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Early-life exposure to Δ9-tetrahydrocannabinol (Δ9-THC), the intoxicating constituent of cannabis, may produce enduring neurochemical changes in brain structures involved in the regulation of sociality but it is still unclear how such changes influence social behavior later in life. In the present study, we exposed male mice to moderate daily doses of Δ9-THC (5 mg/kg, intraperitoneal) during adolescence (postnatal day, PND, 30 to 43) and, when animals reached adulthood (PND70), we assessed their performance in the three-chamber social interaction task before and 3 weeks after injection of the chemical irritant formalin (1 % vol, intraplantar), which produces both immediate and persistent pain-related behaviors in mice. Prior Δ9-THC treatment did not alter social interaction in control adult mice but disrupted it in animals that developed lasting sensory abnormalities following formalin injection. The findings suggest that frequent exposure to Δ9-THC during adolescence causes in male mice a dormant dysfunction in social behavior which can be unmasked in adulthood when the animals experience an aversive state.

The ability to generate memories that persist throughout a lifetime (that is, memory persistence) emerges in early development across species. Although it has been shown that persistent fear memories emerge between late infancy and adolescence in mice, it is unclear exactly when this transition takes place, and whether two major fear conditioning tasks, contextual and auditory fear, share the same time line of developmental onset. Here, we compared the ontogeny of remote contextual and auditory fear in C57BL/6J mice across early life. Mice at postnatal day (P)15, 21, 25, 28, and 30 underwent either contextual or auditory fear training and were tested for fear retrieval 1 or 30 d later. We found that mice displayed 30-d memory for context– and tone–fear starting at P25. We did not find sex differences in the ontogeny of either type of fear memory. Furthermore, 30-d contextual fear retrieval led to an increase in the number of c-Fos positive cells in the prelimbic region of the prefrontal cortex only at an age in which the contextual fear memory was successfully retrieved. These data delineate a precise time line for the emergence of persistent contextual and auditory fear memories in mice and suggest that the prelimbic cortex is only recruited for remote memory recall upon the onset of memory persistence.

This study aimed to clarify the physiological mechanism regulating the growth of primordial follicles in mouse ovaries. In a previous study, we found that increasing the fetal bovine serum concentration in the culture medium promoted the growth of primordial follicles in cultured postnatal day 0 ovaries but not in cultured postnatal day 4 ovaries. Based on these results, we hypothesized that the regulatory system repressing the growth of primordial follicles is established in postnatal day 4 ovaries. To confirm this hypothesis, microarray analysis of postnatal day 0 and 4 ovaries was performed. The results revealed that the expression of mRNA of stefin A homologs increased in postnatal day 4 ovaries. Stefin A belonging to the type 1 cystatin superfamily is an inhibitor of cysteine cathepsins. Consistently, the inhibitor of cathepsins repressed the growth of primordial follicles in cultured postnatal day 0 ovaries. Furthermore, we found that 17β-estradiol promoted the expression of mRNA of stefin A homologs in cultured ovaries and repressed the growth of primordial follicles. Our results demonstrate that 17β-estradiol and cathepsins regulate the growth of primordial follicles in mouse ovaries.

Cross-sectional studies have established a variety of structural, synaptic, and cell physiological changes corresponding to critical periods in cortical development. However, the emergence of functional connectivity (FC) in development has not been fully characterized, and hemodynamic-based measures are vulnerable to any neurovascular coupling changes occurring in parallel. We therefore used optical fluorescence imaging to trace longitudinal calcium FC in the awake, resting-state mouse cortex at 5 developmental timepoints beginning at postnatal day 15 (P15) and ending in early adulthood at P60. Calcium FC displayed coherent functional maps as early as P15, and FC significantly varied in connections between many regions across development, with the developmental trajectory’s shape specific to the functional region. Evaluating 325 seed–seed connections, we found that there was a significant increase in FC between P15 and P22 over the majority of the cortex as well as bilateral connectivity and node degree differences in frontal, motor, and retrosplenial cortices after P22. A rebalancing of inter- and intrahemispheric FC and local-distal FC dominance was also observed during development. This longitudinal developmental calcium FC study therefore provides a resource dataset to the field and identifies periods of dynamic change which cross-sectional studies may target for examination of disease states.

Background: Neonatal pneumomediastinum is seen in 2.5 per 1000 live births and is mostly managed conservatively. An intervention is essential in cases with tension pneumomediastinum. Ultrasonography-guided (USG-guided) relief of pneumomediastinum has been reported in newborns. There are no reported cases of computed tomography-guided (CT-guided) drainage of pneumomediastinum in neonates. Case Presentation: A newborn girl born at 34 weeks of gestation was intubated due to respiratory distress and received intratracheal surfactant treatment. Pneumomediastinum was detected at the chest X-ray on the 6th postnatal hour. On the second postnatal day, the patient's oxygen needs increased, tachypnea and subcostal retractions recurred, so it was decided to intervene. USG-guided drainage of the pneumomediastinum was attempted twice but was unsuccessful. Percutaneous drainage with CT guidance was performed successfully. Conclusion: This report aims to emphasize that CT-guided intervention of pneumomediastinum can be an effective alternative in a newborn if USG-guided intervention fails.

To assess the utilization of SCC implemented in southern India and the effect on SCC utilization of face-to-face verbal education versus video-based content delivery. The study included newborns with postnatal age of less than 2 wk at discharge. Mothers were administered SCCs and provided standardized verbal or video health education based on the time-period of enrollment. Home based monitoring of stool color and return of SCC on postnatal day 21 was advised. Telephone surveys were conducted to identify SCC use among families that did not return the SCC by post. Of the 2254 newborns enrolled, 1130 were in the verbal-counseling group and 1124 in the video-counseling group. No newborns with pale stools and biliary atresia were identified. SCC return rates were 3.8% and 2.8%. Comparing the verbal and video-counseling groups, there were no differences in the conservative (81.8% vs. 81.5%) and optimistic estimates (97.1% vs. 97.3%) of SCC utilization rates. Mothers with better educational status had higher optimistic estimates of SCC utilization. The use of a validated SCC in Tamil with standardized information delivery leads to good utilization rates in southern India, with video content delivery being as effective as face-to-face verbal content delivery. SCC return by post is not a feasible mode of identification of card use. The study is registered under Clinical Trials Registry - India (CTRI/2018/01/011285).

Spiral ganglion neurons (SGNs) form single synapses on inner hair cells (IHCs), transforming sound-induced IHC receptor potentials into trains of action potentials. SGN neurons are classified by spontaneous firing rates as well as their threshold response to sound intensity levels. We investigated the hypothesis that synaptic specializations underlie mouse SGN response properties and vary with pillar versus modiloar synapse location around the hair cell. Depolarizing hair cells with 40 mM K+ increased the rate of postsynaptic responses. Pillar synapses matured later than modiolar synapses. Excitatory postsynaptic current (EPSC) amplitude, area, and number of underlying events per EPSC were similar between synapse locations at steady state. However, modiolar synapses produced larger monophasic EPSCs when EPSC rates were low and EPSCs became more multiphasic and smaller in amplitude when rates were higher, while pillar synapses produced more monophasic and larger EPSCs when the release rates were higher. We propose that pillar and modiolar synapses have different operating points. Our data provide insight into underlying mechanisms regulating EPSC generation. NEW & NOTEWORTHY Data presented here provide the first direct functional evidence of late synaptic maturation of the hair cell- spiral ganglion neuron synapse, where pillar synapses mature after postnatal day 20. Data identify a presynaptic difference in release during stimulation. This difference may in part drive afferent firing properties.

