ABSTRACT
BACKGROUND: The nucleus incertus (NI) was originally described by Streeter in 1903, as a midline region in the floor of the fourth ventricle of the human brain with an 'unknown' function. More than a century later, the neuroanatomy of the NI has been described in lower vertebrates, but not in humans. Therefore, we examined the neurochemical anatomy of the human NI using markers, including the neuropeptide, relaxin-3 (RLN3), and began to explore the distribution of the NI-related RLN3 innervation of the hippocampus. METHODS: Histochemical staining of serial, coronal sections of control human postmortem pons was conducted to reveal the presence of the NI by detection of immunoreactivity (IR) for the neuronal markers, microtubule-associated protein-2 (MAP2), glutamic acid dehydrogenase (GAD)-65/67 and corticotrophin-releasing hormone receptor 1 (CRHR1), and RLN3, which is highly expressed in NI neurons in diverse species. RLN3 and vesicular GABA transporter 1 (vGAT1) mRNA were detected by fluorescent in situ hybridization. Pons sections containing the NI from an AD case were immunostained for phosphorylated-tau, to explore potential relevance to neurodegenerative diseases. Lastly, sections of the human hippocampus were stained to detect RLN3-IR and somatostatin (SST)-IR. RESULTS: In the dorsal, anterior-medial region of the human pons, neurons containing RLN3- and MAP2-IR, and RLN3/vGAT1 mRNA-positive neurons were observed in an anatomical pattern consistent with that of the NI in other species. GAD65/67- and CRHR1-immunopositive neurons were also detected within this area. Furthermore, RLN3- and AT8-IR were co-localized within NI neurons of an AD subject. Lastly, RLN3-IR was detected in neurons within the CA1, CA2, CA3 and DG areas of the hippocampus, in the absence of RLN3 mRNA. In the DG, RLN3- and SST-IR were co-localized in a small population of neurons. CONCLUSIONS: Aspects of the anatomy of the human NI are shared across species, including a population of stress-responsive, RLN3-expressing neurons and a RLN3 innervation of the hippocampus. Accumulation of phosphorylated-tau in the NI suggests its possible involvement in AD pathology. Further characterization of the neurochemistry of the human NI will increase our understanding of its functional role in health and disease.
Subject(s)
Pons , Humans , Pons/metabolism , Male , Hippocampus/chemistry , Hippocampus/metabolism , Female , Relaxin/metabolism , Relaxin/genetics , Aged , Neurons/chemistry , Memory/physiology , Microtubule-Associated Proteins/metabolism , Middle Aged , Aged, 80 and over , Immunohistochemistry , In Situ Hybridization, Fluorescence , Glutamate Decarboxylase/metabolism , Glutamate Decarboxylase/genetics , Receptors, Corticotropin-Releasing HormoneABSTRACT
This study aimed to investigate, for the first time, the potential role of the gigantocellular nucleus, a component of the reticular formation, in the pathogenetic mechanism of Sudden Infant Death Syndrome (SIDS), an event frequently ascribed to failure to arouse from sleep. This research was motivated by previous experimental studies demonstrating the gigantocellular nucleus involvement in regulating the sleep-wake cycle. We analyzed the brains of 48 infants who died suddenly within the first 7 months of life, including 28 SIDS cases and 20 controls. All brains underwent a thorough histological and immunohistochemical examination, focusing specifically on the gigantocellular nucleus. This examination aimed to characterize its developmental cytoarchitecture and tyrosine hydroxylase expression, with particular attention to potential associations with SIDS risk factors. In 68% of SIDS cases, but never in controls, we observed hypoplasia of the pontine portion of the gigantocellular nucleus. Alterations in the catecholaminergic system were present in 61% of SIDS cases but only in 10% of controls. A strong correlation was observed between these findings and maternal smoking in SIDS cases when compared with controls. In conclusion we believe that this study sheds new light on the pathogenetic processes underlying SIDS, particularly in cases associated with maternal smoking during pregnancy.
Subject(s)
Sudden Infant Death , Humans , Sudden Infant Death/pathology , Sudden Infant Death/etiology , Female , Male , Infant , Risk Factors , Case-Control Studies , Infant, Newborn , Pregnancy , Tyrosine 3-Monooxygenase/metabolism , Pons/pathology , Pons/metabolism , Reticular Formation/pathology , Reticular Formation/metabolismABSTRACT
Neurons produce and release neuropeptides to communicate with one another. Despite their importance in brain function, circuit-based mechanisms of peptidergic transmission are poorly understood, primarily due to the lack of tools for monitoring and manipulating neuropeptide release in vivo. Here, we report the development of two genetically encoded tools for investigating peptidergic transmission in behaving mice: a genetically encoded large dense core vesicle (LDCV) sensor that detects presynaptic neuropeptide release and a genetically encoded silencer that specifically degrades neuropeptides inside LDCVs. Using these tools, we show that neuropeptides, not glutamate, encode the unconditioned stimulus in the parabrachial-to-amygdalar threat pathway during Pavlovian threat learning. We also show that neuropeptides play important roles in encoding positive valence and suppressing conditioned threat response in the amygdala-to-parabrachial endogenous opioidergic circuit. These results show that our sensor and silencer for presynaptic peptidergic transmission are reliable tools to investigate neuropeptidergic systems in awake, behaving animals.
