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The ovine model could be an effective translational model but remains underexplored. Here, Blood Oxygen Level dependent functional MRI during visual stimulation and resting-state perfusion MRI were explored. We aimed at investigating the impact of isoflurane anesthesia during visual stimulation and evaluate resting cerebral blood flow and cerebral blood volume parameters in the lamb and adult sheep brain. BOLD fMRI and perfusion MRI after a bolus of DOTAREM were conducted in 4 lambs and 6 adult ewes at 3 T. A visual stimulation paradigm was delivered during fMRI at increasing isoflurane doses (1-3%). Robust but weak BOLD responses (0.21 ± 0.08%) were found in the lateral geniculate nucleus (LGN) up to 3% isoflurane anaesthesia. No significant differences were found beween BOLD responses in the range 1 to 3% ISO (p > 0.05). However, LGN cluster size decreased and functional localization became less reliable at high ISO doses (2.5-3% ISO). BOLD responses were weaker in adult sheep than in lambs (4.6 ± 1.5 versus 13.6 ± 8.5; p = 0.08). Relative cerebral blood volumes (rCBV) and relative cerebral blood flows (rCBF) were significantly higher (p < 0.0001) in lambs than in adult sheep for both gray and white matter. The impact of volatile anesthesia was explored for the first time on BOLD responses demonstrating increased reliability of functional localization of brain activity at low doses. Perfusion MRI was conducted for the first time in both lambs and adult ewes. Assessment of baseline cerebrovascular values are of interest for future studies of brain diseases allowing an improved interpretation of BOLD responses., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Reproduction induces changes within the brain to prepare for gestation and motherhood. However, the dynamic of these central changes and their relationships with the development of maternal behavior remain poorly understood. Here, we describe a longitudinal morphometric neuroimaging study in female mice between pre-gestation and weaning, using new magnetic resonance imaging (MRI) resources comprising a high-resolution brain template, its associated tissue priors (60-µm isotropic resolution) and a corresponding mouse brain atlas (1320 regions of interest). Using these tools, we observed transient hypertrophies not only within key regions controlling gestation and maternal behavior (medial preoptic area, bed nucleus of the stria terminalis), but also in the amygdala, caudate nucleus and hippocampus. Additionally, unlike females exhibiting lower levels of maternal care, highly maternal females developed transient hypertrophies in somatosensory, entorhinal and retrosplenial cortices among other regions. Therefore, coordinated and transient brain modifications associated with maternal performance occurred during gestation and lactation., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Sex differences in the brain and behavior are produced by the perinatal action of testosterone, which is converted into estradiol by the enzyme aromatase in the brain. Although magnetic resonance imaging (MRI) has been widely used in humans to study these differences, the use of animal models, where hormonal status can be properly manipulated, is necessary to explore the mechanisms involved. We used sheep, a recognized model in the field of neuroendocrinology, to assess brain morphological and functional sex differences and their regulation by adult gonadal hormones. To this end, we performed voxel-based morphometry and a resting-state functional MRI approach to assess sex differences in gonadally intact animals. We demonstrated significant sex differences in gray matter concentration (GMC) at the level of the gonadotropic axis, i.e., not only within the hypothalamus and pituitary but also within the hippocampus and the amygdala of intact animals. We then performed the same analysis one month after gonadectomy and found that some of these differences were reduced, especially in the hypothalamus and amygdala. By contrast, we found few differences in the organization of the functional connectome between males and females either before or after gonadectomy. As a whole, our study identifies brain regions that are sexually dimorphic in the sheep brain at the resolution of the MRI and highlights the role of gonadal hormones in the maintenance of these differences., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

During pregnancy, the sequential release of progesterone, 17β-estradiol, prolactin, oxytocin and placental lactogens reorganize the female brain. Brain structures such as the medial preoptic area, the bed nucleus of the stria terminalis and the motivation network including the ventral tegmental area and the nucleus accumbens are reorganized by this specific hormonal schedule such that the future mother will be ready to provide appropriate care for her offspring right at parturition. Any disruption to this hormone pattern, notably by exposures to endocrine disrupting chemicals (EDC), is therefore likely to affect the maternal brain and result in maladaptive maternal behavior. Development effects of EDCs have been the focus of intense study, but relatively little is known about how the maternal brain and behavior are affected by EDCs. We encourage further research to better understand how the physiological hormone sequence prepares the mother's brain and how EDC exposure could disturb this reorganization., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Both systemic and local production contribute to the concentration of steroids measured in the brain. This idea was originally based on rodent studies and was later extended to other species, including humans and birds. In quail, a widely used model in behavioural neuroendocrinology, it was demonstrated that all enzymes needed to produce sex steroids from cholesterol are expressed and active in the brain, although the actual concentrations of steroids produced were never investigated. We carried out a steroid profiling in multiple brain regions and serum of sexually mature male and female quail by gas chromatography coupled with mass spectrometry. The concentrations of some steroids (eg, corticosterone, progesterone and testosterone) were in equilibrium between the brain and periphery, whereas other steroids (eg, pregnenolone (PREG), 5α/β-dihydroprogesterone and oestrogens) were more concentrated in the brain. In the brain regions investigated, PREG sulphate, progesterone and oestrogen concentrations were higher in the hypothalamus-preoptic area. Progesterone and its metabolites were more concentrated in the female than the male brain, whereas testosterone, its metabolites and dehydroepiandrosterone were more concentrated in males, suggesting that sex steroids present in quail brain mainly depend on their specific steroidogenic pathways in the ovaries and testes. However, the results of castration experiments suggested that sex steroids could also be produced in the brain independently of the peripheral source. Treatment with testosterone or oestradiol restored the concentrations of most androgens or oestrogens, respectively, although penetration of oestradiol in the brain appeared to be more limited. These studies illustrate the complex interaction between local brain synthesis and the supply from the periphery for the steroids present in the brain that are either directly active or represent the substrate of centrally located enzymes., (© 2018 British Society for Neuroendocrinology.)