BackgroundPainful procedures in early life cause acute pain and can alter pain processing at a spinal level lasting into adulthood. Current methods of analgesia seem unable to prevent both acute and long-term hypersensitivity associated with neonatal pain. The current study aims to prevent acute and long-term hypersensitivity associated with neonatal procedural pain using methadone analgesia in rat pups.MethodsSprague–Dawley rat pups received either methadone (1 mg/kg) or saline prior to repetitive needle pricks into the left hind paw from the day of birth (postnatal day (P)0) to P7. Control littermates received a tactile stimulus. Mechanical sensitivity was assessed during the neonatal period (P0–P7), from weaning to adulthood (3–7 weeks) and following surgical re-injury of the same dermatome in adulthood.ResultsMethadone administration completely reversed acute hypersensitivity from P0 to P7. In addition, neonatal methadone analgesia prevented prolonged hypersensitivity after re-injury in adulthood, without affecting sensitivity from weaning to adulthood.ConclusionsThe current study shows that neonatal methadone analgesia can attenuate acute as well as long-term hypersensitivity associated with neonatal procedural pain in a rat model.ImpactMethadone treatment attenuates acute and long-term hypersensitivity associated with neonatal pain in a rat model.Clinical effectiveness studies are urgently warranted to assess acute and long-term analgesic effectivity of methadone.

The brain undergoes substantial maturation during adolescence, and repeated exposure to ethanol at this time has been shown to result in long-lasting behavioral and neural consequences. During the broad period of adolescence, different neuronal populations and circuits are refined between early and late adolescence, suggesting the possibility that ethanol exposure at these differing times may lead to differential outcomes. The goal of the current study was to evaluate the impact of adolescent intermittent ethanol (AIE) during early and late adolescence on the formation of goal-directed and habitual behavior in adulthood. Male and female Sprague–Dawley rats were exposed to ethanol via intragastric gavage (4.0 g/kg, 25% v/v) every other day from postnatal day (P) 25–45 or P45–65, considered early and late adolescence, respectively. In adulthood (~P70 early or ~ P90 late), rats were gradually food-restricted and began operant training on a fixed ratio 1 schedule. Rats were then transitioned onto random interval schedules and eventually underwent a sensory-specific satiation procedure as a model of reward devaluation. Few differences as a result of adolescent ethanol exposure were found during instrumental training. Following reward devaluation, rats exposed to water and ethanol during early adolescence exhibited reductions in lever pressing, suggestive of a goal-directed response pattern. In contrast, late AIE males and females demonstrated persistent responding following both devalued and non-devalued trials, findings representative of a habitual behavior pattern. The shifts from goal-directed to habitual behavior noted only following late AIE contribute to the growing literature identifying specific behavioral consequences as a result of ethanol exposure during distinct developmental periods within adolescence. More work is needed to determine whether the greater habit formation following late AIE is also associated with elevated habitual ethanol consumption.

Objective In this study, we evaluated the effect of neonatal ketamine exposure on anxiety-like and exploratory behaviours in adult the Balb/c and C57BL/6 strains of mice which anxiety responses are different. Methods Ketamine was administered at two different doses single dose (10, 20 mg/kg, 0.1 ml/10 g body weight, intraperitoneally) and repeated doses (10, 20 mg/kg every 240 minutes; thrice times) on the 7th postnatal day to male Balb/c and C57BL/6 mice. In adulthood, open-field (OF) and elevated plus maze (EPM) apparatuses were used to evaluate exploratory and anxiety-like behaviour. Results In the C57BL/6 mice, the 20 mg/kg single dose decreased open-arm time and total-arm entries in EPM and increased time of central latency and decreased distance travelled in OF. Both the 10 and 20 mg/kg repetitive doses increased time of central latency and decreased time spent in the centre, frequency of rearing and centre crossing in OF and decreased open-arm time, total-arm entries, number of open-arm entries in EPM. The 20 mg/kg repetitive dose decreased number of head dipping behaviours in EPM. In the Balb/c mice, both the single and repetitive 10-20 mg/kg doses had no significant effect on anxiety-like and exploratory behaviours. Conclusion There were no significant differences in anxiety-like and exploratory behaviour in different strains by the single 10 mg/kg dose. However, in the C57BL/6 mice, both the single and repetitive 20 mg/kg doses and the 10 mg/kg repetitive dose increased anxiety-like behaviour and decreased exploratory behaviour in EPM and OF. In conclusion, hereditary factors may be effective on the effect of neonatal ketamine treatment on anxiety-like and exploratory behaviour.

Maternal nutrition status plays an important role in the development of fetal alcohol spectrum disorders (FASD), but its direct evidence is lacking. This study compared a standard chow with a semi-purified energy-dense (E-dense) diet on birth and metabolic outcomes in rats after ethanol (EtOH) consumption during pregnancy. Pregnant Sprague–Dawley rats were randomised into four groups: chow (n 6), chow + EtOH (20 %, v/v) (n 7), E-dense (n 6) and E-dense + EtOH (n 8). Birth outcomes including litter size, body and organ weights were collected. Metabolic parameters were measured in dams and pups at postnatal day (PD) 7. Maternal EtOH consumption decreased body weights (P < 0·0001) and litter sizes (P < 0·05) in chow-fed dams. At PD7, pups born to dams fed the E-dense diet had higher body (P < 0·002) and liver weights (P < 0·0001). These pups also had higher plasma total cholesterol (P < 0·0001), TAG (P < 0·003) and alanine aminotransferase (P < 0·03) compared with those from chow-fed dams. Dams fed the E-dense diet had higher plasma total (P < 0·0001) and HDL-cholesterol (P < 0·0001) and lower glucose (P < 0·0001). EtOH increased total cholesterol (P < 0·03) and glucose (P < 0·05) only in dams fed the E-dense diet. Maternal exposure to the E-dense diet attenuated prenatal EtOH-induced weight loss and produced different metabolic outcomes in both dams and pups. While the long-lasting effects of these outcomes are unknown, this study highlights the importance of maternal diet quality for maternal health and infant growth and suggests that maternal nutrition intervention may be a potential target for alleviating FASD.

Objective The developing brain is vulnerable to the negative effects of anaesthetics. We aimed to investigate the effect of isoflurane and polyunsaturated fatty acids (PUFAs) on cognition. Methods A total of 64, ten days old rats were randomly divided into 4 groups: group O2 (oxygen group), group Iso (isoflurane group), group Iso-S (isoflurane+saline) and group Iso-PUFAs (isoflurane+intraperitoneal [IP] PUFAs emulsion). Rats in groups Iso, Iso-S and Iso-PUFAs were exposed to 1.5% isoflurane in 50% oxygen for 6 hours. Rats in group O2 breathed only 50% oxygen. Before anaesthesia, rats in group Iso-S were administered 0.5 mL isotonic and rats in group Iso-PUFAs were administered 5 mL kg-1 PUFAs emulsion by IP injection. The Morris water maze (MWM) test was performed on postnatal 28-33 days. Histological evaluation and immune histochemical staining (Bcl-2 antibody) were performed on postnatal day 11 on rat brains. Results As demonstrated by the reduction in the escape latency on days 3, 4 and 5 compared with day 1, all rats learned the task during the acquisition period. In contrast to others, rats in group Iso spent significantly lower time to find the platform on day 2 than on day 1 (p=0.034). No significant difference was found among the groups in terms of time spent in finding the platform. There were no significant differences in probe trials, histological features and Bcl-2 immunoreactivity among the groups. Conclusion Isoflurane did not cause cognitive dysfunction and neuronal death, and a single dose of PUFAs emulsion had no effect on cognition either.

