The effect of prenatal protein malnutrition on central serotonin metabolism was assessed in 220- ... more The effect of prenatal protein malnutrition on central serotonin metabolism was assessed in 220- to 240-d-old male rats. The malnourished rats (denoted 6,25 group) were males born to dams fed a 6% casein diet during pregnancy and fostered at birth to dams fed a control (25% casein) diet. They were compared with males born to dams fed 25% casein diet. Tissue concentrations of serotonin, 5-hydroxyindoleacetic acid, 5-hydroxytryptophan, L-tryptophan and catecholamines in the hippocampal formation in the 6,25 group were similar to those of well-fed controls (25,25 group). However, a twofold greater basal serotonin efflux from hippocampal slices of 6,25 rats compared with slices from 25,25 rats was observed during a 20-min incubation period. Hippocampal [3H]paroxetine binding indicated that there was no alteration of apparent maximal binding and affinity of the serotonin transporter in the 6,25 rats. In addition, there was no difference in serotonin receptor binding in hippocampal membranes from 6,25 and 25,25 rats. The results indicate that prenatal protein malnutrition causes selective changes in central serotonin metabolism.
Partial mammectomy in the Sprague-Dawley rat was studied as a method for producing malnutrition w... more Partial mammectomy in the Sprague-Dawley rat was studied as a method for producing malnutrition without accompanying differences in litter size. Throughout the litter period, experimental litters weighed less than controls. No difference in the rate of development of various anatomical landmarks was noted with this degree of malnutrition. Maternal behavior in the nursing dam was measured with respect to nursing, nesting, and retrieval behavior. Mammectomized subjects built and maintained better nests and spent more time in a nursing posture, but were less likely to retrieve their litter than were control animals. At weaning the intact mammae of the experimental animals were larger than those of control animals.
Temperament ratings using a modified Carey Infant Temperament Questionnaire were assessed in marg... more Temperament ratings using a modified Carey Infant Temperament Questionnaire were assessed in marginally malnourished and healthy comparison infants aged 7-13 months. The children were selected from a total of 81 children in this age range living in a rural region of southern ~ucatan, ~e x i c o. ~f e v e n marginally malnourished infants whose weights fell between one-haIf and two standard deviations below local means and 14 comparison children whose weights fell one-half to two standard deviations above the local means were included in the study. Lengths did not differ between index and comparison groups. Related temperament categories were statistically grouped into two factors. Factor 1 (Difficult Child), which included approach, mood, threshold, adaptability and rhythmicity, showed a significant nutrition x sex interaction; Factor 2 (Activity) did not distinguish the groups. Comparison boys were viewed as significantly easier than marginally malnourished boys, and they were more adaptable to change and predictable in biological functions. Girls were similar regardless of nutritional status, and their scores were intermediate between those of malnourished and well-nourished boys. These findings were not significantly associated with environmental conditions in the home.
1ABSTRACTThe non-linear spatiotemporal features in the continuing EEG recordings could be helpful... more 1ABSTRACTThe non-linear spatiotemporal features in the continuing EEG recordings could be helpful to infer the physio and pathological significance of early insults on the brain, such as early malnutrition and their long-term effects. A unique opportunity is opened with the Barbados Nutrition Study (BNS) dedicated to studying Protein-Energy Malnutrition (PEM) with two groups, children suffering an early PEM episode and their controls. We evaluated the resting-state EEG (N=108, PEM=46) in 1978, and we repeated the EEG (N=97, PEM=46) in 2018. We did a qualitative analysis of the EEG using a semi-quantitative scale (Grand Total EEG (GTE)) and an item response theory (IRT) approach to estimate a latent variable that is able to explain the subjacent neurophysiological status (NPS). Finally, we applied a mixed-effects model with a sensitivity index for ignorability to test differences between the controls and PEM groups while accounting for the missing data mechanisms (nlme (Pinheiro J. 2...