The sheep model was first used in the fields of animal reproduction and veterinary sciences and then was utilized in fundamental and preclinical studies. For more than a decade, magnetic resonance (MR) studies performed on this model have been increasingly reported, especially in the field of neuroscience. To contribute to MR translational neuroscience research, a brain template and an atlas are necessary. We have recently generated the first complete T1-weighted (T1W) and T2W MR population average images (or templates) of in vivo sheep brains. In this study, we 1) defined a 3D stereotaxic coordinate system for previously established in vivo population average templates; 2) used deformation fields obtained during optimized nonlinear registrations to compute nonlinear tissues or prior probability maps (nlTPMs) of cerebrospinal fluid (CSF), gray matter (GM), and white matter (WM) tissues; 3) delineated 25 external and 28 internal sheep brain structures by segmenting both templates and nlTPMs; and 4) annotated and labeled these structures using an existing histological atlas. We built a quality high-resolution 3D atlas of average in vivo sheep brains linked to a reference stereotaxic space. The atlas and nlTPMs, associated with previously computed T1W and T2W in vivo sheep brain templates and nlTPMs, provide a complete set of imaging space that are able to be imported into other imaging software programs and could be used as standardized tools for neuroimaging studies or other neuroscience methods, such as image registration, image segmentation, identification of brain structures, implementation of recording devices, or neuronavigation. J. Comp. Neurol. 525:676-692, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Alzheimer's disease (AD) is the most common cause of adult dementia. Yet the complete set of molecular changes accompanying this inexorable, neurodegenerative disease remains elusive. Here we adopted an unbiased lipidomics and metabolomics approach to surveying frozen frontal cortex samples from clinically characterized AD patients (n = 21) and age-matched controls (n = 19), revealing marked molecular differences between them. Then, by means of metabolomic pathway analysis, we incorporated the novel molecular information into the known biochemical pathways and compared it with the results of a metabolomics meta-analysis of previously published AD research. We found six metabolic pathways of the central metabolism as well as glycerophospholipid metabolism predominantly altered in AD brains. Using targeted metabolomics approaches and MS imaging, we confirmed a marked dysregulation of mitochondrial aspartate metabolism. The altered metabolic pathways were further integrated with clinical data, showing various degrees of correlation with parameters of dementia and AD pathology. Our study highlights specific, altered biochemical pathways in the brains of individuals with AD compared with those of control subjects, emphasizing dysregulation of mitochondrial aspartate metabolism and supporting future venues of investigation.

Purpose: To implement an accelerated five-dimensional (5D) echo-planar J-resolved spectroscopic imaging sequence combining 3 spatial and 2 spectral encoding dimensions and to apply the sequence in human brain., Methods: An echo planar readout was used to acquire a single spatial and a single spectral dimension during one readout. Nonuniform sampling was applied to the two phase-encoded spatial directions and the indirect spectral dimension. Nonlinear reconstruction was used to minimize the ℓ1-norm or the total variation and included a spectral mask to enhance sparsity. Retrospective reconstructions at multiple undersamplings were performed in phantom. Ten healthy volunteers were scanned with 8× undersampling and compared to a fully sampled single slice scan., Results: Retrospective reconstruction of fully sampled phantom data showed excellent quality at 4×, 8×, 12×, and 16× undersampling using either reconstruction method. Reconstruction of prospectively acquired in vivo scans with 8× undersampling showed excellent quality in the occipito-parietal lobes and good quality in the frontal lobe, consistent with the fully sampled single slice scan., Conclusion: By utilizing nonuniform sampling with nonlinear reconstruction, 2D J-resolved spectra can be acquired over a 3D spatial volume with a total scan time of 20 min, which is reasonable for in vivo studies., (© 2015 Wiley Periodicals, Inc.)

Sheep is a developing animal model used in the field of neurosciences for the study of many behavioral, physiological or pathophysiological mechanisms, including for example, the central control of social behavior, brain injury or neurodegenerative diseases. However, sheep remains an orphan species in the field of magnetic resonance imaging (MRI). Therefore, a mean image (template), resulting of registrations of multiple subject images is needed and currently does not exist. In this study, we: i) computed multimodal high resolution 3D in-vivo sheep brain templates of T1 weighted (T1W) and T2W images, ii) computed gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) prior probability maps using linear and optimized non-linear registrations iii) used prior probability maps to perform the segmentation of a single brain tissues. Computed multimodal sheep brain templates showed to preserve and underline all brain patterns of a single T1W or T2W image, and prior probability maps allowed to improve the segmentation of brain tissues. Finally, we demonstrated that these templates and prior probability maps were able to be portable in other publicly available imaging software and could be used as standardized spaces for multi-institution neuroimaging studies or other neuroscience methods., (Copyright © 2015 Elsevier Inc. All rights reserved.)

