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The steroid hormone progesterone is well-known for its role in neuroprotection, in the pre- and postnatal brain development, and is also recognized as a potent respiratory stimulant that reduces the frequency of sleep apnea in adult female subjects. Over the past few years, we have used newborn rats or mice to provide convincing evidence that the respiratory effect of progesterone involves a balance between excitation mediated by progesterone receptors, and an inhibition due to the fast conversion of progesterone to allopregnanolone, a positive allosteric modulator of GABA A receptors. This review focuses on the sex- and age- specific roles of nuclear and membrane progesterone receptors (nPR or mPR), and highlight the clinical potential of these receptors for the treatment of apnea of prematurity. We present original data showing that in newborn rats, selective nPR or mPR agonists are more efficient to reduce apnea frequency at postnatal days 12 than at postnatal day 1, and appear more efficient in males than in females. Furthermore, new results obtained by using intra-cisternal injection of specific siRNA targeting mPRα, mPRβ (two mPR with high brain expression) or nPR suggest that mPRβ regulates the stability of the breathing pattern in males, while effects of nPR appear in females. While several important questions remain to be addressed before a safe clinical use could be proposed, these results highlight the potential role of these drugs as complementary, and sex-specific tools for the treatment of apnea in preterm neonates., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Nasal high-frequency oscillatory ventilation (nHFOV) in neonates is increasingly considered due to enhanced alveolar ventilation, absence of patient-ventilator asynchrony and lessened ventilator-induced lung injury. Although any type of non-invasive respiratory support can lead to gastric distension via esophageal air passage and thus promote gastroesophageal refluxes (GERs), we have shown that nasal continuous positive airway pressure (CPAP; 6 cmH 2 O) and intermittent positive pressure ventilation (15/4 cmH 2 O) conversely inhibit GERs in lambs. The current objective was to test the hypothesis that nHFOV also inhibits GERs compared to spontaneous ventilation without respiratory support. Eight lambs underwent five hours of polysomnographic and esophageal multichannel intraluminal impedance pHmetry recordings to assess GERs and air passage into the esophagus, with and without nHFOV (mean airway pressure = 8 cmH 2 O, oscillation frequency = 8 Hz, amplitude ≈ 20 cmH 2 O and I:E = 1:2). Results revealed that GERs were decreased with nHFOV (p = .03), despite an increase in gas-containing swallows (p = .01). In conclusion, similarly to nasal CPAP and intermittent positive pressure ventilation, nHFOV inhibits GERs in newborn lambs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Maternal immune activation during pregnancy is a risk factor for neurodevelopmental disorders, such as schizophrenia; however, a full mechanistic understanding has yet to be established. The activity of a transient cell population, the subplate neurons, is critical for the development of cortical inhibition and functional thalamocortical connections. Sensitivity of these cells to factors released during inflammation, therefore, may offer a link between maternal immune activation and the aberrant cortical development underlying some neuropsychiatric disorders. An elevated extracellular ATP concentration is associated with inflammation and has been shown to have an effect on neuronal activity. Here, we investigated the effect of ATP on the electrophysiological properties of subplate neurons. Exogenous ATP increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) at micromolar concentrations. Further, ATP released by astrocytes activated by the PAR-1 agonist, TFLLR-NH 2 , also increased the amplitude and frequency of sEPSCs in subplate neurons. The electrophysiological properties of subplate neurons recorded from prefrontal cortical (PFC) slices from neonatal rats were also disrupted in a maternal immune activation rat model of schizophrenia, with a suramin-sensitive increase in frequency and amplitude of sEPSCs. An alternative neurodevelopmental rat model of schizophrenia, MAM-E17, which did not rely on maternal immune activation, however, showed no change in subplate neuron activity. Both models were validated with behavioral assays, showing schizophrenia-like endophenotypes in young adulthood. The purinergic modulation of subplate neuron activity offers a potential explanatory link between maternal immune activation and disruptions in cortical development that lead to the emergence of neuropsychiatric disorders., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Cold environmental conditions and small body size promote heat loss and may create thermoregulatory challenges for marine mammals born in polar regions. However, among polar-born phocid seal species there are variations in physical attributes and environmental conditions at birth, allowing for an interesting contrast in thermoregulatory strategy. We compared thermoregulatory strategies through morphometrics, sculp attributes (conductivity and resistance), nonshivering thermogenesis (NST via uncoupling protein 1; UCP1), and muscle thermogenesis (via enzyme activity) in neonatal harp (Pagophilus groenlandicus), hooded (Cystophora cristata), and Weddell seals (Leptonychotes weddellii). Harp seals are the smallest at birth (9.8±0.7 kg), rely on lanugo (82.49±3.70% of thermal resistance), and are capable of NST through expression of UCP1 in brown adipose tissue (BAT). In contrast, hooded seal neonates (26.8±1.3 kg) have 2.06±0.23 cm of blubber, accounting for 38.19±6.07% of their thermal resistance. They are not capable of NST, as UCP1 is not expressed. The large Weddell seal neonates (31.5±4.9 kg) rely on lanugo (89.85±1.25% of thermal resistance) like harp seals, but no evidence of BAT was found. Muscle enzyme activity was highest in Weddell seal neonates, suggesting that they rely primarily on muscle thermogenesis. Similar total thermal resistance, combined with marked differences in thermogenic capacity of NST and ST among species, strongly supports that thermoregulatory strategy in neonatal phocids is more closely tied to pups' surface area to volume ratio (SA:V) and potential for early water immersion rather than mass and ambient environmental conditions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We investigated whether or not the preferred ambient temperature (Tapref) of the 1-day old chicken hatchling, a precocial neonate with excellent locomotory capacity, clearly identifiable thermogenesis and independence from maternal care, coincides with the lower critical temperature (LCT) of thermoneutrality and minimal oxygen consumption (V̇(O(2))). Tapref of single chicks measured in a thermocline (N=16) averaged 33.5±0.3 °C (mode, 33.3±0.4 °C). The same value was obtained in hatchlings studied in pairs. LCT was computed from the ambient temperature (Ta)-V̇(O(2)) relationship, constructed by slowly decreasing the Ta of a respirometer from 38 to 29 °C over 2.5h, while continuously measuring V̇(O(2)) by an open-flow methodology; LCT averaged 36.4 °C±0.3 or 36.8 °C±0.4, depending on the method of computation. In all hatchlings Tapref was lower than LCT (P<0.001), by a magnitude that depended on the method of computation of the two variables, 2.8 °C±0.3 (P<0.001) or 3.9 °C±0.5. The Tapref-LCT difference implied that, at Tapref, V̇(O(2)) was higher than at thermoneutrality. We conclude that in the chicken hatchling thermal preference does not coincide with thermoneutrality, probably because during development what seems optimal from a thermoregulatory viewpoint may not necessarily be so for other regulatory functions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Neurotrophic factors delivered from target muscles are essential for motoneuronal survival, mainly during development and early postnatal maturation. It has been shown that the disconnection between motoneurons and their innervated muscle by means of axotomy produces a vast neuronal death in neonatal animals. In the present work, we have evaluated the effects of different neurotrophic factors on motoneuronal survival after neonatal axotomy, using as a model the motoneurons innervating the extraocular eye muscles. With this purpose, neonatal rats were monocularly enucleated at the day of birth (postnatal day 0) and different neurotrophic treatments (NGF, BDNF, NT-3, GDNF and the mixture of BDNF+GDNF) were applied intraorbitally by means of a Gelfoam implant (a single dose of 5 μg of each factor). We first demonstrated that extraocular eye muscles of neonatal rats expressed these neurotrophic factors and therefore constituted a natural source of retrograde delivery for their innervating motoneurons. By histological and immunocytochemical methods we determined that all treatments significantly rescued extraocular motoneurons from axotomy-induced cell death. For the dose used, NGF and GDNF were the most potent survival factors for these motoneurons, followed by BDNF and lastly by NT-3. The simultaneous administration of BDNF and GDNF did not increase the survival-promoting effects above those obtained by GDNF alone. Interestingly, the rescue effects of all neurotrophic treatments persisted even 30 days after lesion. The administration of these neurotrophic factors, with the exception of NT-3, also prevented the loss of the cholinergic phenotype observed by 10 days after axotomy. At the dosage applied, NGF and GDNF were revealed again as the most effective neuroprotective agents against the axotomy-induced decrease in ChAT. Two remarkable findings highlighted in the present work that contrasted with other motoneuronal types after neonatal axotomy: first, the extremely high efficacy of NGF as a neuroprotective agent and, second, the long-lasting effects of neurotrophic administration on cell survival and ChAT expression in extraocular motoneurons., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Proprioceptive feedback derived from specialized receptors in skeletal muscle is critical in forming an accurate map of limb position in space, and is used by the central nervous system to plan future movements and to determine accuracy of executed movements. Knockout mouse strains for genes expressed by proprioceptive sensory neurons have been generated that result in generalized motor deficits, but these deficits have not been quantitatively characterized. Here we characterize a conditional knockout mouse model wherein proprioceptive sensory neuron synaptic transmission has been blocked by selective ablation of munc18-1, a synaptic vesicle associated protein required for fusion of synaptic vesicles with the plasma membrane. Proprioceptive munc18-1 conditional mutants are impaired in surface righting--a dynamic postural adjustment task--and display several specific deficits in pivoting, an early locomotor behavior. Before the emergence of forward locomotion during postnatal development, animals explore their surroundings through pivoting, or rotating the upper torso around the relatively immobile base of the hind limbs. 3-D kinematic analysis was used to quantitatively describe this pivoting behavior at postnatal days 5 and 8 in control and munc18-1 conditional mutants. Mutant animals also pivot, but demonstrate alterations in movement strategy and in postural placement of the forelimbs during pivoting when compared to controls. In addition, brief forelimb stepping movements associated with pivoting are altered in mutant animals. Step duration and step height are increased in mutant animals. These results underscore the importance of proprioceptive feedback even at early stages in postnatal development., (© 2013 Elsevier Inc. All rights reserved.)