Female Sprague-Dawley rats were pro vided with an adequate (25% casein) or low (6% casein) protei... more Female Sprague-Dawley rats were pro vided with an adequate (25% casein) or low (6% casein) protein diet, fortified with methionine, starting 5 wk prior to gestation and continuing until the birth of their pups. At birth, the offspring were fostered to well-nourished lactating dams as follows: in Experiment 1, litters con tained eight prenatally malnourished pups; in Experiment 2, litters consisted of four pups with prenatal mal nutrition and four well-nourished pups; control litters for both experiments contained eight well-nourished pups. In Experiment 1, the time spent in passive nursing and pup grooming was significantly higher for dams rearing previously malnourished pups than for those rearing control litters. In Experiment 2, mixed litters were groomed less frequently than control litters, but there was no significant difference between groups for any other measure. In both experiments, the prenatally mal nourished pups showed similar body weight deficits rel ative to well-nourished pups. These findings underscore the usefulness of mixed litters in studying the later ef fects of prenatal malnutrition because later deficits in brain function are less likely to be attributable to changes in the early rearing environment.
The variability in the effects of rearing rats in large litters was examined. Subjects reared in ... more The variability in the effects of rearing rats in large litters was examined. Subjects reared in litters of 16 were stunted and delayed in the appearance of eye-opening and fur-eruption as compared with pups reared in litters of 8. However, the effects of the large-litter treatment were not uniform; pups in this group exhibited markedly higher variability with regard to all measures than did pups from small litters. In fact, some pups from the large litters were heavier and some exhibited developmental landmarks earlier than did most pups reared in small litters.
Prenatal protein malnutrition alters behavioral state modulation of inhibition und facilitation i... more Prenatal protein malnutrition alters behavioral state modulation of inhibition und facilitation in the dentate gyrus. BRAIN RES BULL 28(2) 245-255, 1992.-We have examined the effects of prenatal protein malnutrition on interneuronally mediated inhibition and facilitation in the dentate gyms of the rat using the paired-pulse technique. Field potentials were recorded in the dentate gyms in response to paired stimuli delivered to the perforant path. The paired-pulse index (PPI) was used as a measure of the net short-term facilitation or intemeuronally mediated inhibition effective at the time of the paired-pulse test and was computed by dividing the amplitude of the second population spike (~2) by the amplitude of the first population spike (~1). PPIs were classified according to pl in order to compare PPIs between behavioral states and dietary treatments since population spike amplitudes in the Paired-pulse inhibition Paired-pulse facilitation Prenatal protein malnutrition Sleep-waking states Dentate gyms Vigilance states Local circuit function GABAergic intemeuronal excitability
Physical growth and sexual maturation were measured in a follow-up study of Barbadian girls and b... more Physical growth and sexual maturation were measured in a follow-up study of Barbadian girls and boys aged 11-18 years with histories of kwashiorkor (n = 54) or marasmus (n = 56) in their first year of life. They were compared with healthy neighborhood children matched by sex and age who had normal patterns of growth in early childhood (n = 59). Girls with histories of marasmus had significant delays in the onset of menarche compared with healthy comparison girls. However, their rate of growth during the previous 2 years was accelerated, and the differences in size were smaller than at the earlier testing, confirming catch-up. This pattern was not evident for girls with histories of kwashiorkor, who did not differ from the healthy comparison girls on either onset of menarche, Tanner ratings of sexual maturation, or measures of physical growth. In contrast, boys with histories of kwashiorkor or marasmus did not differ from healthy comparison boys in physical growth or Tanner ratings at these ages.
Temperament ratings using a modified Carey Infant Temperament Questionnaire were assessed in marg... more Temperament ratings using a modified Carey Infant Temperament Questionnaire were assessed in marginally malnourished and healthy comparison infants aged 7-13 months. The children were selected from a total of 81 children in this age range living in a rural region of southern ~ucatan, ~e x i c o. ~f e v e n marginally malnourished infants whose weights fell between one-haIf and two standard deviations below local means and 14 comparison children whose weights fell one-half to two standard deviations above the local means were included in the study. Lengths did not differ between index and comparison groups. Related temperament categories were statistically grouped into two factors. Factor 1 (Difficult Child), which included approach, mood, threshold, adaptability and rhythmicity, showed a significant nutrition x sex interaction; Factor 2 (Activity) did not distinguish the groups. Comparison boys were viewed as significantly easier than marginally malnourished boys, and they were more adaptable to change and predictable in biological functions. Girls were similar regardless of nutritional status, and their scores were intermediate between those of malnourished and well-nourished boys. These findings were not significantly associated with environmental conditions in the home.