After immobilization, patients show impaired postural control and increased risk of falling. Therefore, loss of balance control should already be counteracted during immobilization. Previously, studies have demonstrated that both motor imagery (MI) and action observation (AO) can improve motor performance. The current study elaborated how the brain is activated during imagination and observation of different postural tasks to provide recommendations about the conception of non-physical balance training. For this purpose, participants were tested in a within-subject design in an fMRI-scanner in three different conditions: (a) AO + MI, (b) AO, and (c) MI. In (a) participants were instructed to imagine themselves as the person pictured in the video whereas in (b) they were instructed simply to watch the video. In (c) subjects closed their eyes and kinesthetically imagined the task displayed in the video. Two tasks were evaluated in each condition: (i) static standing balance and (ii) dynamic standing balance (medio-lateral perturbation). In all conditions the start of a new trial was indicated every 2 sec by a sound. During AO + MI of the dynamic task, participants activated motor centers including the putamen, cerebellum, supplementary motor area, premotor cortices (PMv/d) and primary motor cortex (M1). MI showed a similar pattern but no activity in M1 and PMv/d. In the SMA and cerebellum, activity was generally higher in the dynamic than in the static condition. AO did not significantly activate any of these brain areas. Our results showed that (I) mainly AO + MI, but also MI, activate brain regions important for balance control; (II) participants display higher levels of brain activation in the more demanding balance task; (III) there is a significant difference between AO + MI and AO. Consequently, best training effects should be expected when participants apply MI during AO (AO + MI) of challenging postural tasks., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Propofol is commonly used as sedative in newborns and children. Recent experimental studies led to contradictory results, revealing neurodegenerative or neuroprotective properties of propofol on the developing brain. We investigated neurodevelopmental short- and long-term effects of neonatal propofol treatment., Methods: 6-day-old Wistar rats (P6), randomised in two groups, received repeated intraperitoneal injections (0, 90, 180 min) of 30 mg/kg propofol or normal saline and sacrificed 6, 12 and 24 hrs following the first injection. Cortical and thalamic areas were analysed by Western blot and quantitative real-time PCR (qRT-PCR) for expression of apoptotic and neurotrophin-dependent signalling pathways. Long-term effects were assessed by Open-field and Novel-Object-Recognition at P30 and P120., Results: Western blot analyses revealed a transient increase of activated caspase-3 in cortical, and a reduction of active mitogen-activated protein kinases (ERK1/2, AKT) in cortical and thalamic areas. qRT-PCR analyses showed a down-regulation of neurotrophic factors (BDNF, NGF, NT-3) in cortical and thalamic regions. Minor impairment in locomotive activity was observed in propofol treated adolescent animals at P30. Memory or anxiety were not impaired at any time point., Conclusion: Exposing the neonatal rat brain to propofol induces acute neurotrophic imbalance and neuroapoptosis in a region- and time-specific manner and minor behavioural changes in adolescent animals.

Background: In preterm infants, the amplitude-integrated electroencephalogram (aEEG) is not established in clinical routine. The aim of this study was to derive normative data on aEEG parameters by means of longitudinal characterization and to evaluate the impact of gestational age (GA), postnatal age (PNA), postmenstrual age, sedation, and patent ductus arteriosus (PDA)., Methods: Recordings from 61 infants with GA 28-31 weeks were obtained during the first 72 h, then weekly until the age of 4 wk. Infants were divided into three groups: (i) no sedation, no PDA, (ii) sedation, no PDA, and (iii) sedation, PDA. Assessed parameters included background activity, cycling, amplitude, and log ratio of the maximum/minimum amplitude., Results: GA and PNA had a significant impact within 72 h. Sedation modified aEEG, and presence of PDA was associated with reduced aEEG scores within 72 h. The log ratio of the amplitude correlated with GA but was unaffected by sedation and PDA., Conclusion: Evaluation of electrocortical background activity within the first postnatal hours and longitudinally over days and weeks is important to better understand the postnatal factors impacting cerebral function in preterm infants. There is a need to agree on definitions and a standardized reporting system in order to permit comparisons between studies and establish aEEG as a method for routine monitoring of preterm infants.

CEACAM1 is the founder molecule of the family of 'carcinoembryonic antigen-related cell adhesion molecules' and part of the immunoglobulin superfamily. Due to its role as a coreceptor to many other receptors (e.g. Toll-like receptor 2, Toll-like receptor 4, T-cell receptor, B-cell receptor, epidermal growth factor receptor and vascular endothelial growth factor receptor) and its different isoforms, CEACAM1 is a multifunctional protein with an impact on proliferation and differentiation of multiple cell types. Although different modes of action in other tissues are described, the role of CEACAM1 in the developing brain remains elusive. Here we report for the first time that CEACAM1 is expressed ontogenetically in oligodendrocytes of the developing rat brain, and that CEACAM1 expression has a spatiotemporal relation to myelination. In addition, CEACAM1 expression is altered in a model of hyperoxia- and inflammation-induced encephalopathy of prematurity, a myelination disorder of children born preterm. Furthermore, primary oligodendrocytes stimulated with CEACAM1 show increased myelination. Therefore, we postulate that CEACAM1 is, at least in part, involved in hyperoxia- and inflammation-induced disruption of myelination, but may also play a role in intact myelination as it is ontogenetically expressed in myelinating oligodendrocytes., (Copyright © 2013 S. Karger AG, Basel.)