Objective Evaluate the association between carbon dioxide (pCO2), cerebral blood flow (CBF), and cerebral autoregulation (CA) in preterm infants. Study design Cerebral saturations (rScO2, surrogate for CBF using NIRS) and mean arterial blood pressure (MAP) monitored for 96 h in infants 55 mmHg on each postnatal day (p

The increasing interest in manipulating neural circuits in developing brains has created a demand for reliable and accurate methods for delivering viruses to newborn mice. Here we describe a novel 3D-printed mouse neonatal stereotaxic adaptor for intracerebral viral injection that provides enhanced precision and reliability. Using this device, we injected A2a-Cre mice with a Cre-dependent hM4D-mCherry viral construct at postnatal day 1 (P1) and demonstrated selective expression in the striatal indirect pathway neurons on days P7, P11 and P25. Similarly, dopaminergic midbrain neurons were selectively targeted with a Cre-dependent green fluorescent protein virus in Dat-IRES-Cre neonates and expression examined at P25. Our open-source neonatal stereotaxic mouse adaptor facilitates neonatal neuronal targeting, which should improve the ability to label and modify neural circuits in developing mouse brains., METHOD SUMMARY The neonatal mouse stereotaxic adaptor, designed and easily 3D printed in-house, was fitted into the ear and tooth bars of a mouse digital stereotaxic apparatus and held the head of the ice-anesthetized newborn pups in a cone-shaped cradle during the virus injection procedure. After the secured heads were balanced on the AP and ML axes by adjusting the ear and tooth bars, Cre-dependent viruses (AAV5-hSyn-DIO-hM4D-mCherry or AAV5-hSyn-DIO-GFP) were injected to the desired brain region of Cre-expressing transgenic mice, while the animals were partially covered in ice. After completion of each surgery, the neonate was removed from the adaptor and returned to the den for recovery. Neuroanatomical viral expression was verified by immunofluorescence 6, 10 and 24 days after the procedure.

The dendritic arbor of neurons constrains the pool of available synaptic partners and influences the electrical integration of synaptic currents. Despite these critical functions, our knowledge of the dendritic structure of cortical neurons during early postnatal development and how these dendritic structures are modified by visual experience is incomplete. Here, we present a large-scale dataset of 849 3D reconstructions of the basal arbor of pyramidal neurons collected across early postnatal development in visual cortex of mice of either sex. We found that the basal arbor grew substantially between postnatal day 7 (P7) and P30, undergoing a 45% increase in total length. However, the gross number of primary neurites and dendritic segments was largely determined by P7. Growth from P7 to P30 occurred primarily through extension of dendritic segments. Surprisingly, comparisons of dark-reared and typically reared mice revealed that a net gain of only 15% arbor length could be attributed to visual experience; most growth was independent of experience. To examine molecular contributions, we characterized the role of the activity-regulated small GTPase Rem2 in both arbor development and the maintenance of established basal arbors. We showed that Rem2 is an experience-dependent negative regulator of dendritic segment number during the visual critical period. Acute deletion of Rem2 reduced directionality of dendritic arbors. The data presented here establish a highly detailed, quantitative analysis of basal arbor development that we believe has high utility both in understanding circuit development as well as providing a framework for computationalists wishing to generate anatomically accurate neuronal models. SIGNIFICANCE STATEMENT Dendrites are the sites of the synaptic connections among neurons. Despite their importance for neural circuit function, only a little is known about the postnatal development of dendritic arbors of cortical pyramidal neurons and the influence of experience. Here we show that the number of primary basal dendritic arbors is already established before eye opening, and that these arbors primarily grow through lengthening of dendritic segments and not through addition of dendritic segments. Surprisingly, visual experience has a modest net impact on overall arbor length (15%). Experiments in KO animals revealed that the gene Rem2 is positive regulator of dendritic length and a negative regulator of dendritic segments.

Neonatal exposure to bisphenol A (BPA) is hypothesized to advance pubertal development. However, the effects of neonatal BPA exposure on pubertal development has not been described. In this study, female Sprague-Dawley rats were exposed to 0.05, 0.5, 5, or 10 mg·kg-1 ·day-1 BPA, or corn oil vehicle alone from postnatal day 1 (PND1) to PND10 via subcutaneous injection. We evaluated day of vaginal opening (DVO), ovarian morphology, serum hormone concentrations, and hypothalamic expression of Gnrh1 and Kiss1 in female rats at PND35. DVO was significantly advanced in rats exposed to 5 and 10 mg·kg-1 ·day-1 BPA. Serum hormone concentrations increased as BPA dose increased. Additionally, hypothalamic Gnrh1 and Kiss1 expression were increased with BPA exposure; rats exposed to 10 mg·kg-1 ·day-1 BPA had significantly upregulated hypothalamic Gnrh1 and Kiss1 expressions in terms of both messenger RNA and protein levels. Our results suggest that exposure to a 10 mg·kg-1 ·day-1 dose of BPA might advance pubertal development significantly. In addition, within the range of 0 to 10 mg·kg-1 ·day-1 , neonatal exposure to BPA may affect pubertal development in a dose-dependent manner.

Metallophilic macrophages (MMs) are a distinct cell type of the rodent thymus. Our previous research has focused on the morphological characteristics of MMs, as well as on the molecular mechanisms involved in the development and tissue positioning of these cells. However, the postnatal development of MMs has not been sufficiently studied. In the present study, we investigated the positioning of MMs in the rat thymus between postnatal day 0 (P0) and P30. On P0, MMs were evenly distributed all over the thymic tissue-that is, the cortex, cortico-medullary zone and medulla. From P0 to P15, the number of MMs in the thymic cortex significantly decreased, and after P15, this number did not change. Thus, the present study shows that on P15, MMs almost completely disappear from the thymic cortex and show their adult position in the cortico-medullary zone and in the medulla.