The altricial young of the European rabbit (Oryctolagus cuniculus) are not brooded by the mother, and although they are born into an underground nest, depend importantly on the warmth and insulation provided by littermates for their early growth and survival. Consistent with previous studies, heavier pups occupied more central, thermally advantageous positions in the litter huddle, maintained higher body temperatures, obtained more milk, were more efficient at converting it to body mass, and consequently grew faster than their lighter sibs occupying the periphery of the huddle. In the present study we measured the expression of uncoupling protein 1 (UCP-1), which is essential for the metabolism of brown adipose tissue to generate body heat in response to cold. In nine litters of domestic rabbits maintained for the first four postnatal days at temperatures below their critical thermoneutral temperature, peripheral pups showed greater expression of UCP-1 than intermediate pups, and these greater expression than central pups. This suggests that during early development littermates of the rabbit experience differing degrees of activation of the sympathetic nervous system as a consequence of exposure to different thermal environments associated with different positions in the litter huddle. Whether this is associated with long term differences in the physiological response to cold and perhaps in the manner of responding to other environmental challenges is currently under investigation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Brain electrical activity is one means of assessing neural development in awake, reactive infants. The development of the electroencephalogram (EEG) in the first week of infant rhesus macaque life is poorly understood though recent work has demonstrated the utility of using this measure to assess neural responses to biologically meaningful stimuli. Here we report on the emergence of EEG rhythms in one-week-old infant rhesus macaques under both light and dark conditions. Our data show that the 5-7Hz frequency band responds reliably to changes in illumination. As well, we found EEG in higher frequencies (12-20Hz) that significantly increase between dark and light conditions similar to the increase in the beta band of humans during cognitive tasks. These findings demonstrate similarities between infant human and infant monkey EEG and suggest approaches for future translational research in developmental psychobiology., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Excitotoxicity triggered by over-stimulation of glutamatergic receptors is considered to be a major component of damage following acute spinal cord injury (SCI). Using an in vitro model of neonatal rat SCI caused by transient application (1h) of the glutamate agonist kainate (0.05-0.1 mM) to produce limited excitotoxicity, the present study investigated whether riluzole, a drug inhibiting glutamate release and neuronal excitability, could prevent neuronal loss and protect locomotor patterns 24 h later. Immunohistochemical analysis of neuronal and motoneuronal populations was associated with recording of fictive locomotion induced by neurochemicals or dorsal root stimuli. Riluzole (5 μM; 24 h application) per se exerted strong and persistent neurodepressant effects on network synaptic transmission from which recovery was very slow. When continuously applied after kainate, riluzole partially reduced the number of pyknotic cells in the gray matter, although motoneurons remained vulnerable and no fictive locomotion was present. In further experiments, riluzole per se was applied for 3 h (expected to coincide with kainate peak excitotoxicity) and washed out for 24 h with full return of fictive locomotion. When this protocol was implemented after kainate, no efficient histological or functional recovery was observed. No additional benefit was detected even when riluzole was co-applied with kainate and continued for the following 3 h. These results show that modest neuronal losses evoked by excitotoxicity have a severe impact on locomotor network function, and that they cannot be satisfactorily blocked by strong neurodepression with riluzole, suggesting the need for more effective pharmacological approaches., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

It is not well-studied how the ubiquitous neuromodulator adenosine (ADO) affects mammalian locomotor network activities. We analyzed this here with focus on roles of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)-sensitive A(1)-type ADO receptors. For this, we recorded field potentials from ventral lumbar nerve roots and electrically stimulated dorsal roots in isolated newborn rat spinal cords. At ≥ 25μM, bath-applied ADO slowed synchronous bursting upon blockade of anion-channel-mediated synaptic inhibition by bicuculline (20 μM) plus strychnine (1 μM) and this depression was countered by DPCPX (1 μM) as tested at 100 μM ADO. ADO abolished this disinhibited rhythm at ≥ 500 μM. Contrary, the single electrical pulse-evoked dorsal root reflex, which was enhanced in bicuculline/strychnine-containing solution, persisted at all ADO doses (5 μM-2 mM). In control solution, ≥ 500 μM ADO depressed this reflex and pulse train-evoked bouts of alternating fictive locomotion; this inhibition was reversed by 1 μM DPCPX. ADO (5 μM-2 mM) did not depress, but stabilize alternating fictive locomotion evoked by serotonin (10 μM) plus N-methyl-d-aspartate (4-5 μM). Addition of DPCPX (1μM) to control solution did not change either the dorsal root reflex or rhythmic activities indicating lack of endogenous A(1) receptor activity. Our findings show A(1) receptor involvement in ADO depression of the dorsal root reflex, electrically evoked fictive locomotion and spontaneous disinhibited lumbar motor bursting. Contrary, chemically evoked fictive locomotion and the enhanced dorsal root reflex in disinhibited lumbar locomotor networks are resistant to ADO. Because ADO effects in standard solution occurred at doses that are notably higher than those occurring in vivo, we hypothesize that newborn rat locomotor networks are rather insensitive to this neuromodulator., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

Maternal care represents an essential environmental factor during the first post-natal week(s) of rodents and is known to have lasting consequences for neuronal structure, brain function as well as behavioral outcome later in life, including social functions and reward-related processes. Previous experiments have shown that the amount of maternal care received by individual pups varies substantially, even within one litter. During adolescence, mammals display high levels of social play behavior, a rewarding form of social interaction that is of great importance for social and cognitive development. In order to investigate how maternal care influences adaptive social behavior later in life, we here examined whether individual differences in maternal licking and grooming (%LG) received during the first postnatal week affect social play behavior during adolescence. We observed that %LG received by male rats early in life correlates positively with the frequency and duration of pouncing and pinning, the two most characteristic behavioral expressions of social play behavior in rats. The latency to engage in social exploration also correlated with %LG. In female rats we observed no correlation between %LG and any social parameter. The data indicate that subtle variations in maternal care received early in life influence social interactions in male adolescent rats. These changes in social play likely have repercussions for the social development of male rats, suggesting that maternal care can have both direct and indirect effects on the behavioral development of the offspring., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We compared behavioural and physiological responses and recovery time after different acute environmental challenges in groups of salmon parr. The fish were prior to the study conditioned to a flashing light signalling arrival of food 30 s later to study if the strength of Pavlovian conditioned food anticipatory behaviour can be used to assess how salmon parr cope with various challenges. The effect on anticipatory behaviour was compared to the effect on feed intake and physiological responses of oxygen hyper-consumption and cortisol excretion. The challenges were temperature fluctuation (6.5C° over 4 h), hyperoxia (up to 380% O(2) saturation over 4 h), and intense chasing for 10 min. Cortisol excretion was only elevated after hyperoxia and chasing, and returned to baseline levels after around 3 h or less. Oxygen hyper-consumption persisted for even shorter periods. Feed intake was reduced the first feeding after all challenges and recovered within 3 h after temperature and hyperoxia, but was reduced for days after chasing. Food anticipatory behaviour was reduced for a longer period than feed intake after hyperoxia and was low at least 6 h after chasing. Our findings suggest that a recovery of challenged Atlantic salmon parr to baseline levels of cortisol excretion and oxygen consumption does not mean full recovery of all psychological and physiological effects of environmental challenges, and emphasise the need for measuring several factors including behavioural parameters when assessing fish welfare., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Sustained hypoxia is known to decrease embryonic growth and to lower the newborn's ventilatory chemosensitivity (VCS) to hypoxia and hypercapnia. What was unclear is whether or not a difference in birth weight could per se, and independently from hypoxia, have some influence on the magnitude of VCS. VCS, defined as the relative increase in ventilation-oxygen consumption ratio (V(E)/V(O2)), was studied by a modification of the barometric technique in 1-day old chicken hatchlings born at term and selected for large differences in birth weight. The small hatchlings (SM, 35.9+/-0.7 g) had smaller V(O2) and V(E) than the large hatchlings (LG, 47.0+/-0.6 g), both in air and during acute exposures to hypoxia (15% or 10% O(2)) or hypercapnia (2% or 4% CO(2)). However, when normalized by the air values, the metabolic and ventilatory responses coincided. Values of V(E)/V(O2) in air, hypoxia or hypercapnia were the same in SM and LG, and much higher than those previously measured in hatchlings with prenatal hypoxia. It is concluded that (a) birth weight per se does not affect V(E) chemosensitivity, and (b) the blunting effects of hypoxia on body growth and chemosensitivity are parallel events, and the former does not contribute to the latter., (Copyright 2010 Elsevier B.V. All rights reserved.)