An experimental oral bovine spongiform encephalopathy (BSE) challenge study was performed to elucidate the route of infectious prions from the gut to the central nervous system in preclinical and clinical infected animals. Tissue samples collected from the gut and the central and autonomic nervous system from animals sacrificed between 16 and 44 months post infection (mpi) were examined for the presence of the pathological prion protein (PrP(Sc)) by IHC. Moreover, parts of these samples were also bioassayed using bovine cellular prion protein (PrP(C)) overexpressing transgenic mice (Tgbov XV) that lack the species barrier for bovine prions. A distinct accumulation of PrP(Sc) was observed in the distal ileum, confined to follicles and/or the enteric nervous system, in almost all animals. BSE prions were found in the sympathetic nervous system starting at 16 mpi, and in the parasympathetic nervous system from 20 mpi. A clear dissociation between prion infectivity and detectable PrP(Sc) deposition became obvious. The earliest presence of infectivity in the brain stem was detected at 24 mpi, whereas PrP(Sc) accumulation was first detected after 28 mpi. In summary, our results decipher the centripetal spread of BSE prions along the autonomic nervous system to the central nervous system, starting already halfway in the incubation time., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Within the last decade, it became clear that oxygen contributes to the pathogenesis of neonatal brain damage, leading to neurocognitive impairment of prematurely born infants in later life. Recently, we have identified a critical role for receptor-mediated neuronal apoptosis in the immature rodent brain. However, the contribution of the intrinsic apoptotic pathway accompanied by activation of caspase-2 under hyperoxic conditions in the neonatal brain still remains elusive. Inhibition of caspases appears a promising strategy for neuroprotection. In order to assess the influence of specific caspases on the developing brain, we applied a recently developed pentapeptide-based group II caspase inhibitor (5-(2,6-difluoro-phenoxy)-3(R,S)-(2(S)-(2(S)-(3-methoxycarbonyl-2(S)-(3-methyl-2(S)-((quinoline-2-carbonyl)-amino)-butyrylamino)propionylamino)3-methylbutyrylamino)propionylamino)-4-oxo-pentanoic acid methyl ester; TRP601). Here, we report that elevated oxygen (hyperoxia) triggers a marked increase in active caspase-2 expression, resulting in an initiation of the intrinsic apoptotic pathway with upregulation of key proteins, namely, cytochrome c, apoptosis protease-activating factor-1, and the caspase-independent protein apoptosis-inducing factor, whereas BH3-interacting domain death agonist and the anti-apoptotic protein B-cell lymphoma-2 are downregulated. These results coincide with an upregulation of caspase-3 activity and marked neurodegeneration. However, single treatment with TRP601 at the beginning of hyperoxia reversed the detrimental effects in this model. Hyperoxia-mediated neurodegeneration is supported by intrinsic apoptosis, suggesting that the development of highly selective caspase inhibitors will represent a potential useful therapeutic strategy in prematurely born infants.

Aim: MRI is gaining in importance as an imaging tool for brain development and injury in preterm infants. The aim of this study was to evaluate the feasibility of performing MRI in non-sedated preterm-born infants at term-equivalent age (TEA)., Methods: A total of 89 infants born before 32 gestational weeks were recruited. Infants were scanned without sedation. Duration of the entire examination including scan repetition and interruptions was registered., Results: Of the 89 infants, 56 (63%) underwent MRI at TEA. Out-patients required a significantly shorter total MR examination time than did in-patients (32 ± 12 vs. 54 ± 10 min, p < 0.01). Of the 56 infants, 39 (69.6%) were examined without interruption. Only four (7.2%) of the 56 scans were unusable because of motion artefacts. Mean duration of all scans was 36 ± 14 min. In cases with no interruptions, sessions were completed within 32 ± 12 min; MR sessions with interruption lasted 45 ± 13 min., Conclusion: A well-trained team is indispensable in obtaining best-quality images as a prerequisite for good counselling. From our experience, we worked out a guideline to ensure that scans in stable non-sedated preterm-born infants at TEA run smoothly and provide high-quality images., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)

Profound behavioural changes occur in the mother at parturition, together with extensive remodelling of neural circuits. These changes include neurochemical, morphological and functional plasticity. The continuous generation of new neurones in the hippocampus and the olfactory system is an additional form of neuroplasticity that contributes to motherhood. This review describes the reciprocal relationships between hippocampal and olfactory neurogenesis and parental behaviour. Studies in rodents demonstrate that parturition and interactions with the young affect both cell proliferation and survival in a different manner across neurogenic zones. Species in which an individual recognition of the offspring is formed, such as sheep, show a down-regulation of neurogenesis during the perinatal period. This would function to decrease cell competition, favouring the selection of newborn neurones involved in olfactory recognition of the young. Also, in biparental species, increases in olfactory neurogenesis occur in the father in response to pup exposure during the early postpartum period. Oestradiol, corticosterone and prolactin changes associated with parturition are the main physiological factors involved in the regulation of neurogenesis that have been determined so far. In the father, prolactin mediates an enhancement of olfactory neurogenesis. Contradictory evidence indicates a functional link between neurogenesis and parenting behaviour. Mice receiving focal irradiation of the olfactory neurogenic subventricular zone show few disturbances in the expression of maternal behaviour, whereas a reduction of both hippocampal and olfactory neurogenesis as a result of the infusion of an anti-mitotic agent induces behavioural deficits. Disrupting prolactin signalling abolished increased paternal neurogenesis and offspring recognition by the father, and rescuing this neurogenesis restored recognition behaviour. More studies that selectively suppress the changes of neurogenesis are needed to confirm the role of new neurones in regulating parenting behaviour., (© 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.)

We mapped cells immunoreactive for the phosphorylated form (p44/p42) of the mitogen-activated protein kinase (pMAPK--also known as ERK1/2) in the brain of male mice after exposure to female olfactory cues or after the display of male copulatory behaviors. Exposure to soiled bedding from estrous females or the display of coital behaviors rapidly (within 10 min) induced MAPK phosphorylation in most of the brain regions known to be involved in the processing of olfactory cues (main and accessory olfactory bulbs, amygdala, and medial preoptic area) and in the control of copulatory behavior (amygdala and medial preoptic area). MAPK phosphorylation thus seems to be a useful marker to study short-term neural activation associated with the expression of specific behaviors.