One of the main subcortical targets of hippocampal formation efferents is the lateral septum. Previous studies on the subicular projections, as a main output structure of the hippocampus, have shown a clear topographic organization of septal innervation, related to the origin of the fibres along the dorsoventral axis of the subiculum in the adult brain. In contrast, studies on the developing brain depict an extensive rearrangement of subicular projections during the prenatal period, shifting from the medial septum to the lateral septum. Our study aimed to describe the postnatal development of subicular projections to the septum. We injected anterograde tracers into the subiculum of 57 pups of different postnatal ages. Injections covered the proximodistal and dorsoventral axis of the subiculum. The age of the pups at day of tracer injection ranged from the day of birth to postnatal day 30. Analyses revealed that from the first postnatal day projections from subiculum preferentially target the lateral septum. Sparse innervation in the lateral septum was already present in the first few postnatal days, and during the following 3 weeks, the axonal distribution gradually expanded. Subicular projections to the lateral septum are topographically organized depending on the origin along the dorsoventral axis of the subiculum, in line with the adult innervation pattern. Different origins along the proximodistal axis of the subiculum are reflected in changes in the strength of septal innervation. The findings demonstrate that in case of the development of subicular projections, axonal expansion is more prominent than axonal pruning. © 2020 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

The hippocampus in neonatal rats is not fully developed after birth, and the effect of odor-aversion learning on memory consolidation in the immature hippocampus is not well understood. Therefore, the aim of the present study was to explore the effects of odor-aversion learning in neonatal rats on memory consolidation and neurodevelopment in the immature hippocampus. The effect of hippocampal-induced learning was measured at two different developmental stages using the Y-maze and c-Fos protein levels. Furthermore, hippocampal cell proliferation and growth-associated protein 43 (GAP-43) expression were evaluated at different developmental stages, namely, postnatal day 7 (PN7) and PN24, after odor-aversion learning. Both PN7 and PN24 rats avoided conditioned odor stimuli after odor-aversion learning. PN7 and PN24 rats in the odor-averse learning groups exhibited high c-Fos protein levels. PN7 rats exhibited high cell proliferation rates and GAP-43 protein levels after odor-aversion learning. These results showed that the immature hippocampus can participated in odor-aversion learning, which may induce cell proliferation and axonal development.

s This study was conducted to investigate the effects of maternal exposure bisphenol A (BPA) on ovaries development of F1 female mice. The BPA exposure model of pregnant mice was prepared by intragastric administration of BPA at the doses of 0, 2.5, 5, 10, 20, 40 mg kg−1 d−1 at gestation day (GD) 0.5–17.5. The ovarian index of the offspring mice was calculated at postnatal day (PND) 21 and PND 56. The results showed that BPA at 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg significantly increased the abortion rate of the pregnant mice, and each dose of BPA significantly reduced the survival rate of the pups (P

Using histochemical stain for acetylcholinesterase (AChE), the lateral posterior pulvinar complex (LP-P) was analyzed in kittens aged 0–123 postnatal days and in adult cats. In the lateral nucleus of the complex (LPl) of kittens aged 4–21 days, a transient clustered AChE staining of neuropil was revealed. The average size of AChE clusters varied between 200 and 300 mkm; the inter-cluster distance varied between 430 and 600 mkm. Optical contrast of clusters increased rapidly from the 4th to the 14th postnatal day and, thereafter, rapidly decreased up to the 21st-28th postnatal day. Since AChE is directly linked to neuronal differentiation and development and AChE clusters are located in the same area with neurons responsible for thalamocortical connections, the transient clusters of AChE expression could be related to the development of visual structures.

The aim of study was to investigate the relationships among serum diamine oxidase (DAO) activity, postnatal days and the plasma copper (Cu) concentration, using calves with or without diarrhea. In healthy calves, the serum DAO activity was significantly higher at 2 postnatal days than at ≥7 postnatal days, and no significant changes were observed after 7 postnatal days. In addition, no significant correlation was found between serum DAO activity and plasma Cu concentration at all postnatal days in healthy calves. Although, the serum DAO activity in 14 diarrheic calves (66.78 ± 14.37 IU/ml) was lower than that in 19 healthy calves (170.33 ± 97.83 IU/ml, P

Simple Summary Valproic acid (VPA) is a well-known antiepileptic medication and mood stabiliser that is frequently prescribed for the treatment of epilepsy, particularly in children, and has proven human teratogenic activity. VPA inhibits histone deacetylase, which causes teratogenicity and cell toxicity. VPA-induced autism in rodents during the pre- and postnatal periods has shown the development of an autism-like phenotype. In mice, the 14th postnatal day is thought to correspond to the third trimester of human development; it is an important period in which neuronal migration, differentiation, myelination, synaptogenesis and gliogenesis occur in the cerebellum, striatum and hippocampus. Therefore, we exposed postnatal day 14 (PND 14) mice to VPA, which resulted in autistic-like behaviours manifested as reduced social interaction, increased repetitive stereotyped behaviour and anxiety, cognitive dysfunction, lowered sensitivity to pain and neurodevelopmental delay. BALB/c mice were used in this work because they are less reactive to social contact in VPA-induced autism than many other inbred mouse strains, such as C57/129 mice. In humans, two to three times more men are affected by autism spectrum disorder (ASD) than women, and, for this reason, the current study compares the histopathological changes and 5-hydroxy-tryptamine 2A (5-HT2A) receptor protein expression in the brain tissue of male and female animals with VPA-induced autism. Abstract Autism spectrum disorder (ASD) is characterised by problems with social interaction, verbal and nonverbal communication and repetitive behaviour. In mice, the 14th postnatal day is believed to correspond to the third trimester of human embryonic development and is considered a vital period for central nervous system development. It has been shown that ASD affects 2 to 3 times more male than female individuals. In the present study, ASD was induced in 14 postnatal day (PND) BALB/c mice using valproic acid (VPA). VPA administration brought about substantial differences in the histoarchitecture of the brain in both male and female mice, linked to behavioural deficits. We observed that both male and female mice showed similar morphological changes in the prefrontal cortex, hippocampus and Purkinje cells. We also observed hair loss from PND 17 to 25, which was again similar between male and female mice. However, there were higher rates of change in the cerebral cortex, frontal cortex and temporal lobe and hippocampus in VPA-treated male animals. With respect to the cerebellum, we did not observe any alterations by haematoxylin and eosin (H&E) staining, but detailed morphological observation using scanning electron microscopy (SEM) showed a higher rate of phenotype changes in VPA-treated male animals. Moreover, 5-HT2A receptor protein levels were upregulated in the cerebral cortex, hippocampus and Purkinje cells in VPA-treated male mice compared with control animals and VPA-treated female mice, as shown by immunohistochemical analysis. Based on all these findings, we conclude that male animals are more susceptible to VPA-induced ASD than females.

Neuronal circuits are shaped by experience during time windows of increased plasticity in postnatal development. In the auditory system, the critical period for the simplest sounds—pure frequency tones—is well defined. Critical periods for more complex sounds remain to be elucidated. We used in vivo electrophysiological recordings in the mouse auditory cortex to demonstrate that passive exposure to frequency modulated sweeps (FMS) from postnatal day 31 to 38 leads to long-term changes in the temporal representation of sweep directions. Immunohistochemical analysis revealed a decreased percentage of layer 4 parvalbumin-positive (PV+) cells during this critical period, paralleled with a transient increase in responses to FMS, but not to pure tones. Preventing the PV+ cell decrease with continuous white noise exposure delayed the critical period onset, suggesting a reduction in inhibition as a mechanism for this plasticity. Our findings shed new light on the dependence of plastic windows on stimulus complexity that persistently sculpt the functional organization of the auditory cortex.

