses. The experiments were conducted on normal and malnourished rats 45-50 d of age. Prenatal malnutrition was induced by restricting the food consumption of pregnant rats to 40%, from d 8 postconception to parturition. At birth, prenatally malnourished rats had significantly greater whole-brain noradrenaline concentration as well as significantly enhanced noradrenaline release in the visual cortex. At 45-50 d of age, the malnourished group had a significantly smaller cortical area, exhibiting transcallosal evoked responses; in addition, the amplitude of these responses was significantly smaller. Malnourished rats showed a significant reduction of the normal interhemispheric asymmetry of visual evoked responses. The addition of 0.3% alpha-methyl-p-tyrosine to the diet of malnourished pregnant rats during the last 2 wk of gestation prevented functional disorders induced in the offspring by prenatal malnutrition on interhemispheric connectivity of visual areas and on interhemispheric bioelectrical asymmetry, probably by reducing the elevated brain noradrenaline activity and thereby restoring the normal trophic role of this neurotransmitter.

Rats submitted to fetal growth retardation by in utero malnutrition develop hypertension when adult, showing increased hypothalamic mRNA expression for corticotropin-releasing hormone (CRH) and increased central noradrenergic activity. As hypothalamic CRH serves as an excitatory neurotransmitter within the locus coeruleus (LC) and coerulear norepinephrine plays a similar role within the paraventricular nucleus (PVN) of the hypothalamus, we studied, in both normal and prenatally undernourished 40-day-old anesthetized rats, the effects of intra-LC microinjection of CRH and intra-PVN microinjection of the alpha(1)-adrenoceptor antagonist prazosin on multiunit neuronal activity recorded simultaneously from the two nuclei, as well as the effects on systolic pressure. Undernutrition was induced during fetal life by restricting the diet of pregnant mothers to 10 g daily, whereas mothers of control rats received the same diet ad libitum. At day 40 of postnatal life: (i) undernourished rats showed increased neuronal activity in the PVN and LC, as well as increased systolic pressure; (ii) intra-LC CRH stimulated LC and PVN neurons and increased systolic pressure only in normal rats; (iii) intra-PVN prazosin decreased LC and PVN neuronal activity and systolic pressure only in undernourished rats; and (iv) in normal rats, prazosin prevented the stimulatory effect of CRH only in PVN activity; in undernourished rats, prazosin allowed CRH to regain its stimulatory effects. The results point to the existence of an excitatory PVN-LC closed loop, which seems to be hyperactive in prenatally undernourished rats as a consequence of fetal programming; this loop could be responsible, in part, for the hypertension developed by these animals.

No abstract

No abstract