Current quantitative metabolomic research in brain tissue is challenged by several analytical issues. To compare data of metabolite pattern, ratios of individual metabolite concentrations and composed classifiers characterizing a distinct state, standardized workup conditions, and extraction medium are crucial. Differences in physicochemical properties of individual compounds and compound classes such as polarity determine extraction yields and, thus, ratios of compounds with varying properties. Also, variations in suppressive effects related to coextracted matrix components affect standards or references and their concentration-dependent responses.The selection of a common tissue extraction protocol is an ill-posed problem because it can be regarded as a multiple objective decision depending on factors such as sample handling practicability, measurement precision, control of matrix effects, and relevance of the chemical assay. This study systematically evaluates the impact of extraction solvents and the impact of the complex brain tissue on measured metabolite levels, taking into account ionization efficiency as well as challenges encountered in the trace-level quantification of the analytes in brain matrices. In comparison with previous studies that relied on nontargeted platforms, consequently emphasizing the global behavior of the metabolomic fingerprint, here we focus on several series of metabolites spanning over extensive polarity, concentration, and molecular mass ranges., (Copyright 2010 Elsevier Inc. All rights reserved.)

Production of new neurons continues throughout life in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus and is influenced by both endocrine and social factors. In sheep parturition is associated with the establishment of a selective bond with the young based on an olfactory learning. The possibility exists that endocrine changes at parturition together with interactions with the young modulate cell proliferation in the neurogenic zones. In the present study, we first investigated the existence of cell proliferation in sheep. Newly born cells labeled by the cell proliferation marker 5-bromo-2'-deoxyuridine (BrdU) were found in the SVZ, the main olfactory bulb (MOB) and the DG and completely co-localized with Ki-67, another mitotic marker. Forty to 50% of the BrdU-labeled cells contained GFAP suggestive of the presence of neural stem cells. Secondly, parturition with or without interactions with the lamb for 2 days, down-regulated the number of BrdU-labeled cells in the 3 proliferation sites in comparison to no pregnancy. An additional control provided evidence that this effect is specific to early postpartum period: estrus with interactions with males did not affect cell proliferation. Our results provide the first characterization of neural cell proliferation in the SVZ, the DG and unexpectedly in the MOB of adult sheep. We hypothesize that the down-regulation of cell proliferation observed in the early postpartum period could facilitate the olfactory perceptual and memory demands associated with maternal behavior by favouring the survival and integration of neurons born earlier., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Kisspeptins are a family of small peptides that play a key role in the neuroendocrine regulation of the reproductive function through neural pathways that have not yet been completely identified. The present study aimed to investigate the distribution of kisspeptin neurone fibres in the female rat brain by comparing precisely the immunoreactive pattern obtained with two antibodies: one specifically directed against kisspeptin-52 (Kp-52), the longest isoform, and the other directed against kisspeptin-10 (Kp-10), whose sequence is common to all putative mature isoforms. With both antibodies, immunoreactive cell bodies were exclusively observed in the arcuate nucleus, and immunoreactive fibres were confined to the septo-preoptico-hypothalamic continuum of the brain. Fibres were observed in the preoptic area, the diagonal band of Broca, the septohypothalamic area, the anteroventral periventricular, suprachiasmatic, supraoptic, paraventricular and periventricular nuclei, the dorsal border of the ventromedian nucleus, the dorsomedial and arcuate nuclei, and the median eminence. In the latter structure, varicose fibres were mainly distributed in the internal layer and were detected to a lesser extent throughout the external layer, including around the deeper part of the infundibular recess. Most regions of immunoreactive cells and fibres matched perfectly for the two antibodies. However, fibres in the dorsolateral septum, anterior fornix, accumbens nucleus and the lateral bed nucleus of the stria terminalis were only recognised by antibody anti-Kp-10, suggesting that anti-Kp-10 may recognise a wider range of kisspeptin isoforms than anti-Kp-52 or cross-react with molecules other than kisspeptin in rat tissue. Overall, these results illustrate the variety of projection sites of kisspeptin neurones in the rat and suggest that these peptides play a role in different functions., (© 2010 The Authors. Journal of Neuroendocrinology © 2010 Blackwell Publishing Ltd.)

A new approach for fMRI group data analysis is introduced to overcome the limitations of standard voxel-based testing methods, such as Statistical Parametric Mapping (SPM). Using a Bayesian model selection framework, the functional network associated with a certain cognitive task is selected according to the posterior probabilities of mean region activations, given a pre-defined anatomical parcellation of the brain. This approach enables us to control a Bayesian risk that balances false positives and false negatives, unlike the SPM-like approach, which only controls false positives. On data from a mental calculation experiment, it detected the functional network known to be involved in number processing, whereas the SPM-like approach either swelled or missed the different activation regions.