Belly nosing is an abnormal oral-nasal behavior that can develop to high levels in newly weaned piglets and may signal nutritional need. The effects of feed restriction on both behavior and metabolic serum parameters were examined in 128 weaned piglets. All pigs were fed ad libitum during week 1, and during week 2, half of all pens (N=8) were restricted to 65% of ad libitum intake. Blood samples were collected on days 3 and 10 after weaning and behavior was observed from video recordings on days 5 and 12. Piglets were classified as early 'nosers' or early 'non-nosers' based on their behavior on day 5. Feed restriction resulted in elevated non-esterified fatty acids (NEFA), beta-hydroxybutyrate (BHB) and both lower glucose and a NEFA/glucose ratio, but belly nosing was not affected. Piglets classified as 'nosers' did not have blood profiles indicating they were in greater nutritional need compared to 'non-nosers' in the first week of weaning, nor did they increase belly nosing or other piglet directed behaviors when restricted in week 2. Overall, no associations were found between blood parameters indicative of nutritional stress and belly nosing. This study identifies serum glucose, BHB and NEFA as well as the glucose/NEFA ratio as useful indicators of nutritional stress in newly weaned piglets., ((c) 2010 Elsevier Inc. All rights reserved.)

During separation in a novel cage, guinea pig pups exhibit passive behavior that appears due to increased proinflammatory activity. To determine if separation also produces a febrile response, the present study used telemetry to provide continuous core temperature measurement of pups exposed to a novel cage for 3h while either alone or with their mother on two consecutive days. Separation from the mother increased core temperature, with the clearest effects occurring early during separation the second day. The increased temperature was not associated with an increase in locomotor activity. Further, passive behavior during isolation exhibited pronounced sensitization from the first to second day of separation. These results show that separation produces an increase in core temperature in our testing situation, and suggest that this increase represents true fever. The findings also provide further support for the hypothesis that maternal separation induces aspects of an acute phase response in guinea pig pups. The potential role of proinflammatory activity in promoting change across days in temperature and behavior is discussed., ((c) 2010 Elsevier Inc. All rights reserved.)

Ectothermic vertebrates, such as reptiles, thermoregulate behaviorally by choosing from available temperatures in their environment. As neonates, bearded dragons (Pogona vitticeps) are often observed to aggregate in vertical strata. A proximate mechanism for this behavior is the thermal advantage of heat storage (i.e., grouped lizards benefit through a decreased surface area to volume ratio), although competition for limited thermal resources, or aggregation for social reasons are alternative explanations. This study was designed to gain an understanding of how aggregation and thermoregulation interact. We observed that both isolated and grouped individuals achieved a similar level of thermoregulation (mean T(b) over trial) within a thermal gradient, but that individuals within a group had lower thermoregulatory precision. An experimental design in which light and ambient temperature (T(a)) (20 versus 30 degrees C) were altered established that a light bulb (source of heat) was a limited and valuable resource to both isolated and grouped neonatal lizards. Lizards aggregated more when the light was on at both temperatures, suggesting that individuals were equally attracted to or repelled from the heat source, depending on the ambient temperature. These data suggest aggregation occurs in neonatal bearded dragons through mutual attraction to a common resource. Further, increased variability in thermal preference occurs in groups, demonstrating the potential for agonistic behaviors to compromise optimal thermoregulation in competitive situations, potentially leading to segregation, rather than aggregation., (Crown Copyright 2010. Published by Elsevier Inc. All rights reserved.)

Complex milk lipids (CMLs) provide a critical nutritional source for generating both energy and essential nutrients for the growth of the newborn. The present study investigated nutritional supplementation with a CML containing gangliosides and phospholipids in pregnant and lactating rats on learning behavior and postnatal growth in male offspring. Wistar female rats were supplemented during pregnancy and lactation with either control or CML to provide gangliosides at a dose of 0.01% (low) and 0.05% (high) based on total food intake. The CML-supplemented dams showed no differences in comparison to controls regarding growth, food intake, and litter characteristics. There were significant differences in brain composition in male offspring at postnatal day 2 (P2) with higher concentrations of gangliosides (high dose, P < .05) and lower concentrations of phospholipids (low and high dose, P < .05) in the CML-supplemented groups. The distribution of individual ganglioside species was not significantly different between treatment groups. Brain weight at P2 was also significantly higher in the CML groups. Differences in the brain composition and weight were not significant by weaning (P21). As adults (P80), adiposity was reduced in the low CML-supplemented group compared to controls. No significant differences were detected between any of the treatment groups in any of the behavioral tasks (water maze, object recognition, and operant learning). These data suggest that maternal supplementation with a CML during pregnancy and lactation is safe and has a significant early impact on brain weight and ganglioside and phospholipid content in offspring but did not alter long-term behavioral function using standard behavioral techniques., (Copyright 2010 Elsevier Inc. All rights reserved.)

Toxoplasmosis is a serious disease in humans and may cause abortion or congenital infection if a woman is exposed to the disease for the first time during pregnancy. Infection before pregnancy normally results in immunity protecting the foetus, suggesting that it may be possible to block vertical transmission of the parasite by appropriate vaccination before pregnancy. We found that the vaccination of CBA/J mice, before pregnancy, with exosomes secreted by SRDCs pulsed in vitro with Toxoplasma gondii-derived antigens (TAg) induced a protective response in the pups. Indeed, vaccination resulted in the presence of significantly fewer cysts in pup brains. This protection was associated with strong humoral responses in the serum in vivo. We also observed cellular responses in vivo, with cell proliferation associated with the production of cytokines by the splenocytes. Thus, exosomes are nucleic acid-free vesicles able to induce immune responses correlated with protection against T. gondii infection in a congenital model. They are therefore a potentially useful tool for vaccination against infectious disease.

Neonatal food restriction (FR) in rats, by means of increased litter size, has been used as a model for developmental programming by several investigators. However, the results reported have been inconsistent and difficult to compare between studies. In the present study, we aim to characterize the effects of this model throughout life in both sexes of one particular strain. On the second day of life, Wistar rat pups were randomly assigned to a litter of 10 (control) or 20 (FR). All litters had an equal number of males and females, and pups were weaned on day 25. Body dimensions and food intake were measured regularly until the age of one year. Serum leptin levels were determined in four subsets of different ages. FR acutely reduced growth in all body dimensions and serum leptin levels. Despite catch-up after weaning, all these parameters remained reduced throughout life. Male and female FR rats had a significantly reduced absolute energy intake throughout life. Male FR rats had significantly higher energy intake adjusted for body weight immediately after weaning. During catch-up growth, both FR males and females showed significantly enhanced feed efficiency. These results suggest that neonatal food restriction programmed both male and female Wistar rats to remain small and lean in adult life, with a lower food intake. Low neonatal leptin levels may play a mechanistic role in this process.