A reduced behavioral sensitivity to drugs acting on central GABAergic, serotonergic, opioid and c... more A reduced behavioral sensitivity to drugs acting on central GABAergic, serotonergic, opioid and cholinergic systems has previously been identified in predominantly male malnourished animals. The present study sought to compare the effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 on responding maintained by a differential reinforcement of low rates (DRL-18s) operant schedule in two groups of rats with different prenatal nutritional histories (well-nourished and protein restricted). The schedule required that the rats space their responses at least 18 s apart in order to obtain food reinforcement (timing behavior). After training to a stable high proficiency, MK-801 was administered to female rats (Experiment 1) at doses of 0 (saline), 0.004, 0.008, 0.016, 0.024 or 0.032 mg/kg (doses expressed as the free-base). MK-801 produced dose-dependent decreases in the percentage efficiency of responding and the number of rewarded responses, with dose-depend...
Protein malnutrition during gestation alters brain development and produces specific behavioral a... more Protein malnutrition during gestation alters brain development and produces specific behavioral and cognitive changes that persist into adulthood and increase the risks of neuropsychiatric disorders. Given evidence for the role of the prefrontal cortex in such diseases, it is significant that studies in humans and animal models have shown that prenatal protein malnutrition specifically affects functions associated with prefrontal cortex. However, the neural basis underlying these changes is unclear. In the current study, prenatally malnourished and control rats performed a sustained attention task with an unpredictable distractor, a task that depends on intact prefrontal cortical function. Radiolabeled 2-deoxyglucose was used to measure neural and brain network activity during the task. Results confirmed that adult prenatally malnourished rats were more distractible than controls and exhibited lower functional activity in prefrontal cortices. Thus, prefrontal activity was a predicto...
The effect of prenatal protein deprivation on the timing of neurogenesis and on the number of neu... more The effect of prenatal protein deprivation on the timing of neurogenesis and on the number of neurons generated in the locus coeruleus of the rat was studied. These neurons are of interest as their axon projections are involved in the earliest stages of cerebral cortical development. Dams were maintained on a 25% casein diet or a 6% casein diet five weeks prior to mating and the diets continued throughout the pregnancy. At birth, all pups were cross-fostered to dams on a 25% casein diet. BrDU, a thymidine analog that is incorporated into the nuclear DNA during the synthetic phase of the cell cycle, was used as a marker of the generation period. It was administered intraperitoneally (25 mg/kg body weight) on embryonic day 10, 11, 12, 13, or 14. On postnatal day 30, the brain stems were processed with BrDU immunocytochemistry to determine the relative number of neurons generated on each day, and with Nissl stain to determine the total number of neurons generated in the two groups. The...
Protein malnutrition during gestation alters brain development and produces specific behavioral a... more Protein malnutrition during gestation alters brain development and produces specific behavioral and cognitive changes that persist into adulthood and increase the risks of neuropsychiatric disorders. Given evidence for the role of the prefrontal cortex in such diseases, it is significant that studies in humans and animal models have shown that prenatal protein malnutrition specifically affects functions associated with prefrontal cortex. However, the neural basis underlying these changes is unclear. In the current study, prenatally malnourished and control rats performed a sustained attention task with an unpredictable distractor, a task that depends on intact prefrontal cortical function. Radiolabeled 2-deoxyglucose was used to measure neural and brain network activity during the task. Results confirmed that adult prenatally malnourished rats were more distractible than controls and exhibited lower functional activity in prefrontal cortices. Thus, prefrontal activity was a predicto...
According to the World Health Organization, 45% of deaths among children under 5 years of age are... more According to the World Health Organization, 45% of deaths among children under 5 years of age are caused by childhood malnutrition, which affects 224 million children worldwide. The Barbados Nutrition Study (BNS) is a 50+year longitudinal study on a Barbadian cohort (N=258) with histories of moderate to severe protein-energy malnutrition (PEM) in the first year of life and healthy controls. Interestingly, a recent BNS publication used quantitative electroencephalography (EEG) to show differences in brain function (lower alpha1 activity and higher theta, alpha2 and beta activity) in children who suffered from early PEM compared to healthy controls. However, the adult brain function following early childhood PEM has not been reported in this cohort. In the current study, EEG recordings were undertaken during a Go-No-Go task on a subsample of the BNS cohort (n=55) at ages 45-51 years. Evoked-related potentials (ERP) analyses show that, compared to the control group (n=29), participants...