The hair bundle is the mechanosensory organelle of hair cells that detects mechanical stimuli caused by sounds, head motions, and fluid flows. Each hair bundle is an assembly of cellular-protrusions called stereocilia, which differ in height to form a staircase. Stereocilia have different heights, widths, and separations in different species, sensory organs, positions within an organ, hair-cell types, and even within a single hair bundle. The dimensions of the stereociliary assembly dictate how the hair bundle responds to stimuli. These hair-bundle properties have been measured previously only to a limited degree. In particular, mammalian data are either incomplete, lack control for age or position within an organ, or have artifacts owing to fixation or dehydration. Here, we provide a complete set of measurements for postnatal day (P) 11 C57BL/6J mouse apical inner hair cells (IHCs) obtained from living tissue, tissue mildly-fixed for fluorescent imaging, or tissue strongly fixed and dehydrated for scanning electronic microscopy (SEM). We found that hair bundles mildly-fixed for fluorescence had the same dimensions as living hair bundles, whereas SEM-prepared hair bundles shrank uniformly in stereociliary heights, widths, and separations. By determining the shrinkage factors, we imputed live dimensions from SEM that were too small to observe optically. Accordingly, we created the first complete blueprint of a living IHC hair bundle. We show that SEM-prepared measurements strongly affect calculations of a bundle’s mechanical properties – overestimating stereociliary deflection stiffness and underestimating the fluid coupling between stereocilia. The methods of measurement, the data, and the consequences we describe illustrate the high levels of accuracy and precision required to understand hair-bundle mechanotransduction.

Binaural hearing is critically important for the perception of sound spatial locations. The primary auditory cortex (AI) has been demonstrated to be necessary for sound localization. However, after hearing onset, how the processing of binaural cues by AI neurons develops, and how the binaural processing of AI neurons is affected by reversible unilateral conductive hearing loss (RUCHL), are not fully elucidated. Here, we determined the binaural processing of AI neurons in four groups of rats: postnatal day (P) 14–18 rats, P19–30 rats, P57–70 adult rats, and RUCHL rats (P57–70) with RUCHL during P14–30. We recorded the responses of AI neurons to both monaural and binaural stimuli with variations in interaural level differences (ILDs) and average binaural levels. We found that the monaural response types, the binaural interaction types, and the distributions of the best ILDs of AI neurons in P14–18 rats are already adult-like. However, after hearing onset, there exist developmental refinements in the binaural processing of AI neurons, which are exhibited by the increase in the degree of binaural interaction, and the increase in the sensitivity and selectivity to ILDs. RUCHL during early hearing development affects monaural response types, decreases the degree of binaural interactions, and decreases both the selectivity and sensitivity to ILDs of AI neurons in adulthood. These new evidences help us to understand the refinements and plasticity in the binaural processing of AI neurons during hearing development, and might enhance our understanding in the neuronal mechanism of developmental changes in auditory spatial perception.

Exposure to early-life stress (ES) increases the risk to develop obesity later in life, and these effects may be sex-specific, but it is currently unknown what underlies the ES-induced metabolic vulnerability. We have previously shown that ES leads to a leaner phenotype under standard chow diet conditions, but to increased fat accumulation when exposed to an unhealthy obesogenic diet. However these diets were fed without a choice. An important, yet under investigated, element contributing to the development of obesity in humans is the choice of the food. There is initial evidence that ES leads to altered food choices but a thorough testing on how ES affects the choice of both the fat and sugar component, and if this is similar in males and females, is currently missing. We hypothesized that ES increases the choice for unhealthy foods, while it at the same time also affects the response to such a diet. In a mouse model for ES, in which mice are exposed to limited nesting and bedding material from postnatal day (P)2–P9, we investigated if ES exposure affected i) food choice with a free choice high-fat high-sugar diet (fcHFHS), ii) the response to such a diet, iii) the brain circuits that regulate food intake and food reward and iv) if such ES effects are sex-specific. We show that there are sex differences in food choice under basal circumstances, and that ES increases fat intake in females when exposed to a mild acute stressor. Moreover, ES impacts the physiologic response to the fcHFHS and the brain circuits regulating food intake in sex-specific manner. Our data highlight sex-specific effects of ES on metabolic functioning and food choice., Highlights • Strong sex differences exist in food choice and metabolism in mice. • Early-life stress (ES) increases fat intake in females after mild acute stress exposure. • The physiological response to the diet is affected by ES in a sex-dependent manner. • ES modulates the hedonic feeding circuitry.

Rationale: Primary cardiomyocytes are invaluable for understanding postnatal heart development and elucidating disease mechanisms in genetic and pharmacological models, however, a method to obtain freshly purified cardiomyocytes at any postnatal age, without using different age-dependent isolation procedures and cell culture, is lacking. Objective: To develop a standardized method that allows rapid isolation and purification of cardiomyocytes in high yield and viability from individual neonatal, infant, and adult mice. Methods and Results: Hearts of C57BL/6J mice were cannulated using a novel in situ aortic cannulation procedure optimized to allow cannulation of even the very small vessel of neonates (postnatal day 0-2, P0-2). Hearts were then subjected to Langendorff retrograde perfusion and enzymatic digestion. Cardiomyocytes were isolated after subsequent tissue disaggregation and filtration, in high yield (1.56-2.2x106 cardiomyocytes/heart) and viability (~70-100%). The larger size of infant (P10 and P13) and adult (P70), but not neonatal, cardiomyocytes relative to non-myocytes, allowed enrichment by differential centrifugation. Cardiomyocytes from all ages were further purified by immunomagnetic bead-based depletion of non-myocytes. Together, these procedures resulted in the isolation of highly purified cardiomyocytes (~94%) within 1 hour, enabling experiments using individual replicates. For example, RNA-sequencing of cardiomyocytes purified from one P2 male and female heart per litter (n=4 litters) showed distinct clustering by litters and sex differences for nine differentially expressed genes (FDR

We hypothesized that a cumulative heart rate characteristics (HRC) index in real-time throughout the neonatal intensive care unit (NICU) hospitalization, alone or combined with birth demographics and clinical characteristics, can predict a composite outcome of death or neurodevelopmental impairment (NDI).We performed a retrospective analysis using data from extremely low birth weight infants who were monitored for HRC during neonatal intensive care. Surviving infants were assessed for NDI at 18-22 months of age. Multivariable predictive modeling of subsequent death or NDI using logistic regression, cross-validation with repeats, and step-wise feature elimination was performed each postnatal day through day 60.Among the 598 study participants, infants with the composite outcome of death or moderate-to-severe NDI had higher mean HRC scores during their stay in the NICU (3.1 ± 1.8 vs 1.3 ± 0.8; P .001). Predictive models for subsequent death or NDI were consistently higher when the cumulative mean HRC score was included as a predictor variable. A parsimonious model including birth weight, sex, ventilatory status, and cumulative mean HRC score had a cross-validated receiver-operator characteristic curve as high as 0.84 on days 4, 5, 6, and 8 and as low as 0.78 on days 50-52 and 56-58 to predict subsequent death or NDI.In extremely low birth weight infants, higher mean HRC scores throughout their stay in the NICU were associated with a higher risk of the composite outcome of death or NDI.ClinicalTrials.gov: NCT00307333.