In rats, expression of the immediate early gene, c-fos observed in the brain following male copulatory behavior relates mostly to the detection of olfactory information originating from the female and to somatosensory feedback from the penis. However, quail, like most birds, are generally considered to have a relatively poorly developed sense of smell. Furthermore, quail have no intromittent organ (e.g., penis). It is therefore intriguing that expression of male copulatory behavior induces in quail and rats a similar pattern of c-fos expression in the medial preoptic area (mPOA), bed nucleus of the stria terminalis (BSTM) and parts of the amygdala. We analyzed here by immunocytochemistry Fos expression in the mPOA/BSTM/amygdala of male quail that had been allowed to copulate with a female during standardized tests. Before these tests, some of the males had either their nostrils plugged, or their cloacal area anesthetized, or both. A control group was not exposed to females. These manipulations did not affect frequencies of male sexual behavior and all birds exposed to a female copulated normally. In the mPOA, the increased Fos expression induced by copulation was not affected by the cloacal gland anesthesia but was markedly reduced in subjects deprived of olfactory input. Both manipulations affected copulation-induced Fos expression in the BSTM. No change in Fos expression was observed in the amygdala. Thus immediate early gene expression in the mPOA and BSTM of quail is modulated at least in part by olfactory cues and/or somatosensory stimuli originating from the cloacal gland. Future work should specify the nature of these stimuli and their function in the expression of avian male sexual behavior.

Enhanced glutamate release and inflammation play an important role in the pathogenesis of developmental brain injury. Although N-methyl-d-aspartate receptor (NMDAR) antagonists potently attenuate neonatal brain damage in several animal models, they can also impact trophic functions in the developing brain. As a consequence, high-affinity NMDAR antagonists have been shown to trigger widespread apoptotic neurodegeneration in the newborn brain. Dextromethorphan (DM), a low-affinity NMDAR antagonist with anti-inflammatory properties, may be neuroprotective against excitotoxic and inflammation-enhanced excitotoxic brain injury, without the associated stimulation of apoptotic degeneration. Using an established newborn mouse model of excitotoxic brain damage, we determined whether systemic injection of DM significantly attenuates excitotoxic lesion size. We investigated several doses and time regimens; a dose of 5 microg/g DM given in a combination of both pre-injury and repetitive post-injury treatment proved most effective. DM treatment significantly reduced lesion size in gray and white matter by reducing cell death as shown by a decreased Fluoro-Jade B staining and caspase-3 activation. Pre-treatment with interleukin-1beta and lipopolysaccharide enhanced NMDAR-mediated excitotoxic brain injury and microglial cell activation. This sensitizing effect was abolished by DM treatment, as the effectiveness of DM in reducing lesion size and microglial cell activation was similar to phosphate-buffered saline-pre-treated controls. In all cases, no gender-specific differences were detected. DM treatment did not trigger any apoptotic neurodegeneration (caspase-3 cleavage, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, Fluoro-Jade B staining). Although functional parameters were not measured, our data corroborate reports that DM is neuroprotective and that it may therefore improve functional outcome following perinatal brain injury.

This technical note describes a collection of test statistics accounting for estimation uncertainties at the within-subject level, that can be used as alternatives to the standard t statistic in one-sample random-effect analyses, i.e. when testing the mean effect of a population. We build such test statistics by estimating the across-subject distribution of the effects using maximum likelihood under a nonparametric mixed-effect model. For inference purposes, the statistics are calibrated using permutation tests to achieve exact false positive control under a symmetry assumption regarding the across-subject distribution. The new tests are implemented in a freely available toolbox for SPM called Distance.

Estrogens are classically viewed as hormones that bind to intracellular receptors, which then act as transcription factors to modulate gene expression; however, they also affect many aspects of neuronal functioning by rapid nongenomic actions. Brain estrogen production can be regulated within minutes by changes in aromatase (estrogen synthase) activity as a result of calcium-dependent phosphorylations of the enzyme. To determine the effects of rapid changes in estrogen availability on male copulatory behavior, we mimicked in male mice the rapid upregulation and downregulation of brain estrogen concentration that should occur after inactivation or activation of aromatase activity. A single injection of different aromatase inhibitors [Vorozole, 1,4,6-androstatrien-3,17-dione (ATD), or its metabolite 17-OH-ATD (1,4,6-androstatrien-17beta-ol-3-one)] almost completely suppressed male sexual behavior (mounts and intromissions) expressed 10-20 min later by C57BL/6J mice but did not affect behavior in aromatase knock-out (ArKO) mice, activated by daily injections of estradiol benzoate, thereby confirming the specificity of the behavioral inhibition observed in wild-type mice. The rapid ATD-induced inhibition was reversed by the simultaneous injection of a large dose of estradiol. A single injection of estradiol to ArKO mice also activated male sexual behavior within 15 min. Thus, rapid increases or decreases in brain estrogen concentrations are followed within minutes by corresponding changes in male sexual behavior. Sexual behavior can thus be used to monitor changes in local estrogen concentrations and analyze the mechanisms mediating the rapid decline in estrogen signaling that takes place after inhibition of estrogen synthesis.

In sheep the onset of maternal responsiveness and the development of the mutual mother-young bond are under the combined influence of hormonal and visceral somatosensory stimulations. These stimuli are provided in the mother by parturition (via steroids and vaginocervical stimulation) and in the neonate by the first suckling episodes (via cholecystokinin and oro-gastro-intestinal stimulation). In addition, each partner relies on specific chemosensory stimulation for reciprocal attraction: amniotic fluids for the mother, colostrum for the young. In the ewe parturition activates several brain structures to respond specifically to sensory cues emanating from the young. The main olfactory bulbs undergo profound neurophysiological changes when exposed to offspring odors at parturition. Additional activations in the hypothalamus - preoptic area - and the amygdala - medial and cortical nuclei - also contribute to maternal responsiveness and memorization of lamb odors. In the neonate, post-ingestive stimulations activate the brain stem via vagal afferents. Like in the ewe, several regions of the hypothalamus and the amygdala respond to colostrum ingestion suggesting common ground for the integrative neural processes involved in early learning and bonding. This leads to rapid visual and auditory recognition in both partners although olfaction remains important in the ewe to display selective nursing. It is concluded that the biological basis for the development of maternal and filial bonding in sheep presents striking similarities.