Objective This study assessed the effect of varying prenatal protein levels on the development of... more Objective This study assessed the effect of varying prenatal protein levels on the development of homing orientation in rat pups. Methods Long-Evans rats were fed one of the four isocaloric diets containing 6% (n = 7 litters), 12% (n = 9), 18% (n = 9), or 25% (n = 10) casein prior to mating and throughout pregnancy. At birth, litters were fostered to well-nourished control mothers fed a 25% casein diet during pregnancy, and an adequate protein diet (25% casein) was provided to weaning. On postnatal days 5, 7, 9, 11, and 13, homing behaviors, including activity levels, rate of successful returns to the nest quadrant and latencies to reach the nest over a 3-minute test period were recorded from two starting positions in the home cage. Adult body and brain weights were obtained at sacrifice (postnatal day 130 or 200). Results Growth was impaired in pups whose mothers were fed a 6% or, to a lesser extent, a 12% casein diet relative to pups whose mothers were fed the 18 and 25% casein di...
Prenatal protein malnutrition (PPM) in rats causes enduring changes in brain and behavior includi... more Prenatal protein malnutrition (PPM) in rats causes enduring changes in brain and behavior including increased cognitive rigidity and decreased inhibitory control. A preliminary gene microarray screen of PPM rat prefrontal cortex (PFC) identified alterations in KCNJ3 (GIRK1/Kir3.1), a gene important for regulating neuronal excitability. Follow-up with polymerase chain reaction and Western blot showed decreased KCNJ3 expression in the PFC, but not hippocampus or brainstem. To verify localization of the effect to the PFC, baseline regional brain activity was assessed with (14)C-2-deoxyglucose. Results showed decreased activation in the PFC but not hippocampus. Together these findings point to the unique vulnerability of the PFC to the nutritional insult during early brain development, with enduring effects in adulthood on KCNJ3 expression and baseline metabolic activity.
Prenatal protein malnutrition has been demonstrated to result in alterations in the serotonergic ... more Prenatal protein malnutrition has been demonstrated to result in alterations in the serotonergic and GABAergic neurotransmitter systems in the rat hippocampus. In the present study, whole-cell patch clamp recordings of CA1 pyramidal cells were employed in an effort to gain insight into the specific cellular locus and functional consequences of the previously reported changes. Hippocampal slices were prepared from Sprague-Dawley rats whose dams were fed either a normal (25% casein) or low (6% casein) protein diet during pregnancy. The development of GABA(A) receptor-mediated miniature inhibitory postsynaptic currents (mIPSCs) and their modulation by the benzodiazipine agonist zolpidem were compared in cells from the two nutritional groups at postnatal days 7, 14, 21 and >90. The modulation of mIPSCs by serotonin was also examined in cells from 21 day old rats. No significant differences were observed in the characteristics of mIPSCs in cells from control vs. prenatally protein mal...
A reduced behavioral sensitivity to drugs acting on central GABAergic, serotonergic, opioid and c... more A reduced behavioral sensitivity to drugs acting on central GABAergic, serotonergic, opioid and cholinergic systems has previously been identified in predominantly male malnourished animals. The present study sought to compare the effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 on responding maintained by a differential reinforcement of low rates (DRL-18s) operant schedule in two groups of rats with different prenatal nutritional histories (well-nourished and protein restricted). The schedule required that the rats space their responses at least 18 s apart in order to obtain food reinforcement (timing behavior). After training to a stable high proficiency, MK-801 was administered to female rats (Experiment 1) at doses of 0 (saline), 0.004, 0.008, 0.016, 0.024 or 0.032 mg/kg (doses expressed as the free-base). MK-801 produced dose-dependent decreases in the percentage efficiency of responding and the number of rewarded responses, with dose-depend...