Polar lipids, which are found in human milk, serve essential functions within biological membranes, hence their importance in brain development and cognition. Therefore, we aimed to evaluate the longitudinal effects on brain macrostructural and microstructural development and recognition memory of early-life polar lipid supplementation using the translational pig model. Twenty-eight intact (i.e., not castrated) male pigs were provided either a control diet (n = 14) or the control diet supplemented with polar lipids (n = 14) from postnatal day 2 until postnatal week 4. After postnatal week 4, all animals were provided the same nutritionally-adequate diets until postnatal week 24. Pigs underwent magnetic resonance imaging at 8 longitudinal time-points to model brain macrostructural and microstructural developmental trajectories. The novel object recognition task was implemented at postnatal weeks 4 and 8 to evaluate recognition memory. Subtle differences were observed between groups in hippocampal absolute brain volumes and fractional anisotropy, and no differences in myelin water fraction developmental patterns were noted. Behavioral outcomes did not differ in recognition memory, and only minimal differences were observed in exploratory behaviors. Our findings suggest that early-life dietary supplementation of polar lipids has limited effect on brain developmental patterns, object recognition memory, and exploratory behaviors.

SummaryBefore hearing onset (postnatal day 12 in mice), inner hair cells (IHC) spontaneously fire action potentials thereby driving pre-sensory activity in the ascending auditory pathway. The rate of IHC action potential bursts is modulated by inner supporting cells (ISC) of Kölliker’s organ through the activity of the Ca2+ activated Cl- channel TMEM16A. Here we show that conditional deletion of Tmem16a in mice disrupts the generation of Ca2+ waves within Kölliker’s organ, reduces the burst firing activity and the frequency-selectivity of auditory brainstem neurons in the medial nucleus of the trapezoid body (MNTB), and also impairs the refinement of MNTB projections to the lateral superior olive (LSO). These results reveal the importance of the activity of Kölliker’s organ for the refinement of central auditory connectivity. In addition, our study suggests a mechanism for the generation of Ca2+ waves, which may also apply to other tissues expressing TMEM16A.

International audience; Over the past twenty years, the reuniens and rhomboid (ReRh) nuclei, which constitute the ventral midline thalamus, have received constantly growing attention. Since our first review article about the functional contributions of ReRh nuclei (Cassel et al., 2013), numerous (>80) important papers have extended anatomical knowledge, including at a developmental level, introduced new and very original electrophysiological insights on ReRh functions, and brought novel results on cognitive and non-cognitive implications of the ReRh. The current review will cover these recent articles, more on Re than on Rh, and their contribution will be approached according to their affiliation with work before 2013. These neuroanatomical, electrophysiological or behavioral findings appear coherent and point to the ReRh nuclei as two major components of a multistructural system supporting numerous cognitive (and noncognitive) functions. They gate the flow of information, perhaps especially from the medial prefrontal cortex to the hippocampus and back, and coordinate activity and processing across these two (and possibly other) brain regions of major cognitive relevance.

WOS:000528260100005.; International audience; Development can change the way organisms represent their environment and affect their behavior. In vision, complex stimuli are treated as the sum of their elements (elemental perception) in children or as a whole (configural perception) in adults. However, the influence of development in elemental/configural perception has never been tested in olfaction. Here we explored this issue in young rabbits, which are known to perceive during the neonatal period certain binary odor mixtures elementally and others weak configurally. Using conditioning and behavioral testing procedures, we set out six experiments evaluating the putative evolution of their odor perception between birth and weaning. Results highlighted that between postnatal days 2 and 9 the perception of an initially weak configural mixture became robust configural while that of two elemental mixtures did not. Additional switches from elemental to configural perception were observed at postnatal day 24. The use of a chemically more complex senary mixture resulted also in a shift from weak to robust configural perception between postnatal days 2 and 9. Thus, the perception of certain odor mixtures may rapidly evolve toward a more holistic mode in young rabbits, which may help simplifying their representation of the environment once out of the nest.

Pregnancies, as a whole, has extended and widen changes for an antenatal mother. Maternal schemes play an important role in mother, baby and family during the antenatal period. 60 (30 experimental groups and 30 control group) patients (postnatal mothers) who met the inclusion criteria were selected by using non-probability convenience sampling technique. After selecting the sample, the investigator explained the purpose of the study and informed consent was obtained. Demographic variables were collected pre-test was done by using the REEDA scale (experimental and control group). For the experimental group, the saltwater application was given twice a day for five days in 8 hours. Control group receives the routine hospital care. On the third postnatal day, post-test was done for the experimental and control group. The data were tabulated and analysed by descriptive and inferential statistics. The result shows that in experimental group pre-test (3.33%) were mild healed, and 29(97%) were not healed and in control group 30(100%) were not healed. post-test in experimental group 22(73%) were healed, and 8(27%) were moderately healed, in the control group 2(7%) were healed, 15(50%) were moderately healed and 13(43%) were mild healed. The calculated‘t' value is significant at P< 0.005. The study indicates that the application of salt water is effective on episiotomy wound healing among postnatal mothers.

Di-isononyl phthalate (DINP) is considered one of the main industrial alternatives to di(2-ethylhexyl)phthalate (DEHP), a well-known chemical with various toxic effects including the disruption with lipid metabolism. However, the potential effects of DINP on lipid metabolism have rarely been investigated in mammals. Our study demonstrated that exposure of neonatal mice to DEHP and DINP at a daily dose of 0.048 or 4.8 mg/kg from postnatal day 0 (PND0) to PND21 caused nonmonotonic as well as tissue- and gender-specific alterations of total fatty acid (FA) compositions in plasma, heart, and adipose tissues. However, the patterns of disruption differed between DEHP- and DINP-treated groups. On the basis of targeted lipidomic analyses, we further identified gender-specific alterations of eight lipid classes in plasma following DEHP or DINP exposure. At the higher dose, DEHP induced decreases in total phosphatidylcholines and phosphatidylinositol (PI) in females and increases in phosphatidylethanolamines (PEs) and triglycerides in males. By contrast, DINP at the higher dose caused alterations of PEs, PIs, phosphatidylserines, and cholesterols exclusively in male mice, but no changes were observed in female pups. Although the most significant dysregulation of lipid metabolism was often observed for the higher dose, the lower one could also disrupt lipid profiles and sometimes its effects may even be more significant than those induced by the higher dose. Our study for the first time identified tissue- and gender-specific disruptions of FA compositions and lipidomic profiles in mice neonatally exposed to DINP. These findings question the suitability of DINP as a safe DEHP substitute and lay a solid foundation for further elucidation of its effects on lipid metabolism and underlying mechanisms.

Previously observed antidepressant-like effects of caffeine in adolescent rats have been shown in individually housed (IH) rats. Because IH presents a social stressor that may create depressant-like effects in control animals, this study sought to compare the effects of chronic caffeine in IH and pair-housed (PH) adolescent male and female rats. Housing conditions began on postnatal day 24 (P24) and half of the rats were provided caffeine (0.25 g/l) in their drinking water beginning on P28. Open-field behavior was assessed on P42, a light/dark test was conducted on P43, and a forced swim test was conducted on P44-P45. PH and caffeine separately increased behavior in the open-field test and females reared more than males. In the light/dark test, IH animals and males showed greater anxiety-like behavior than PH animals and females, respectively. In the forced swim test, PH animals showed less overall immobility and caffeine decreased immobility in IH rats and PH females but increased immobility in PH males. Swimming behavior was higher in PH rats overall and caffeine increased swimming in IH rats but decreased swimming in PH rats. Climbing behavior was increased by caffeine in all groups except PH males with the greatest increase in PH females. We conclude that the effects of caffeine on depressive-like and anxiety-like behavior in adolescents are dependent on sex and housing conditions.