Inferring the position of functionally active regions from a multi-subject fMRI dataset involves the comparison of the individual data and the inference of a common activity model. While voxel-based analyzes, e.g. Random Effect statistics, are widely used, they do not model each individual activation pattern. Here, we develop a new procedure that extracts structures individually and compares them at the group level. For inference about spatial locations of interest, a Dirichlet Process Mixture Model is used. Finally, inter-subject correspondences are computed with Bayesian Network models. We show the power of the technique on both simulated and real datasets and compare it with standard inference techniques.

Many sophisticated techniques for the visualization of volumetric data such as medical data have been published. While existing techniques are mature from a technical point of view, managing the complexity of visual parameters is still difficult for non-expert users. To this end, this paper presents new ideas to facilitate the specification of optical properties for direct volume rendering. We introduce an additional level of abstraction for parametric models of transfer functions. The proposed framework allows visualization experts to design high-level transfer function models which can intuitively be used by non-expert users. The results are user interfaces which provide semantic information for specialized visualization problems. The proposed method is based on principal component analysis as well as on concepts borrowed from computer animation.

Brain lesions induced in newborn mice or rats by the glutamatergic agonists ibotenate (acting on NMDA and metabotropic receptors) or S-bromowillardiine (acting on AMPA-kainate receptors) mimic some aspects of white matter cysts and transcortical necrosis observed in human perinatal brain damage associated with cerebral palsy. Exogenous and endogenous cannabinoids have received increasing attention as potential neuroprotective agents in a number of neurodegenerative disorders of the adult. One recent study showed neuroprotection by the cannabinoid agonist WIN-55212 in a newborn rat model of acute severe asphyxia. The present study was designed to assess the neuroprotective effects of the endogenous cannabinoid anandamide using a well-defined rodent model of neonatal excitotoxic brain lesions. In this model, anandamide provided dose-dependent and long-lasting protection of developing white matter and cortical plate reducing the size of lesions induced by S-bromowillardiine. Anandamide had only marginal neuroprotective effect against ibotenate-induced cortical grey matter lesions. Anandamide-induced neuroprotection against AMPA-kainate receptor-mediated brain lesions were blocked by a CB1 antagonist but not by a CB2 antagonist. Furthermore, anandamide effects were mimicked by a CB1 agonist but not by a CB2 agonist. Real-time PCR confirmed the expression of CB1 receptors, but not CB2 receptors, in the untreated newborn neocortex. Finally, neuroprotective effects of anandamide in white matter involved increased survival of preoligodendrocytes and better preservation of myelination. The present study provides experimental support for the role of endocannabinoids as a candidate therapy for excitotoxic perinatal brain lesions.

Background: Previous studies have shown that HIV-infected children have abnormal cerebral metabolites, measured by proton MR spectroscopy (1H MRS), but the stability of these measurements over time has not been described in HIV-infected children. The authors recently reported a study of cerebral metabolites in 20 HIV-infected children (6 to 16 years of age); the current study followed 12 of these children (10.0 years +/- 3.7 years) and repeated the MR spectroscopy at 24.1 +/- 3.7 weeks and 42.2 +/- 3.5 weeks following the entry time with repeated neuropsychological testing., Methods: 1H MR spectra were acquired at 1.5 T (GE Signa, PRESS localization, repetition time = 3,000 msec, echo time = 30 msec). Five brain regions were studied: right frontal white matter, left frontal white matter, right basal ganglia, right hippocampus, and midfrontal gray matter. The concentrations of N-acetylaspartate (NAA), choline (CHO), creatine (CR), and myo-inositol (mI) and the ratio of each metabolite to CR were determined., Results: There were no changes in the metabolite concentrations or metabolite/CR ratios at the three time periods. Similarly, during this follow-up period, HIV-positive children showed no changes in clinical signs, HIV viral loads, CD4%, or CD4 counts, except for improved spatial memory with repeat testing., Conclusion: In a clinically and neurologically stable group of HIV-infected children, cerebral metabolites were stable over a 10-month time period, suggesting that it is possible to assess changes in cerebral metabolites as a measure of cerebral health, but longer follow-up in a larger sample is needed.

Object: Hypervolemia and hypertension therapy is routinely used for prophylaxis and treatment of symptomatic cerebral vasospasm at many institutions. Nevertheless, there is an ongoing debate about the preferred modality (hypervolemia, hypertension, or both), the degree of therapy (moderate or aggressive), and the risk or benefit of hypervolemia, moderate hypertension, and aggressive hypertension in patients following subarachnoid hemorrhage., Methods: Monitoring data and patient charts for 45 patients were retrospectively searched to identify periods of hypervolemia, moderate hypertension, or aggressive hypertension. Measurements of central venous pressure, fluid input, urine output, arterial blood pressure, intracranial pressure, and oxygen partial pressure (PO2) in the brain tissue were extracted from periods ranging from 1 hour to 24 hours. For these periods, the change in brain tissue PO2 and the incidence of complications were analyzed. During the 55 periods of moderate hypertension, an increase in brain tissue PO2 was found in 50 cases (90%), with complications occurring in three patients (8%). During the 25 periods of hypervolemia, an increase in brain oxygenation was found during three intervals (12%), with complications occurring in nine patients (53%). During the 10 periods of aggressive hypervolemic hypertension, an increase in brain oxygenation was found during six of the intervals (60%), with complications in five patients (50%)., Conclusions: When hypervolemia treatment is applied as in this study, it may be associated with increased risks. Note, however, that further studies are needed to determine the role of this therapeutic modality in the care of patients with cerebral vasospasm. In poor-grade patients, moderate hypertension (cerebral perfusion pressure 80-120 mm Hg) in a normovolemic, hemodiluted patient is an effective method of improving cerebral oxygenation and is associated with a lower complication rate compared with hypervolemia or aggressive hypertension therapy.