Feeding and stress neurocircuits are intertwined. Among the neurotransmitters and receptors common to both circuits, the serotonin 2C receptor is particularly intriguing because its distribution is limited to the central nervous system. Hence, deficits in energy balance and stress responses in mice lacking this gene are likely due to defects in central regulation. The phenotype of the serotonin 2C receptor null (KO) mouse is adult-onset hyperphagia, depressed metabolic rate, and disruption in satiety, with a progression to midlife obesity. A provocative feature of this obese model is our recent finding of a childhood component where the KO mouse is heavier at weaning, a distinction that only returns in adulthood. To determine when the KO mouse becomes heavier, longitudinal and cross-sectional timecourse studies followed weight gain and found significantly heavier body weight, higher plasma leptin, and rectal temperature, only in unhandled KO compared to sibling wildtype controls. To map what metabolic compensations cause the KO weight increase, we launched thermal and behavioral studies in 10 day old mice before there was any genotype difference in body weight, corticosterone levels, or the levels leptin during the developmental leptin peak. The heavier KO weanling is, in part, explained by hyperphagia, lower metabolic rate and activity, and behavioral thermogenesis measured at 10 days of age. However, the infant KO mouse is stress-sensitive and growth is impaired with handling. The serotonin 2C receptor has a role in fine-tuning energetic and stress demands even as neurocircuits are developing, and unbalanced compensations in infancy may program responses in adulthood that are "off target" from optimal function.

The brainstem nucleus hypoglossus innervates the tongue which must contract rhythmically during respiration, chewing and swallowing. Such rhythmic discharges are due to network bursting mediated by AMPA receptor-dependent glutamatergic transmission. The contribution by hypoglossal motoneurons themselves to rhythmicity remains, however, unclear as they might simply express cyclic patterns produced by premotoneurons or, in analogy to spinal motoneurons, might participate to bursting due to activation of their N-methyl-D-aspartate (NMDA) receptors. Using patch clamp recording from hypoglossal motoneurons in slice preparations of neonatal rat brainstem, we observed that NMDA directly depolarized motoneurons to generate various discharge patterns. Most motoneurons produced transient bursts which were consistently restored by repolarizing membrane potential to rest. Fewer motoneurons generated either sustained bursting or random firing. Rhythmic bursts were recorded from XII nerve rootlets even when single motoneuron bursting required hyperpolarization. NMDA evoked bursts were blocked by the Ca2+ antagonist Cd2+, the gap junction blocker carbenoxolone, or Mg2+ free solution, and partially inhibited by tetrodotoxin or nifedipine. Under voltage clamp, NMDA-induced bursting persisted at negative or positive potentials and was resistant to high extracellular Mg2+ in accordance with the observation of widespread motoneuron expression of NMDA 2D receptor subunits that confer poor Mg2+ sensitivity. It is proposed that NMDA depolarized motoneurons with the contribution of Mg2+ insensitive channels, and triggered bursting via cyclic activation/deactivation of voltage-dependent Na+, Ca2+ and K+ currents spread through gap junctions. The NMDA-evoked bursting pattern was similar to the rhythmic discharges previously recorded from the XII nerve during milk sucking by neonatal rats.

In the present study, we examined whether exposing rats to a high-dose regimen of manganese chloride (Mn) during the postnatal period would depress presynaptic dopamine functioning and alter nonassociative and associative behaviors. To this end, rats were given oral supplements of Mn (750 microg/day) on postnatal days (PD) 1-21. On PD 90, dopamine transporter (DAT) immunoreactivity and [3H]dopamine uptake were assayed in the striatum and nucleus accumbens, while in vivo microdialysis was used to measure dopamine efflux in the same brain regions. The effects of postnatal Mn exposure on nigrostriatal functioning were evaluated by assessing rotorod performance and amphetamine-induced stereotypy in adulthood. In terms of associative processes, both cocaine-induced conditioned place preference (CPP) and sucrose-reinforced operant responding were examined. Results showed that postnatal Mn exposure caused persistent declines in DAT protein expression and [3H]dopamine uptake in the striatum and nucleus accumbens, as well as long-term reductions in striatal dopamine efflux. Rotorod performance did not differ according to exposure condition, however Mn-exposed rats did exhibit substantially more amphetamine-induced stereotypy than vehicle controls. Mn exposure did not alter performance on any aspect of the CPP task (preference, extinction, or reinstatement testing), nor did Mn affect progressive ratio responding (a measure of motivation). Interestingly, acquisition of a fixed ratio task was impaired in Mn-exposed rats, suggesting a deficit in procedural learning. In sum, these results indicate that postnatal Mn exposure causes persistent declines in various indices of presynaptic dopaminergic functioning. Mn-induced alterations in striatal functioning may have long-term impact on associative and nonassociative behavior.

Recent studies in rats and mice suggest that developmental plasticity of HPA-stress and fear responses could be mediated by environment-dependent variations in maternal behaviour. The present study was designed to examine this question further by varying the adversity of the maternal environment to study its effects on nest-attendance and maternal care and on the HPA and fear responses in the adult offspring. C57BL/6 dams and their litter were housed in a cage system composed of a nest cage (NC) and a foraging cage (FC) connected by a tunnel. Using a 2 x 2 factorial design, we varied the maternal foraging environment (FC) by the presence or absence of rat odour (feces) and shelters (MouseHouse and tube) from postnatal days 1-14 and assessed the adult offspring's corticosterone response to isolation/novelty stress and their behaviour in three tests of fearfulness (elevated-O-maze, open-field, free exploration). While the presence of shelters in the FC reduced time spent in the NC (nest site attendance), the presence of rat odour in the FC increased active maternal care without altering nest site attendance. Alterations of the offspring's HPA and fear responses were rather subtle. The presence of shelters in the dam's foraging environment decreased fearfulness in the offspring in the free exploration test. In addition, males reared by dams exposed to rat odour were less fearful in the open-field test, and both males and females reared by dams without shelters and rat odour in the FC showed a greater corticosterone response to isolation/novelty stress. Multiple regression analysis indicated a negative relationship between maternal licking/grooming and fearfulness in males and a positive relationship between nest site attendance and fearfulness in females. Taken together, these results indicate that mouse dams adjust specific aspects of maternal behaviour in response to the specific properties of their environment, and that active maternal care and nest site attendance are two aspects of maternal behaviour that may affect the offspring's stress and fear systems independent of each other and in a sex-specific way.

Numerous studies have documented the consequences of exposure to anesthesia in models of term and post-term infants, evaluating the incidence of cell loss, physiological alterations and cognitive dysfunction. However, surprisingly few studies have investigated the effect of anesthetic exposure on outcomes in newborn rodents, the developmental equivalent of premature human infants. This is critical given that one out of every eight babies born in the United States is premature, with an increased prevalence of surgical procedures required in these individuals. Also, no studies have investigated if the genetic sex of the individual influences the response to neonatal anesthesia. Using the newborn rat as the developmental equivalent of the premature human, we documented the effect of a single bout of exposure to either the inhalant isoflurane or the injectable barbiturate phenobarbital on hippocampal anatomy, hippocampal dependent behavioral performance and normal developmental endpoints in male and female rats. While both forms of anesthesia led to significant decrements in cognitive abilities, along with a significant reduction in volume and neuron number in the hippocampus in adulthood, the decrements were significantly greater in males than in females. Interestingly, the deleterious effects of anesthesia were manifest on developmental measures including surface righting and forelimb grasp, but were not evident on basic physiological parameters including body weight or suckling. These findings point to the hazardous effects of exposure to anesthesia on the developing CNS and the particular sensitivity of males to deficits.

In vitro studies have demonstrated that angiotensin II (ANG II) induces adipocyte hyperplasia and hypertrophy. The aim of the present study was to determine the effect of angiotensin-converting enzyme inhibition on body weight, adiposity and blood pressure in Sprague-Dawley rats. From birth half of the animals (n=15) were given water to drink, while the remainder were administered perindopril in their drinking water (2 mg/kg/day). Food intake, water intake and body weight were measured weekly. Blood pressure was measured by tail cuff plethysmography at 11-weeks. Body fat content and distribution were assessed using dual energy X-ray absorptiometry and Magnetic Resonance Imaging at 12 weeks. Animals administered with perindopril had a body fat proportion that was half that of controls. This was consistent with, but disproportionately greater than the observed differences in food intake and body weight. Perindopril treatment completely removed hypertension. We conclude that the chronic inhibition of ANG II synthesis from birth specifically reduces the development of adiposity in the rat.