The present set of experiments investigated the effects of a moderate dose of ethanol (2 g/kg; 20% v/v intragastrically) during late gestation (G17–20 [gestational day]) on ethanol-induced conditioned taste aversion (CTA) in adolescence, and on ethanol consumption during adolescence and early adulthood. In experiment 1, male and female Sprague-Dawley rats were given 30-min access to a sweetened “supersaccharin” (SS) solution or sodium chloride (NaCl), followed by an intraperitoneal injection of 20% ethanol (0, 1, 1.25, or 1.5 g/kg) for three conditioning/test sessions. Among animals conditioned with SS, prenatally ethanol-exposed males exhibited attenuated ethanol-induced CTA relative to males prenatally gavaged with water or non-manipulated, whereas prenatal treatment had no effect on CTA in females. Among animals conditioned with NaCl, there were no exposure group differences in males, with modest evidence for attenuated CTA in prenatally ethanol-exposed females. In experiment 2, the effects of prenatal ethanol exposure on ethanol consumption in adolescents (P35 ± 1 day [postnatal day]) and adults (P56–60) were explored. At the beginning of the dark cycle, pair-housed rats were given three bottles containing 0, 5, and 10% ethanol for 18 h every other day (i.e., Monday, Wednesday, Friday) for 3 weeks. Relative to water controls, adult males prenatally exposed to ethanol showed greater preference and more intake (g/kg) of 5% ethanol, while showing lower intake of 10% ethanol. These intake and preference differences were not evident in adolescent males. Among females at both ages, ethanol-exposed animals showed lower preference and intake (g/kg) of 5% ethanol than their water-exposed controls. Thus, moderate ethanol exposure during late gestation produced a largely male-specific attenuation in the aversive effects of ethanol during adolescence that could contribute to later increases in preference and intake of a 5% ethanol solution, although this emergent effect was not evident in adolescence (or in females), but only manifested in adulthood.

Objectives In the developing auditory cortex, maturation of electrophysiological properties and cell types before and after hearing onset has been reported previously. However, the exact timing of firing pattern change has not been reported. In this study, firing pattern change was investigated from postnatal day 3 (P3) to P12 in auditory cortical layer II/III neurons to investigate whether firing pattern changes dramatically after a specific point during development. Methods ICR mice pups aged from P3 to P12 were sacrificed to obtain 300-mm-thick brain slices containing the primary auditory cortex. From cortical layer II/III neurons, the patterns of action potential firing generated by current injection were examined using whole cell current clamp technique and the characteristics of Na+ currents involved in action potential firing were investigated using whole cell voltage clamp technique. Results From P3 to P6, most cells did not show action potential firing (29 of 46 cells), and some cells responding to current injection showed a single action potential at the initial depolarizing current step (17 of 46 cells). This firing pattern changes from P7. From P7 to P9, cells begin to show regular spiking to current injection. The spiking frequency increased after P10. In studying Na+ current with whole cell voltage clamp, Na+ current densities increased gradually (32.0±2.0 pA/pF [P3-P6, n=7], 51.2±2.0 pA/pF [P7-P9, n=13], and 69.5±3.7 pA/pF [P10-P12, n=13]) in low external [Na+] condition. Na+ current recovery was accelerated and inactivation curves shifted to hyperpolarization with age. Conclusion As regular spiking cells were observed from P7 but never from P3 to P6, P7 might be regarded as an important milestone in the development of auditory cortical layer II/III neurons. This change might mainly result from the increase in Na+ current density.

The aim of this study was to investigate the effects of scalp acupuncture and electrostimulation, combined or not, in a disuse model consisted of early sensorimotor restriction in rats. Male Wistar pups received sensorimotor restriction from the second postnatal day (P2) until P28. Animals were divided into five different groups (n = 6): control (CT), sensorimotor restricted (SR), acupuncture (AC), electrostimulation (EL), and electroacupuncture (AC+EL). Experimental animals received sham, acupuncture, or electrical stimulation, combined or not, of two scalp regions for 7 days (P29-P35). Before treatment period (P29) and after treatment (P36), animals were evaluated with the narrow suspended bar, horizontal ladder, and stride length tests. SR animals had worse performance in the narrow suspended and horizontal ladder tasks compared with SR animals at P29 (p ≤ 0.005). Significant improvements were observed in both tasks in AC, EL, and EL+AC groups comparing P29 and P36 (p

The neurodevelopment period is susceptible to alterations by genetic and environmental factors, such as the exposure to organophosphates (OP). The OP is neurotoxic and has been associated with neurological diseases pathophysiology. The OP temephos is widely used against Aedes aegypti in Brazil's public health programs. Purpose To evaluate behavioral effects of prenatal exposition to temephos in Wistar rats. Methods First, we divided pregnant females into groups: those who received temephos diluted in distilled water by gavage between gestational days 6-13 and those who received only distilled water in the same period and volume. Then, we divided pups according to sex and exposure, and we made the behavioral tests on postnatal day 30. Results Prenatal exposure to temephos caused hyperactivity, stereotyped behavior, and social impairment in animals. Conclusion These results are similar to the altered behavior presented in some neurobiological diseases models, like Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorders, and this study may bring a red alert to the large use of temephos in Brazil, due to the damage caused by its exposure.

Research shows that memory for a context generalizes (i.e., becomes less precise) over time. In this series of experiments, we examined the impact of early life stress on context generalization. Early life stress was modeled using a maternal separation procedure, whereby pups were separated from the dam for 3 hr a day from postnatal Day 2 to 14, or reared as normal. In adulthood, rats were trained to fear a context, and were then tested for freezing in either the training context or a generalization context. Across 5 experiments, we found that maternally separated animals showed generalization when tested 1 day after training (Experiments 1a, 2, 3a, 3b), whereas standard reared rats discriminated at this time point (Experiments 1a & 3b). When tested 1 week after training, all rats generalized (Experiment 1b). Furthermore, maternally separated animals froze more to the training context than the generalization context when tested 1 hour after training (Experiment 2), indicating that the increased generalization expressed by these animals when tested after 1 day is not due to a general inability to discriminate. Manipulations that have been found to reduce generalization in standard reared animals failed to enhance memory specificity at the 1-day retention interval in maternally separated animals (i.e., a pretest reminder, Experiment 3a, and context preexposure, Experiment 3b). Thus, early life stress results in faster generalization that is more resistant to treatments designed to enhance memory specificity. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Neurons in parasubiculum (PaS), presubiculum (PrS), and medial entorhinal cortex (MEC) code for place (grid cells) and head direction. Directional input has been shown to be important for stable grid cell properties in MEC, and PaS and PrS have been postulated to provide this information to MEC. In line with this, head direction cells in those brain areas are present at postnatal day 11 (P11), having directional tuning that stabilizes shortly after eye opening, which is before premature grid cells emerge in MEC at P16. Whether functional connectivity between these structures exists at those early postnatal stages is unclear. Using anatomical tracing, voltage-sensitive dye imaging and single-cell patch recordings in female and male rat brain slices between P2 and P61, we determined when the pathways from PaS and PrS to MEC emerge, become functional, and how they develop. Anatomical connections from PaS and PrS to superficial MEC emerge between P4 and P6. Monosynaptic connectivity from PaS and PrS to superficial MEC was measurable from P9 to P10 onward, whereas connectivity with deep MEC was measurable from P11 to P12. From P14/P15 on, reactivity of MEC neurons to parasubicular and presubicular inputs becomes adult-like and continues to develop until P28-P30. The maturation of the efficacy of both inputs between P9 and P21 is paralleled by maturation of morphological properties, changes in intrinsic properties of MEC principal neurons, and changes in the GABAergic network of MEC. In conclusion, synaptic projections from PaS and PrS to MEC become functional and adult-like before the emergence of grid cells in MEC.SIGNIFICANCE STATEMENTHead direction information, crucial for grid cells in medial entorhinal cortex (MEC), is thought to enter MEC via parasubiculum (PaS) and presubiculum (PrS). Unraveling the development of functional connections between PaS, PrS, and MEC is key to understanding how spatial navigation, an important cognitive function, may evolve. To gain insight into the development, we used anatomical tracing techniques, voltage-sensitive dye imaging, and single-cell recordings. The combined data led us to conclude that synaptic projections from PaS and PrS to MEC become functional and adult-like before eye opening, allowing crucial head direction information to influence place encoding before the emergence of grid cells in rat MEC.