The effect of prenatal protein malnutrition on central serotonin metabolism was assessed in 220- ... more The effect of prenatal protein malnutrition on central serotonin metabolism was assessed in 220- to 240-d-old male rats. The malnourished rats (denoted 6,25 group) were males born to dams fed a 6% casein diet during pregnancy and fostered at birth to dams fed a control (25% casein) diet. They were compared with males born to dams fed 25% casein diet. Tissue concentrations of serotonin, 5-hydroxyindoleacetic acid, 5-hydroxytryptophan, L-tryptophan and catecholamines in the hippocampal formation in the 6,25 group were similar to those of well-fed controls (25,25 group). However, a twofold greater basal serotonin efflux from hippocampal slices of 6,25 rats compared with slices from 25,25 rats was observed during a 20-min incubation period. Hippocampal [3H]paroxetine binding indicated that there was no alteration of apparent maximal binding and affinity of the serotonin transporter in the 6,25 rats. In addition, there was no difference in serotonin receptor binding in hippocampal membranes from 6,25 and 25,25 rats. The results indicate that prenatal protein malnutrition causes selective changes in central serotonin metabolism.
Partial mammectomy in the Sprague-Dawley rat was studied as a method for producing malnutrition w... more Partial mammectomy in the Sprague-Dawley rat was studied as a method for producing malnutrition without accompanying differences in litter size. Throughout the litter period, experimental litters weighed less than controls. No difference in the rate of development of various anatomical landmarks was noted with this degree of malnutrition. Maternal behavior in the nursing dam was measured with respect to nursing, nesting, and retrieval behavior. Mammectomized subjects built and maintained better nests and spent more time in a nursing posture, but were less likely to retrieve their litter than were control animals. At weaning the intact mammae of the experimental animals were larger than those of control animals.
Temperament ratings using a modified Carey Infant Temperament Questionnaire were assessed in marg... more Temperament ratings using a modified Carey Infant Temperament Questionnaire were assessed in marginally malnourished and healthy comparison infants aged 7-13 months. The children were selected from a total of 81 children in this age range living in a rural region of southern ~ucatan, ~e x i c o. ~f e v e n marginally malnourished infants whose weights fell between one-haIf and two standard deviations below local means and 14 comparison children whose weights fell one-half to two standard deviations above the local means were included in the study. Lengths did not differ between index and comparison groups. Related temperament categories were statistically grouped into two factors. Factor 1 (Difficult Child), which included approach, mood, threshold, adaptability and rhythmicity, showed a significant nutrition x sex interaction; Factor 2 (Activity) did not distinguish the groups. Comparison boys were viewed as significantly easier than marginally malnourished boys, and they were more adaptable to change and predictable in biological functions. Girls were similar regardless of nutritional status, and their scores were intermediate between those of malnourished and well-nourished boys. These findings were not significantly associated with environmental conditions in the home.
1ABSTRACTThe non-linear spatiotemporal features in the continuing EEG recordings could be helpful... more 1ABSTRACTThe non-linear spatiotemporal features in the continuing EEG recordings could be helpful to infer the physio and pathological significance of early insults on the brain, such as early malnutrition and their long-term effects. A unique opportunity is opened with the Barbados Nutrition Study (BNS) dedicated to studying Protein-Energy Malnutrition (PEM) with two groups, children suffering an early PEM episode and their controls. We evaluated the resting-state EEG (N=108, PEM=46) in 1978, and we repeated the EEG (N=97, PEM=46) in 2018. We did a qualitative analysis of the EEG using a semi-quantitative scale (Grand Total EEG (GTE)) and an item response theory (IRT) approach to estimate a latent variable that is able to explain the subjacent neurophysiological status (NPS). Finally, we applied a mixed-effects model with a sensitivity index for ignorability to test differences between the controls and PEM groups while accounting for the missing data mechanisms (nlme (Pinheiro J. 2...