The aim of the present study is to highlight and evaluate the role of flavour prenatal exposure in postnatal feeding preferences in sheep after weaning and until the early stages of puberty. 16 lambs were selected from two groups of ewes; the first group was fed with a control diet, consisted of concentrated feed and alfalfa hay and the second group with the same diet, with the only difference that the concentrate was supplemented with oregano essential oil (1 ml/kg), during the period of pregnancy (50th-130th day). Lambs were later individually subjected to feeding preference tests, at the age of 3, 4.5, 6, 7.5 months old. Each test lasted 25 min and it was a free choice situation between 3 different test feeds supplemented with eucalyptus or orange or oregano essential oil (1 ml/kg). Lambs born to oregano-treated ewes ate higher amounts of the oregano supplemented test feed during all feeding preference tests compared to lambs from the control group (P<0.01). Rates for occurrences and duration of eating were also greater in lambs born to oregano-treated ewes than the offspring of the control ewe group (P<0.01). On the other hand, animals without a flavour exposure precedent did not exhibit an evident strong preference for a specific test feed, although orange supplemented feed tended to be more preferable compared to the other offered feeds. Average total intake of lambs were not different between groups during all feeding preference tests at 3, 41/2, 6 and 71/2 months old. As it is concluded, prenatal exposure to oregano essential oil via maternal ingestion drastically influences lamb feeding preferences till adulthood.

The olfactory memory acquired during the early postnatal period is known to be maintained for a long period, however, its neural mechanism remains to be clarified. In the present study, we examined the effect of olfactory conditioning during the early postnatal period on neurogenesis in the olfactory bulb of rats. Using the bromodeoxyuridine-pulse chase method, we found that the olfactory conditioning, which was a paired presentation of citral odor (conditioned stimulus) and foot shock (unconditioned stimulus) in rat pups on postnatal day 11, stimulated the proliferation of neural stem/progenitor cells in the anterior subventricular zone (aSVZ), but not in the olfactory bulb, at 24 h after the conditioning. However, the number of newborn cells in the olfactory bulb was increased at 2 weeks, but not 8 weeks, after such conditioning. Neither the exposure of a citral odor alone nor foot shock alone affected the proliferation of neural stem/progenitor cells in the aSVZ at 24 h after and the number of newborn cells in the olfactory bulb at 2 weeks after. The majority of newborn cells in the olfactory bulb of either the conditioned rats or the unconditioned rats expressed the neural marker NeuN, thus indicating that the olfactory conditioning stimulated neurogenesis in the olfactory bulb. These results suggest that olfactory conditioning during the early postnatal period temporally stimulates neurogenesis in the olfactory bulb of rats.

The role of natural variations in pre-weaning litter size in rodent adult emotionality and the importance of maternal care as a possible mediating factor have been frequently neglected. To address these issues, maternal behaviour of Sprague-Dawley dams differing in natural number of pups was studied for the first seven postnatal days. Later, adult behaviour of representative male offspring was studied in the elevated plus-maze, the circular corridor, the dark-light box and the forced swimming test. Three groups of offspring were selected in function of the number of littermates: L<10 group (less than 10 pups per dam), L10-15 (between 10 and 15 pups per dam) and L>15 group (more than 15 pups per dam). L<10 litters showed a reduced habituation of activity across time in a circular corridor and as compared to L>15 litters, L<10 litters showed a lower activity during the first 5 min of exposure to the circular corridor. L<10 litters had also higher signs of anxiety in the elevated plus-maze, in comparison to the other two groups. In addition, L<10 litters showed in the forced swimming test reduced struggling and more mild swimming behavior than the other two groups. These abnormalities in L<10 litters are not explained by maternal behavior since they received individually more maternal care than L>15, as assessed by total licking-grooming observed during the whole observation period divided by number of pups. Although previous data from several laboratories have demonstrated that low maternal care is associated with heightened emotionality at adulthood, the present results suggest an important contribution of spontaneous litter size to adult emotional behavior that cannot be explained by concomitant changes in maternal care.

Adult dolphins are capable of sleeping with one eye open and exhibiting slow wave activity in the electroencephalogram (EEG) of one hemisphere at a time. The aim of this study was to examine the postpartum sleep behavior of bottlenose dolphin calves and their mothers. The behavior of three dolphin mother-calf pairs was monitored from birth to 13 months postpartum. Dolphin mothers and their calves exhibited a complete disappearance of rest at the surface for a minimum of 2 months postpartum, swimming in echelon formation on average in 97-100% of the observation time. Calves surfaced to breathe more often than their mothers between the postpartum age of 2 and 8 weeks. During the first postpartum month two dolphin mothers surfaced with both eyes open on average in 93 and 98% of the time while in their calves both eyes were open in 90 and 60% of the cases. In calves, the eye directed toward the mother was open more often (on average in 95% of all observations in calf 1 and 99% in calf 2) than the eye directed to the opposite side (82% in calf 1 and 60% in calf 2). Our data indicate that dolphin mothers and calves are highly active and vigilant during the initial period of the calf's life, continuously monitoring their position relative to each other by sight during wakefulness and sleep. We hypothesize that episodes of EEG slow wave activity at this time are likely to be brief, fragmenting EEG defined sleep into short episodes.

Organotypic cultures of rat cortex were used to test the hypotheses that nerve growth factor (NGF) is neuroprotective for immature cortical neurons and that ethanol abolishes this neuroprotection in a developmental stage-dependent manner. Samples were obtained on gestational day (G) 16 or postnatal day (P) 3 and cultured with ethanol (0 or 400 mg/dl) and NGF (0 or 30 ng/ml) for 72 h. Dying neurons were identified as exhibiting terminal nick-end labeling, immunoreactivity for activated caspase 3, or condensed nuclear chromatin. Two cortical compartments were examined in fetal tissue: a superficial, cell-sparse marginal zone (MZ) and a cell-dense cortical plate (CP). At P3, the CP was subdivided into a cell-dense upper cortical plate (UCP) and a less densely packed lower cortical plate (LCP). Neuronal death in the MZ was affected by neither NGF nor ethanol at both ages. In the fetal CP, NGF did not affect the incidence of cell death, but ethanol increased it. Treatment with NGF caused an upregulation of the expression of Neg, a gene known to be affected by NGF and ethanol. NGF did not ameliorate the ethanol-induced death. In pups, ethanol increased the amount of death in the LCP. NGF did protect against this death. Neither ethanol nor NGF altered the incidence of cell death in the UCP. The laminar-dependent neuroprotection did not correlate with expression of NGF receptors or Neg. Thus, NGF can be protective against the neurotoxic effect of ethanol in the neonatal brain. This effect is site selective and time dependent and it targets postmigratory, differentiating neurons.

Effective gas exchange after birth requires clearance of most of the liquid filling the lung during gestation. To date the focus has been on active Na(+) transport from lung lumen to interstitium, but Na(+) transport begins only close to delivery, making it an unlikely mechanism for clearing the bulk of fetal lung liquid. We hypothesised that fetal trunk muscle contractions, known to occur in labour, are involved in lung liquid clearance. We measured maternal uterine contractions, fetal tracheal flow directly and fetal electromyograms in thoracic and abdominal muscles. During labour in five fetal sheep, brief flow pulses were observed in the trachea, most of which expelled a small volume of lung liquid. Tracheal flow pulses were associated with fetal muscle contractions 89% of the time, which were associated on 91% of occasions with uterine contractions. Our results suggest that liquid contained in the fetal lung is cleared before and during labour as a result of fetal muscular effort, perhaps stimulated by uterine contractions.

At birth, with the first breath, pulmonary vessels undergo profound adaptive processes. A failure in the ability of pulmonary vessels to adapt at birth results in persistent pulmonary hypertension of the new born. The mechanisms regulating pulmonary adaptation at birth are still unclear. Progress in this area is slow, not least because genetically modified mice have not yet been used to address questions in this area of research, principally because pulmonary vessels in new born mice are very small making the study of dilator response in vitro difficult. In the current study we have used precision cut lung slices to characterise the functional vasomotor changes in lung vessels of new born mice (1-4 days old), 8-15 day old mice or adult mice. The internal luminal area of pulmonary artery and airways was measured digitally. Vasoconstriction and vasodilatation were expressed as the percentage change in internal luminal area compared with the control area. The thromboxane A(2) mimetic U-46619 (3x10(-7) M) caused a significant vasoconstriction in vessels of all groups. However, acetylcholine (3x10(-5) M) induced arterial dilation only in the 8-15 days, and adult groups. By contrast, sodium nitroprusside, which acts independently of the endothelium, was an effective vasodilator in lung vessels from neonates. These data are the first to characterise the development of endothelium dependent vasodilatation in lung after birth in mice. This approach can be used with genetically modified mice, which is important to further our understanding of the physiology in this area.