In sheep, ewes at parturition are responsive to any newborn lamb, but within less than 1 h, mothers learn to recognize the odor of their lamb and restrict maternal care to their own offspring (maternal selectivity). In a first experiment, we investigated the long-term retention of maternal selectivity after various mother-young contact and separation durations. After 4 h of contact, 36 h of separation leads to a total loss of selectivity. Increasing contact duration to 7 days prior to this separation maintains selectivity. These data suggest that lamb memory after going through an initial labile state after parturition, is consolidated over time into a more stable long-term memory. Fos immunohistochemistry reveals that reintroduction of the lamb after 4 h of mother-young contact and 3 h of separation activates different maternal brain regions than reintroduction of the lamb after 7 days of mother-young contact and 3 h of separation. While the piriform cortex shows an enhanced activation at both times, a selective enhancement of activation is observed in the frontal medial and orbitofrontal cortices only after 7 days of mother-young contact. These data suggest that as consolidation occurs, the neurobiological networks sustaining lamb memory involve different structures.

Mouse embryos genetically null for the alphav integrin subunit develop intracerebral hemorrhages at midgestation and die shortly after birth. A key question is whether the hemorrhage arises from primary defects in vascular endothelial cells or pericytes or from other causes. We have previously reported normal initiation of cerebral vessels comprising branched tubes of endothelial cells. Here we show that the onset of hemorrhage is not due to defects in pericyte recruitment. Additionally, most alphav-null vessels display ultrastructurally normal endothelium-pericyte associations and normal interendothelial cell junctions. Thus, endothelial cells and pericytes appear to establish their normal relationships in cerebral microvessels. However, by both light and electron microscopy, we detected defective associations between cerebral microvessels and the surrounding brain parenchyma, composed of neuroepithelial cells, glia, and neuronal precursors. These data suggest a novel role for alphav integrins in the association between cerebral microvessels and central nervous system parenchymal cells.

Prostanoid forming capacity in vitro and convulsion-induced prostanoid formation in vivo were studied in the developing rat brain. For comparison, prostanoid synthesis in homogenates of primary astrocyte cultures of different ages was also examined. There was no significant prostanoid production in homogenates from primary astrocyte cultures prepared one week after cultivation. Two-week-old astrocyte cultures possessed a prostanoid synthesizing system of high specific activity. The relative proportions of the products were similar to those obtained in brain homogenates of adult rats, prostaglandin D2 (PGD2) being the major product. Prostanoid forming capacity of brain homogenates was low at birth, increased during development and nearly reached adult values by day 21. Generalized convulsions could be evoked by pentylenetetrazol (PTZ) irrespective of age, but convulsion-induced prostanoid formation characteristic of adult rodents did not take place before the third week of postnatal life. The close similarities between the characteristic features of prostanoid synthesis in both brain and astroglial homogenates, together with the coincidence during brain development of the expression of cerebral prostanoid synthesis with the appearance of mature astrocytes suggest that astrocytes are an important source of brain prostanoids.

The difference in Hounsfield number between white and gray brain tissue is calculated from published chemical compositions and density values. The result of 5.5 Hounsfield units at typical CT energies is in excellent agreement with experiments. The difference arises because gray matter contains 8% more oxygen and 8% less carbon, due to its higher water and lower lipid content, and this increases the photoelectric absorption. Efforts to obtain greater contrast by lowering the X-ray energy will be offset by the noise increase at low energies.

BackgroundEndophenotypes are laboratory-based measures hypothesized to lie in the causal chain between genes and clinical disorder, and to serve as a more powerful way to identify genes associated with the disorder. One promise of endophenotypes is that they may assist in elucidating the neurobehavioral mechanisms by which an associated genetic polymorphism affects disorder risk in complex traits. We evaluated this promise by testing the extent to which variants discovered to be associated with schizophrenia through large-scale meta-analysis show associations with psychophysiological endophenotypes.MethodWe genome-wide genotyped and imputed 4905 individuals. Of these, 1837 were whole-genome-sequenced at 11× depth. In a community-based sample, we conducted targeted tests of variants within schizophrenia-associated loci, as well as genome-wide polygenic tests of association, with 17 psychophysiological endophenotypes including acoustic startle response and affective startle modulation, antisaccade, multiple frequencies of resting electroencephalogram (EEG), electrodermal activity and P300 event-related potential.ResultsUsing single variant tests and gene-based tests we found suggestive evidence for an association between contactin 4 (CNTN4) and antisaccade and P300. We were unable to find any other variant or gene within the 108 schizophrenia loci significantly associated with any of our 17 endophenotypes. Polygenic risk scores indexing genetic vulnerability to schizophrenia were not related to any of the psychophysiological endophenotypes after correction for multiple testing.ConclusionsThe results indicate significant difficulty in using psychophysiological endophenotypes to characterize the genetically influenced neurobehavioral mechanisms by which risk loci identified in genome-wide association studies affect disorder risk. [ABSTRACT FROM PUBLISHER]