Female Sprague-Dawley rats were pro vided with an adequate (25% casein) or low (6% casein) protei... more Female Sprague-Dawley rats were pro vided with an adequate (25% casein) or low (6% casein) protein diet, fortified with methionine, starting 5 wk prior to gestation and continuing until the birth of their pups. At birth, the offspring were fostered to well-nourished lactating dams as follows: in Experiment 1, litters con tained eight prenatally malnourished pups; in Experiment 2, litters consisted of four pups with prenatal mal nutrition and four well-nourished pups; control litters for both experiments contained eight well-nourished pups. In Experiment 1, the time spent in passive nursing and pup grooming was significantly higher for dams rearing previously malnourished pups than for those rearing control litters. In Experiment 2, mixed litters were groomed less frequently than control litters, but there was no significant difference between groups for any other measure. In both experiments, the prenatally mal nourished pups showed similar body weight deficits rel ative to well-nourished pups. These findings underscore the usefulness of mixed litters in studying the later ef fects of prenatal malnutrition because later deficits in brain function are less likely to be attributable to changes in the early rearing environment.
The variability in the effects of rearing rats in large litters was examined. Subjects reared in ... more The variability in the effects of rearing rats in large litters was examined. Subjects reared in litters of 16 were stunted and delayed in the appearance of eye-opening and fur-eruption as compared with pups reared in litters of 8. However, the effects of the large-litter treatment were not uniform; pups in this group exhibited markedly higher variability with regard to all measures than did pups from small litters. In fact, some pups from the large litters were heavier and some exhibited developmental landmarks earlier than did most pups reared in small litters.
Prenatal protein malnutrition alters behavioral state modulation of inhibition und facilitation i... more Prenatal protein malnutrition alters behavioral state modulation of inhibition und facilitation in the dentate gyrus. BRAIN RES BULL 28(2) 245-255, 1992.-We have examined the effects of prenatal protein malnutrition on interneuronally mediated inhibition and facilitation in the dentate gyms of the rat using the paired-pulse technique. Field potentials were recorded in the dentate gyms in response to paired stimuli delivered to the perforant path. The paired-pulse index (PPI) was used as a measure of the net short-term facilitation or intemeuronally mediated inhibition effective at the time of the paired-pulse test and was computed by dividing the amplitude of the second population spike (~2) by the amplitude of the first population spike (~1). PPIs were classified according to pl in order to compare PPIs between behavioral states and dietary treatments since population spike amplitudes in the Paired-pulse inhibition Paired-pulse facilitation Prenatal protein malnutrition Sleep-waking states Dentate gyms Vigilance states Local circuit function GABAergic intemeuronal excitability
Physical growth and sexual maturation were measured in a follow-up study of Barbadian girls and b... more Physical growth and sexual maturation were measured in a follow-up study of Barbadian girls and boys aged 11-18 years with histories of kwashiorkor (n = 54) or marasmus (n = 56) in their first year of life. They were compared with healthy neighborhood children matched by sex and age who had normal patterns of growth in early childhood (n = 59). Girls with histories of marasmus had significant delays in the onset of menarche compared with healthy comparison girls. However, their rate of growth during the previous 2 years was accelerated, and the differences in size were smaller than at the earlier testing, confirming catch-up. This pattern was not evident for girls with histories of kwashiorkor, who did not differ from the healthy comparison girls on either onset of menarche, Tanner ratings of sexual maturation, or measures of physical growth. In contrast, boys with histories of kwashiorkor or marasmus did not differ from healthy comparison boys in physical growth or Tanner ratings at these ages.
Temperament ratings using a modified Carey Infant Temperament Questionnaire were assessed in marg... more Temperament ratings using a modified Carey Infant Temperament Questionnaire were assessed in marginally malnourished and healthy comparison infants aged 7-13 months. The children were selected from a total of 81 children in this age range living in a rural region of southern ~ucatan, ~e x i c o. ~f e v e n marginally malnourished infants whose weights fell between one-haIf and two standard deviations below local means and 14 comparison children whose weights fell one-half to two standard deviations above the local means were included in the study. Lengths did not differ between index and comparison groups. Related temperament categories were statistically grouped into two factors. Factor 1 (Difficult Child), which included approach, mood, threshold, adaptability and rhythmicity, showed a significant nutrition x sex interaction; Factor 2 (Activity) did not distinguish the groups. Comparison boys were viewed as significantly easier than marginally malnourished boys, and they were more adaptable to change and predictable in biological functions. Girls were similar regardless of nutritional status, and their scores were intermediate between those of malnourished and well-nourished boys. These findings were not significantly associated with environmental conditions in the home.