The embryonic modal value of heart rate (MHR) differs between broiler and White Leghorn chickens, but the initial development of cholinergic chronotropic control of embryonic heart rate (HR) does not. Thus, we hypothesized that hatchling MHR should also differ between broiler and White Leghorn strains, while the development of a physiological regulation, such as the endothermic HR response, should not be different between hatchlings of the two strains. To test this, we measured the response of HR and cloaca temperature (Tb) to alteration of ambient temperature (Ta); i.e., 35 degrees C-25 degrees C-35 degrees C, in four groups of hatchlings on Days 0 and 1 post-hatch. Fertile eggs of both strains with similar mass were incubated simultaneously in the same incubator. Eggs of broiler chickens hatched approximately 7 h earlier than White Leghorn chicken eggs. Chick mass at hatching was identical in both strains, but diverged during 2 days after hatching. Tb measured at the initial Ta of 35 degrees C was identical in both strains. MHR at the same Ta was approximately 30 bpm lower in broiler chicks than in White Leghorn chicks, but the difference was reversed to that observed in the embryos. The endothermic HR response was advanced by approximately 1 day in broiler chicks compared with White Leghorn chicks. As a result, eggs of similar mass in both strains produced chicks with similar mass and Tb at hatching, but during 2 days of post-hatch life their masses diverged and regulation of the endothermic HR response developed earlier in broiler than in White Leghorn hatchlings. This physiological heterochrony between strains is most likely due to genetic selection for fast growth in broiler chickens.

Prenatal alcohol exposure (PAE) has been shown to alter the somatosensory cortex in both human and animal studies. In rodents, PAE reduced the size, but not the pattern of the posteromedial barrel subfield (PMBSF) associated with the representation of the whiskers, in newborn, juvenile, and adult rats. However, the PMBSF is not present at birth, but rather first appears in the middle of the first postnatal week during the brain-growth spurt period. These findings raise questions whether early postnatal alcohol exposure might disrupt both barrel field pattern and size, questions that were investigated in the present study. Newborn Sprague-Dawley rats were assigned into alcohol (Alc), nutritional gastric control (GC), and suckle control (SC) groups on postnatal day 4 (P4). Rat pups in Alc and GC were artificially fed with alcohol and maltose-dextrin dissolved in milk, respectively, via an implant gastrostomy tube, from P4 to P9. Pups in the Alc group received alcohol (6.0 g/kg) in milk, while the GC controls received isocaloric equivalent maltose-dextrin dissolved in milk. Pups in the SC group remained with their mothers and breast fed throughout the experimental period. On P10, pups in each group were weighed, sacrificed, and their brains removed and weighed. Cortical hemispheres were separated, weighed, flattened, sectioned tangentially, stained with cytochrome oxidase, and PMBSF measured. The sizes of barrels and the interbarrel septal region within PMBSF, as well as body and brain weights were compared between the three groups. The sizes of PMSBF barrel and septal areas were significantly smaller (P<.01) in Alc group compared to controls, while the PMBSF barrel pattern remained unaltered. Body, whole-brain, forebrain, and hemisphere weights were significantly reduced (P<.01) in Alc pups compared to control groups. GC and SC groups did not differ significantly in all dependent variables, except body weight at P9 and P10 (P<.01). These results suggest that postnatal alcohol exposure, like prenatal exposure, significantly influenced the size of the barrel field, but not barrel field pattern formation, indicating that barrel field pattern formation consolidated prior to P4. These results are important for understanding sensorimotor deficits reported in children suffering from fetal alcohol spectrum disorder (FASD).

The vulnerability to develop alcoholism is dependent on both genetic and environmental factors. The neurobiological mechanisms underlying these factors are not fully understood but individual divergence in the endogenous opioid peptide system may contribute. We have previously reported that early-life experiences can affect endogenous opioids and also adult voluntary ethanol intake. In the present study, this line of research was continued and the effects of long-term voluntary ethanol drinking on the opioid system are described in animals reared in different environmental settings. Rat pups were subjected to 15 min (MS15) or 360 min (MS360) of daily maternal separation during postnatal days 1-21. At 10 weeks of age, male rats were exposed to voluntary ethanol drinking in a four-bottle paradigm with 5%, 10% and 20% ethanol solution in addition to water for 2 months. Age-matched controls received water during the same period. Immunoreactive (ir) Met-enkephalin-Arg6Phe7 (MEAP) and dynorphin B (DYNB) peptide levels were thereafter measured in the pituitary gland and several brain areas. In water-drinking animals, lower ir MEAP levels were observed in the MS360 rats in the hypothalamus, medial prefrontal cortex, striatum and the periaqueductal gray, whereas no differences were seen in ir DYNB levels. Long-term ethanol drinking induced lower ir MEAP levels in MS15 rats in the medial prefrontal cortex and the periaqueductal gray, whereas higher levels were detected in MS360 rats in the hypothalamus, striatum and the substantia nigra. Chronic voluntary drinking affected ir DYNB levels in the pituitary gland, hypothalamus and the substantia nigra, with minor differences between MS15 and MS360. In conclusion, manipulation of the early environment caused changes in the opioid system and a subsequent altered response to ethanol. The altered sensitivity of the opioid peptides to ethanol may contribute to the previously reported differences in ethanol intake between MS15 and MS360 rats.

The present study was undertaken to characterize the regional and temporal patterns of brain-derived neurotrophic factor (BDNF) in the rat forebrain and upper brain stem during postnatal development using an immunohistochemical approach. Results indicated that BDNF-immunoreactive (IR) cells could be divided into three groups based on their postnatal developmental patterns: (group 1) BDNF-IR cells were first detected between postnatal days (PND) 1 and 7, and thereafter they increased in number and remained stable during later stages of ontogeny; (group 2) BDNF-IR cells progressively increased in number with age, and then decreased in adults; (group 3) numerous BDNF-IR cells detected between PND 1 and 7 showed a dramatic reductions in number with few IR cells in adults. In contrast, the developmental pattern of most BDNF-IR fibers differed from that of IR neurons, i.e. they appeared between PND 1-28 and thereafter continued to increase in number showing a maximum level in adults. Additionally, BDNF-IR cells in the superficial layer of the neocortex and IR fibers in the stratum oriens of CA2 first appeared as late as PND 28 and in adults, respectively. After colchicine treatment, reexpression or a marked increase in the number of BDNF-IR neurons was observed in many areas of the adult brain where a progressive decrease in BDNF-IR cell numbers during development and scant or some IR neurons in adults were shown. These results showed both transient and persistent expression of BDNF in various regions of the developing rat brain.

During hatching, there is a maturation of the mechanisms controlling the respiratory physiology involved in endotherm in precocial avian species. Here we examined the timing of the development of an endothermic response of oxygen uptake (MO2) to an alteration of ambient temperature (T(a)) in a model precocial species, the preterm and hatching emu (Dromaius novaehollandiae). Late stage pre-pipped and pipped embryos and hatchlings were measured for responses of MO2 and shell or skin temperature (T(s)) to altered T(a) (DeltaT(a)). MO2 remained unchanged in pre-pipped and internally pipped (IP) embryos at the end of 1.5h exposure to DeltaT(a) of +/-10 degrees C. Externally pipped (EP) embryos responded to a cooling and a warming exposure with marked increase and decrease in MO2, as hatchlings responded to DeltaT(a) with an endothermic change in MO2. The demonstration of the endothermic inverse metabolic response first appearing in EP embryos suggests that pre-EP embryos may also possess the ability to produce the endothermic inverse metabolic response, but they are restricted by the eggshell gas conductance. Late pre-pipped and IP embryos were measured again for responses of [Formula: see text] to DeltaT(a) in air and then in a 40% O(2) environment. The metabolic response of pre-pipped embryos at 90% of incubation was partially altered by switching from air to hyperoxia. IP embryos responded to DeltaT(a) in 40% O(2) with apparent inverse changes in MO2. The late stage emu embryo possesses the ability to produce an endothermic metabolic response at an earlier stage of development than in chickens, but this response is limited by the eggshell gas conductance.

The pattern and control of respiration is virtually unknown in hatchling sea turtles. Using incubator-raised turtles, we measured oxygen consumption, frequency, tidal volume, and minute volume for leatherback (Dermochelys coriacea) and olive ridley (Lepidochelys olivacea) turtle hatchlings for the first six days after pipping. In addition, we tested the hatchlings' response to hypercapnic, hyperoxic, and hypoxic challenges over this time period. Hatchling sea turtles generally showed resting ventilation characteristics that are similar to those of adults: a single breath followed by a long respiratory pause, slow frequency, and high metabolic rate. With hypercapnic challenge, both species responded primarily by elevating respiratory frequency via a decrease in the non-ventilatory period. Leatherback resting tidal volume increased with age but otherwise, neither species' resting respiratory pattern nor response to gas challenge changed significantly over the first few days after hatching. At the time of nest emergence, sea turtles have achieved a respiratory pattern that is similar to that of actively diving adults.