Retinopathy of prematurity (ROP) adalah salah satu penyebab kebutaan pada anak. Metode oxygen-induced retinopathy (OIR) pada tikus, menilai patogenesis dan terapi neovaskularisasi retina pada ROP. Hiperoksia retina berperan dalam patogenesis ROP dengan meningkatkan Reactive Oxygen Species (ROS). L-carnitine (LC) berpotensi melawan stres peroksidatif dengan mencegah pembentukan ROS. Tujuan penelitian ini mengetahui efek L-carnitine (LC) terhadap neovascular tuft pada retina tikus dengan oxygen induced retinopathy. Penelitian ini dilakukan dari Februari–April 2018 di Fakultas Kedokteran Universitas Andalas menggunakan 36 tikus baru lahir galur Wistar yang terbagi dalam 2 kelompok. Kelompok 1 diberi paparan oksigen 75% dan mendapat L-carnitine intraperitoneal 0,2 mg/gram/hari. Kelompok 2 hanya mendapat paparan oksigen 75%. Setelah tikus berusia 13 hari, kedua kelompok dipindahkan ke ruangan biasa dan usia 20 hari dilakukan enukleasi dan pemeriksaan histopatologi menggunakan imunohistokimia griffonia simplicifolia lectin (GSL) untuk menilai neovascular tuft . Bobot badan tikus kelompok OIR dengan LC rerata lebih berat daripada tikus OIR tanpa LC. Neovascular tuft yang dinilai adalah rerata jumlah neovascular tuft per 10 -4 panjang penampang retina. Jumlah rerata neovascular tuft kelompok OIR tanpa LC sebanyak 62,98±14 dibanding dengan kelompok OIR dengan LC; 22,43±9,87 (p

Callosal projections establish topographically organized maps between cortical areas. Neuropilin-1 (Nrp1) cortical gradient induces an early segregation of developing callosal axons. We investigated later roles of Nrp1 on the development of callosal projections from layer (L) 2/3 of the primary (S1) and secondary (S2) somatosensory (SS) areas, which express higher and lower levels of Nrp1, respectively. We used in utero electroporation to knock down or overexpress Nrp1 combined with retrograde tracers, to map connections at postnatal day 16 and 30. High levels of Nrp1 blocked contralateral S2 innervation while promoted the late postnatal growth of homotopic S1L2/3 and heterotopic S2L2/3 branches into S1. Conversely, knocking down Nrp1 increased the growth of heterotopic S1L2/3 projections into S2, and the overall refinement of S2L2/3 branches, thereby diminishing the number of P30 S2L2/3 callosally projecting neurons. Thus, the Nrp1 gradient determines homotopic SSL2/3 callosal connectivity by regulating late postnatal branching and refinement in a topographic manner.

Colostrum intake by neonatal piglets can be measured using the immunoglobulin immunocrit assay (iCrit). Lactocrine effects occur when maternally derived, milk-borne bioactive factors are transferred to the neonatal circulation with consumption of colostrum during nursing and affect development of somatic tissues, which can have long-term consequences in adulthood. Lactocrine deficiency, indicated by low neonatal iCrit, altered uterine gene expression and reduced fecundity in adult, neonatally lactocrine-deficient gilts. Litter size in pigs is dependent on both ovarian and uterine function. It was hypothesized that lactocrine deficiency affects development of ovarian follicles in gilts. The objective was to determine the number of primordial, primary, and secondary follicles in ovaries of gilts with high (12% ± 0.5; n = 10) or low (1.9% ± 0.4; n = 10) iCrit, determined on postnatal day (PND) 1 after birth. Paired high- and low-iCrit gilts were chosen from the same litters (birth weight; 3.1 ± 0.2 lbs). On PND 14, ovaries were collected and histological sections prepared (3 sections per animal; 30–150 µm apart). Ovarian follicles in each section were staged and the number of follicles in each category were quantified and subjected to ANOVA. Total number of ovarian follicles did not differ with iCrit (P = 0.55; 1,370.6 ± 147.8 follicles per section). The proportion of primordial, primary, and secondary follicles was 89.6 ± 1.15%, 7.7 ± 0.87%, 2.7 ± 0.51%, respectively. The number of primordial (P = 0.55), primary (P = 0.64), and secondary (P = 0.93) follicles did not differ with iCrit. Results indicate that ovarian follicular development of neonatal gilts is not sensitive to immunocrit status. Although lactocrine deficiency did not influence the ovarian follicular profile at PND 14, it remains unknown whether lactocrine programming alters ovarian follicular dynamics in neonatally lactocrine-deficient adults. USDA is an equal opportunity provider and employer.

ALS is characterized by progressive inability to execute movements. Motor neurons innervating fast-twitch muscle-fibers preferentially degenerate. The reason for this differential vulnerability and its consequences on motor output is not known. Here, we uncover that fast motor neurons receive stronger inhibitory synaptic inputs than slow motor neurons, and disease progression in the SOD1G93A mouse model leads to specific loss of inhibitory synapses onto fast motor neurons. Inhibitory V1 interneurons show similar innervation pattern and loss of synapses. Moreover, from postnatal day 63, there is a loss of V1 interneurons in the SOD1G93A mouse. The V1 interneuron degeneration appears before motor neuron death and is paralleled by the development of a specific locomotor deficit affecting speed and limb coordination. This distinct ALS-induced locomotor deficit is phenocopied in wild-type mice but not in SOD1G93A mice after appearing of the locomotor phenotype when V1 spinal interneurons are silenced. Our study identifies a potential source of non-autonomous motor neuronal vulnerability in ALS and links ALS-induced changes in locomotor phenotype to inhibitory V1-interneurons., Here the authors show in a model of ALS that motor neurons receive stronger inhibitory synaptic inputs than slow motor neurons, and disease progression is associated with specific loss of inhibitory synapses onto fast motor neurons.