A reduced behavioral sensitivity to drugs acting on central GABAergic, serotonergic, opioid and c... more A reduced behavioral sensitivity to drugs acting on central GABAergic, serotonergic, opioid and cholinergic systems has previously been identified in predominantly male malnourished animals. The present study sought to compare the effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 on responding maintained by a differential reinforcement of low rates (DRL-18s) operant schedule in two groups of rats with different prenatal nutritional histories (well-nourished and protein restricted). The schedule required that the rats space their responses at least 18 s apart in order to obtain food reinforcement (timing behavior). After training to a stable high proficiency, MK-801 was administered to female rats (Experiment 1) at doses of 0 (saline), 0.004, 0.008, 0.016, 0.024 or 0.032 mg/kg (doses expressed as the free-base). MK-801 produced dose-dependent decreases in the percentage efficiency of responding and the number of rewarded responses, with dose-depend...
Protein malnutrition during gestation alters brain development and produces specific behavioral a... more Protein malnutrition during gestation alters brain development and produces specific behavioral and cognitive changes that persist into adulthood and increase the risks of neuropsychiatric disorders. Given evidence for the role of the prefrontal cortex in such diseases, it is significant that studies in humans and animal models have shown that prenatal protein malnutrition specifically affects functions associated with prefrontal cortex. However, the neural basis underlying these changes is unclear. In the current study, prenatally malnourished and control rats performed a sustained attention task with an unpredictable distractor, a task that depends on intact prefrontal cortical function. Radiolabeled 2-deoxyglucose was used to measure neural and brain network activity during the task. Results confirmed that adult prenatally malnourished rats were more distractible than controls and exhibited lower functional activity in prefrontal cortices. Thus, prefrontal activity was a predicto...
The effect of prenatal protein deprivation on the timing of neurogenesis and on the number of neu... more The effect of prenatal protein deprivation on the timing of neurogenesis and on the number of neurons generated in the locus coeruleus of the rat was studied. These neurons are of interest as their axon projections are involved in the earliest stages of cerebral cortical development. Dams were maintained on a 25% casein diet or a 6% casein diet five weeks prior to mating and the diets continued throughout the pregnancy. At birth, all pups were cross-fostered to dams on a 25% casein diet. BrDU, a thymidine analog that is incorporated into the nuclear DNA during the synthetic phase of the cell cycle, was used as a marker of the generation period. It was administered intraperitoneally (25 mg/kg body weight) on embryonic day 10, 11, 12, 13, or 14. On postnatal day 30, the brain stems were processed with BrDU immunocytochemistry to determine the relative number of neurons generated on each day, and with Nissl stain to determine the total number of neurons generated in the two groups. The...
Protein malnutrition during gestation alters brain development and produces specific behavioral a... more Protein malnutrition during gestation alters brain development and produces specific behavioral and cognitive changes that persist into adulthood and increase the risks of neuropsychiatric disorders. Given evidence for the role of the prefrontal cortex in such diseases, it is significant that studies in humans and animal models have shown that prenatal protein malnutrition specifically affects functions associated with prefrontal cortex. However, the neural basis underlying these changes is unclear. In the current study, prenatally malnourished and control rats performed a sustained attention task with an unpredictable distractor, a task that depends on intact prefrontal cortical function. Radiolabeled 2-deoxyglucose was used to measure neural and brain network activity during the task. Results confirmed that adult prenatally malnourished rats were more distractible than controls and exhibited lower functional activity in prefrontal cortices. Thus, prefrontal activity was a predicto...
According to the World Health Organization, 45% of deaths among children under 5 years of age are... more According to the World Health Organization, 45% of deaths among children under 5 years of age are caused by childhood malnutrition, which affects 224 million children worldwide. The Barbados Nutrition Study (BNS) is a 50+year longitudinal study on a Barbadian cohort (N=258) with histories of moderate to severe protein-energy malnutrition (PEM) in the first year of life and healthy controls. Interestingly, a recent BNS publication used quantitative electroencephalography (EEG) to show differences in brain function (lower alpha1 activity and higher theta, alpha2 and beta activity) in children who suffered from early PEM compared to healthy controls. However, the adult brain function following early childhood PEM has not been reported in this cohort. In the current study, EEG recordings were undertaken during a Go-No-Go task on a subsample of the BNS cohort (n=55) at ages 45-51 years. Evoked-related potentials (ERP) analyses show that, compared to the control group (n=29), participants...