The amygdala is important for the formation of emotions that are affected by olfactory information. The piriform cortex is involved in information processing related to olfaction. To investigate functional interactions between the piriform cortex and amygdala and their relation to medullary respiratory activity, we developed a novel in vitro preparation including the limbic system, brainstem, and spinal cord of newborn rats. With the use of optical and electrophysiologic recordings, we analyzed spontaneous neuronal activity in the piriform-amygdala complex in limbic-brainstem-spinal cord preparations from 0- to 1-day-old rats. For optical recordings, the preparation was stained with a voltage-sensitive dye, and inspiratory activity was monitored from the fourth cervical (C4) ventral root. Spontaneous oscillatory burst activity (up to 10/min) was detected from the rostral cut surface of limbic and para-limbic regions including the piriform cortex and amygdala. The burst activity initially appeared in the piriform cortex and then propagated to the amygdala. We averaged the imaging data in the limbic area with the use of C4 inspiratory activity as a trigger signal. The results suggest functional coupling of the rhythmic burst activity in the piriform-amygdala complex to medullary inspiratory activity, which was confirmed electrophysiologically by cross-correlation analysis of these signals. This rhythmic burst activity may be involved in the development of neuronal circuits that process information related to olfaction, emotion, and respiration.

Perinatal exposure to methylmercury (MeHg) in rodents has been linked to changes in sensitivity to dopaminergic agents later in life. In an effort to determine the behavioral and neurochemical response to the indirect dopaminergic and serotonergic agonist amphetamine following neonatal exposure to MeHg, male BALB/c mice were administered MeHg during critical periods of neural development and challenged with amphetamine as adults. Mice were observed 15, 30 and 60 min after a single amphetamine injection (7.5 mg/kg i.p.) for presence of stereotypic and self-injurious behaviors, abnormal posture, and hyperthermia. Mice treated with 2 or 4 mg/kg MeHg on alternate days 3-15 of life demonstrated an increase in body temperature and the appearance of stereotypic and self-injurious behaviors not observed when amphetamine was administered to either vehicle-exposed mice or those treated with an equivalent total amount of MeHg administered on postnatal days 13 and 15. Neurochemical analysis of MeHg- and vehicle-exposed mice challenged with amphetamine or saline revealed alterations in dopaminergic and serotonergic activity which corresponded to the sensitized behavioral response to amphetamine. These observations demonstrate a critical window for MeHg exposure affecting the later appearance of amphetamine-induced self-injurious behavior and support the hypothesis that early exposure to environmental neurotoxicants may predispose individuals to engage in aberrant, intrusive behaviors later in life.

Polybrominated diphenyl ethers (PBDEs), which are used as flame retardants, have recently been shown to increase in the environment and in human milk, which is also true for the decabrominated congener, 2,2',3,3',4,4',5,5',6,6'-decaBDE (PBDE 209). We have recently reported that neonatal exposure to PBDE 209 can induce persistent aberrations in spontaneous behaviour, in mice, effects that get worse with age. Other PBDE congeners affect learning and memory functions and the cholinergic system in adult mice and rats. The present study indicates that spontaneous behaviour, along with the cholinergic system during its developing stage, can be targets for PBDE 209 in the rat. Neonatal oral exposure of male Sprague-Dawley rats, on postnatal day 3, to 6.7, and 20.1 mg PBDE 209/kg body weight, was shown to disrupt normal spontaneous behaviour at 2 months of age. Also, rats exposed to the high dose of PBDE 209 showed a different response to adult nicotine treatment, compared to control rats. These findings show similarities to observations made from neonatal exposure of rats or mice to 2,2',4,4',5-pentaBDE (PBDE 99), 2,2',4,4',5,5'-hexaBDE (PBDE 153) and certain PCBs, compounds shown to affect both spontaneous behaviour and the cholinergic system. It is also clear from the present study and from recent studies from our research group that both lower and higher brominated diphenyl ethers can cause similar developmental neurotoxic effects in both mice and rats.

The presence of human immunodeficiency virus type 1 (HIV-1) in the brain is believed to be responsible for mediating the pathogenesis of neurological abnormalities through the viral toxins gp120 and Tat. Numerous studies indicate neurotoxic effects of the HIV-1-protein Tat, with demonstrated neurobehavioral and cognitive alterations. However, less clear is the neurotoxic effect of gp120 on neurobehavior. This study was designed to characterize the potential deficits in sensory-motor and preattentive functions, following intrahippocampal administration of gp120. Using a randomized-block design, male and female pups of eight Sprague-Dawley litters were injected bilaterally with either vehicle (VEH) (1 microl volume) or one of the three gp120 doses (1.29, 12.9, or 129 ng/microl) at postnatal day (P)1. Sensory-motor functions were assessed at P3, as measured by the righting reflex and at P8, as measured by negative geotaxis. At P24 animals were tested on preattentive processes, as indexed by sensorimotor gating. Sensorimotor gating was measured by prepulse inhibition (PPI) of the auditory startle response (ASR) (ISIs of 0, 8, 40, 80, 120, and 4000 ms, six trial blocks, Latin-square design). Results indicated gp120-induced neurotoxicity on the righting reflex but not negative geotaxis. For sensorimotor gating, the PPI test demonstrated a reduced inhibition response on peak ASR latency as the dose of gp120 increased. No effect was noted for response inhibition on peak ASR amplitude. These data suggest that intrahippocampal injection of gp120 (0, 1.29, 12.9, or 129 ng/microl) had transient neurotoxic effects on sensory-motor function and limited effects on preattentive processes early in development.

Changes in the volumes of sexually dimorphic brain nuclei are often used as a biomarker for developmental disruption by endocrine-active compounds (EACs). However, these gross, morphological analyses do not reliably predict disruption of cell phenotype or neuronal function. In the present experiments, we used a more comprehensive approach to assess whether postnatal exposure to the EACs genistein (GEN) or bisphenol-A (BIS) affected the development of two sexually dimorphic brain regions in male rats: the anteroventral periventricular nucleus of the hypothalamus (AVPV) and the sexually dimorphic nucleus of the preoptic area (SDN). In addition to nuclear volumes, we also measured the number of immunopositive calbindin neurons in the SDN and the activational patterns of gonadotropin-releasing hormone (GnRH) neurons, a neuronal population that is functionally linked to the AVPV. In rats, exposure of the neonatal male brain to endogenous estrogen, aromatized from testicular testosterone, is essential for the proper sexual differentiation of these endpoints. Thus, we hypothesized that exposure to BIS and GEN during this critical period could disrupt brain sexual differentiation. Animals were given four subcutaneous injections of sesame oil (control), 250 microg GEN, or 250 microg BIS at 12 h intervals over postnatal days (PND) 1 and 2, gonadectomized on PND 85, and treated sequentially with estrogen and progesterone to stimulate Fos expression in GnRH neurons, a marker for their activation. A cohort of age-matched ovariectomized (OVX) females that were given the same hormone treatment in adulthood served as a positive control group. SDN volume was unchanged by treatment, but the number of calbindin neurons in the SDN was significantly increased by both BIS and GEN. GEN, but not BIS, demasculinized male AVPV volume, but patterns of GnRH neuronal activation were not affected by either compound. These results suggest that acute exposure to EACs during a critical developmental period can independently alter nuclear volumes of sexually dimorphic nuclei and their phenotypic profiles in a region specific manner.

Early life events have been implicated in the programming of adult chronic diseases. Several investigations suggest that the role of early environment in influencing development mainly involves the hypothalamic-pituitary-adrenal axis. Therefore, we examined whether 1) daily neonatal handling, applied from birth to weaning induces HPA hormones alterations in mice lasting up to the adult age; and 2) if the administration of an antisense oligodeoxynucleotide versus pro-opiomelanocortin (As-POMC) prevents hormonal alterations observed in previously handled mice (Handled). In the adult phase (90 days), Handled are overweight and have higher basal plasma immuno-reactive (ir)-corticosterone and adrenocorticotropin (ir-ACTH), and higher pituitary ir-ACTH; while they have lower hypothalamic ir-ACTH and corticotropin-releasing hormone (ir-CRH) in comparison with the non-handled mice. As-POMC (0.05-0.1 nmol/g body weight per day) administered during the same period dose-dependently prevents the increase in body weight, in plasma ir-corticosterone, ir-ACTH, and pituitary ir-ACTH, also preventing the decrease in hypothalamic ir-CRH and ir-ACTH; while the mismatch oligonucleotide is nearly inactive. This data indicates that pharmacological treatment in neonatal life may have enduring effects, reducing the alterations in hormonal homeostatic programming mechanisms induced by early repeated handling.