Objective This study assessed the effect of varying prenatal protein levels on the development of... more Objective This study assessed the effect of varying prenatal protein levels on the development of homing orientation in rat pups. Methods Long-Evans rats were fed one of the four isocaloric diets containing 6% (n = 7 litters), 12% (n = 9), 18% (n = 9), or 25% (n = 10) casein prior to mating and throughout pregnancy. At birth, litters were fostered to well-nourished control mothers fed a 25% casein diet during pregnancy, and an adequate protein diet (25% casein) was provided to weaning. On postnatal days 5, 7, 9, 11, and 13, homing behaviors, including activity levels, rate of successful returns to the nest quadrant and latencies to reach the nest over a 3-minute test period were recorded from two starting positions in the home cage. Adult body and brain weights were obtained at sacrifice (postnatal day 130 or 200). Results Growth was impaired in pups whose mothers were fed a 6% or, to a lesser extent, a 12% casein diet relative to pups whose mothers were fed the 18 and 25% casein di...
Prenatal protein malnutrition (PPM) in rats causes enduring changes in brain and behavior includi... more Prenatal protein malnutrition (PPM) in rats causes enduring changes in brain and behavior including increased cognitive rigidity and decreased inhibitory control. A preliminary gene microarray screen of PPM rat prefrontal cortex (PFC) identified alterations in KCNJ3 (GIRK1/Kir3.1), a gene important for regulating neuronal excitability. Follow-up with polymerase chain reaction and Western blot showed decreased KCNJ3 expression in the PFC, but not hippocampus or brainstem. To verify localization of the effect to the PFC, baseline regional brain activity was assessed with (14)C-2-deoxyglucose. Results showed decreased activation in the PFC but not hippocampus. Together these findings point to the unique vulnerability of the PFC to the nutritional insult during early brain development, with enduring effects in adulthood on KCNJ3 expression and baseline metabolic activity.
Prenatal protein malnutrition has been demonstrated to result in alterations in the serotonergic ... more Prenatal protein malnutrition has been demonstrated to result in alterations in the serotonergic and GABAergic neurotransmitter systems in the rat hippocampus. In the present study, whole-cell patch clamp recordings of CA1 pyramidal cells were employed in an effort to gain insight into the specific cellular locus and functional consequences of the previously reported changes. Hippocampal slices were prepared from Sprague-Dawley rats whose dams were fed either a normal (25% casein) or low (6% casein) protein diet during pregnancy. The development of GABA(A) receptor-mediated miniature inhibitory postsynaptic currents (mIPSCs) and their modulation by the benzodiazipine agonist zolpidem were compared in cells from the two nutritional groups at postnatal days 7, 14, 21 and >90. The modulation of mIPSCs by serotonin was also examined in cells from 21 day old rats. No significant differences were observed in the characteristics of mIPSCs in cells from control vs. prenatally protein mal...
A reduced behavioral sensitivity to drugs acting on central GABAergic, serotonergic, opioid and c... more A reduced behavioral sensitivity to drugs acting on central GABAergic, serotonergic, opioid and cholinergic systems has previously been identified in predominantly male malnourished animals. The present study sought to compare the effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 on responding maintained by a differential reinforcement of low rates (DRL-18s) operant schedule in two groups of rats with different prenatal nutritional histories (well-nourished and protein restricted). The schedule required that the rats space their responses at least 18 s apart in order to obtain food reinforcement (timing behavior). After training to a stable high proficiency, MK-801 was administered to female rats (Experiment 1) at doses of 0 (saline), 0.004, 0.008, 0.016, 0.024 or 0.032 mg/kg (doses expressed as the free-base). MK-801 produced dose-dependent decreases in the percentage efficiency of responding and the number of rewarded responses, with dose-depend...
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Papers by JR Galler