Systemic C-fiber blockade (CFB) has been reported to inhibit induced swallowing in adult guinea pigs. The aim of this study was to investigate the effects of CFB on spontaneous, non-nutritive swallowing (NNS) frequency and NNS-respiration coordination in the neonatal period. Seven CFB lambs and seven control lambs aged 2+/-1 days were chronically instrumented for recording electroencephalogram, eye movements, diaphragm EMG, thyroarytenoid muscle EMG, nasal airflow and electrocardiogram. Polysomnographic recordings were performed in non-sedated lambs, using radiotelemetry transmission. CFB lambs spent more time in active sleep than controls (p=0.02). Frequency of non-nutritive swallowing was not different in CFB and control lambs, whatever the state of alertness. In addition, CFB did not disrupt the overall respiratory-swallowing coordination, inspiratory-related NNS being the most frequent and expiratory-related NNS the least in both CFB and control lambs. Further analyses revealed that CFB had no effect on baseline respiratory and heart rate, and apnea and sigh frequency, whatever the state of alertness. Our results suggest that, in the neonatal period, C-fibers are not involved in NNS frequency and have no influence on the overall respiratory-swallowing coordination.

Painted turtles (Chrysemys picta) typically spend their first winter of life in a shallow, subterranean hibernaculum (the natal nest) where they seemingly withstand exposure to ice and cold by resisting freezing and becoming supercooled. However, turtles ingest soil and fragments of eggshell as they are hatching from their eggs, and the ingestate usually contains efficient nucleating agents that cause water to freeze at high subzero temperatures. Consequently, neonatal painted turtles have only a modest ability to undergo supercooling in the period immediately after hatching. We studied the limit for supercooling (SCP) in hatchlings that were acclimating to different thermal regimes and then related SCPs of the turtles to the amount of particulate matter in their gastrointestinal (GI) tract. Turtles that were transferred directly from 26 degrees C (the incubation temperature) to 2 degrees C did not purge soil from their gut, and SCPs for these animals remained near -4 degrees C for the 60 days of the study. Animals that were held at 26 degrees C for the duration of the experiment usually cleared soil from their GI tract within 24 days, but SCPs for these turtles were only slightly lower after 60 days than they were at the outset of the experiment. Hatchlings that were acclimating slowly to 2 degrees C cleared soil from their gut within 24 days and realized a modest reduction in their SCP. However, the limit of supercooling in the slowly acclimating animals continued to decline even after all particulate material had been removed from their GI tract, thereby indicating that factors intrinsic to the nucleating agents themselves also may have been involved in the acclimation of hatchlings to low temperature. The lowest SCPs for turtles that were acclimating slowly to 2 degrees C were similar to SCPs recorded in an earlier study of animals taken from natural nests in late autumn, so the current findings affirm the importance of seasonally declining temperatures in preparing animals in the field to withstand conditions that they will encounter during winter.

This study investigated the somatic maturation and ontogeny of reflexes in neonate rats treated with sertraline (Sert) during the suckling period. The animals were divided into four groups; three that received daily doses of Sert (5, 10 or 15 mg/kg s.c.; groups Sert5, Sert10, and Sert15, respectively), and a fourth group that received distilled water (Dw) (1 ml/kg/b.w.). Growth indicators (body weight, axis of the head and tail length) were measured daily, from the 1st to the 21st postnatal day. The reflexes (righting, free-fall righting, negative geotaxis, cliff avoidance, auditory startle response, vibrissa placing and palm grasp) and physical-feature maturation (ear unfolding, auditory conduit opening, irruption of the lower incisors and eye opening) were recorded each day of the animal's life. All groups were compared to the Dw group. The body weight gain was reduced in all the Sert groups. Moreover, a delay in the growth of the body length was observed in all the Sert groups. Higher Sert doses reduced the speed of growth in the tail length. The medio-lateral head axis reduced in Sert15 and Sert5 doses. Otherwise, Sert10 had a temporary acceleration in this growth, but the growth of the anteroposterior head axis had a delay in all the Sert groups. The highest doses induced a delay in physical-feature maturation. The palm grasp reflex (disappearance) was retarded in Sert10; cliff avoidance advanced in Sert10; negative-geotaxis and free-fall righting retarded in Sert15. The findings suggest that altered serotonergic system activity induced by sertraline early in life could play a role in the retardation of the somatic growth ontogeny as well as a delay in the maturation of some reflexes.

11beta-Hydroxysteroid dehydrogenase type 2 is a glucocorticoid metabolizing enzyme that catalyzes rapid inactivation of corticosterone and cortisol to inert 11-keto derivatives. As 11beta-hydroxysteroid dehydrogenase type 2 is highly expressed in the developing brain, but not in the adult CNS, we hypothesized that it may represent a protective barrier to the deleterious actions of corticosteroids on proliferating cells. To test this hypothesis we have investigated the development and growth of the cerebellum in neonatal C57BL/6 mice and mice lacking 11beta-hydroxysteroid dehydrogenase type 2 (-/-). 11beta-Hydroxysteroid dehydrogenase type 2-/- mice had consistently lower body weight throughout the neonatal period, coupled with a smaller brain size although this was normalized when corrected for body weight. The cerebellar size was smaller in 11beta-hydroxysteroid dehydrogenase type 2-/- mice, due to decreases in size of both the molecular and internal granule layers. When exogenous corticosterone was administered to the pups between postnatal days 4 and 13, 11beta-hydroxysteroid dehydrogenase type 2(-/-) mice were more sensitive, showing further inhibition of cerebellar growth while the wildtype mice were not affected. Upon withdrawal of exogenous steroid, there was a rebound growth spurt so that at day 21 postnatally, the cerebellar size in 11beta-hydroxysteroid dehydrogenase type 2-/- mice was similar to untreated mice of the same genotype. Furthermore, 11beta-hydroxysteroid dehydrogenase type 2-/- mice had a delay in the attainment of neurodevelopmental landmarks such as negative geotaxis and eye opening. We therefore suggest that 11beta-hydroxysteroid dehydrogenase type 2 acts as to protect the developing nervous system from the deleterious consequences of glucocorticoid overexposure.

The environmental mechanisms that have contributed to the rapid increases in overweight and obesity in the US over the past 25-30 years have yet to be fully specified. One hypothesis that has been forwarded is that increased consumption of calories in liquid form may be a contributing factor, since some studies support the idea that caloric compensation is less adequate for liquid calories compared to calories delivered in more solid form. Work from our laboratory using rats has examined the role that differences in diet viscosity may play in altering energy intake and body weight regulation. This work has suggested that when offered diets matched on caloric density, macronutrient and micronutrient composition, and differing only in viscosity, adult rats fail to compensate for calories delivered in low-viscosity form in short-term intake tests. Further, long-term consumption of low-viscosity diets leads to enhanced weight gain in adult rats. In the present studies, we examined whether short- or long-term exposure to varying relationships between viscosity and calories led to altered food intake or body weight regulation in juvenile rats. The results demonstrated that animals given either short- or long-term experience with direct relationships between viscosity and calories (high viscosity, high calorie meals and low viscosity, low calorie meals) did not differ in food intake or body weight gain compared to animals given short- or long-term experience with indirect relationships between viscosity and calories (high viscosity, low calorie meals and low viscosity, high calorie meals). When juvenile rats were given long-term (9 weeks) exposure to a single, high or low viscosity diet supplement, matched on caloric density and differing only in viscosity, there were no effects on body weight gain. However, analysis of body composition using DEXA demonstrated that animals consuming the low viscosity supplements had significantly greater body fat than animals that consumed either the high viscosity supplement or no dietary supplement at all. These differences in body fat persisted for at least 3 months following the cessation of dietary supplements; during this 3-month period, animals previously exposed to the low viscosity supplement also gained significantly more weight than animals previously exposed to the high viscosity supplement. Taken together, the results suggest that consuming calories in low viscosity form may contribute to poor intake regulation over the short-term and to increased adiposity over the long term. When animals experience these diets as juveniles, these effects may persist into adulthood.