Subject(s)
Fear , Neuropeptides , Animals , Neuropeptides/metabolism , Mice , Fear/physiology , Amygdala/metabolism , Amygdala/physiology , Synaptic Transmission , Male , Mice, Inbred C57BL , Pons/metabolism , Pons/physiology , Conditioning, Classical , Presynaptic Terminals/metabolism , Neurons/metabolism , Neurotransmitter Agents/metabolismABSTRACT
The aim of this exploratory study was the assessment of the metabolic profiles of persons with complete spinal cord injury (SCI) in three region-of-interests (pons, cerebellar vermis, and cerebellar hemisphere), with magnetic resonance spectroscopy, and their correlations to clinical scores. Group differences and association between metabolic and clinical scores were examined. Fifteen people with chronic SCI (cSCI), five people with subacute SCI (sSCI) and fourteen healthy controls were included. Group comparison between cSCI and HC showed lower total N-acetyl-aspartate (tNAA) in the pons (p = 0.04) and higher glutathione (GSH) in the cerebellar vermis (p = 0.02). Choline levels in the cerebellar hemisphere were different between cSCI and HC (p = 0.02) and sSCI and HC (p = 0.02). A correlation was reported for choline containing compounds (tCho) to clinical scores in the pons (rho = - 0.55, p = 0.01). tNAA to total creatine (tNAA/tCr ratio) correlated to clinical scores in the cerebellar vermis (rho = 0.61, p = 0.004) and GSH correlated to the independence score in the cerebellar hemisphere (rho = 0.56, p = 0.01). The correlation of tNAA, tCr, tCho and GSH to clinical scores might be indicators on how well the CNS copes with the post-traumatic remodeling and might be further examined as outcome markers.
Subject(s)
Cerebellum , Spinal Cord Injuries , Humans , Proton Magnetic Resonance Spectroscopy , Cerebellum/metabolism , Spinal Cord Injuries/metabolism , Pons/diagnostic imaging , Pons/metabolism , Creatine/metabolism , Metabolome , Choline/metabolism , Receptors, Antigen, T-Cell/metabolism , Aspartic Acid/metabolismABSTRACT
OBJECTIVES: Standardised uptake value ratio (SUVR) is usually obtained by dividing the SUV of the region of interest (ROI) by that of the cerebellar cortex. Cerebellar cortex is not a valid reference in cases where amyloid ß deposition or lesions are present. Only few studies have evaluated the use of other regions as references. We compared the validity of the pons and corpus callosum as reference regions for the quantitative evaluation of brain positron emission tomography (PET) using 11C-PiB compared to the cerebellar cortex. METHODS: We retrospectively evaluated data from 86 subjects with or without Alzheimer's disease (AD). All subjects underwent magnetic resonance imaging, PET imaging, and cognitive function testing. For the quantitative analysis, three-dimensional ROIs were automatically placed, and SUV and SUVR were obtained. We compared these values between AD and healthy control (HC) groups. RESULTS: SUVR data obtained using the pons and corpus callosum as reference regions strongly correlated with that using the cerebellar cortex. The sensitivity and specificity were high when either the pons or corpus callosum was used as the reference region. However, the SUV values of the corpus callosum were different between AD and HC (p < 0.01). CONCLUSIONS: Our data suggest that the pons and corpus callosum might be valid reference regions.
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Corpus Callosum/metabolism , Corpus Callosum/pathology , Retrospective Studies , Positron-Emission Tomography/methods , Brain/metabolism , Pons/diagnostic imaging , Pons/metabolism , Pons/pathology , Aniline CompoundsABSTRACT
Transient receptor potential melastatin 8 (TRPM8), a cold-mediated ion channel, is well known to be expressed in primary sensory neurons; however, limited information is currently available on the distribution of TRPM8-expressing trigeminal nerve fibers in the brainstem. The present study showed the distribution of TRPM8-expressing fibers in the pons and medulla oblongata of the TRPM8 KO mice engineered by knocking in EGFP at the frame of the start codon of TRPM8. In addition, TRPM8-expressing fibers were also observed in the brachium pontis, middle cerebellar peduncle, the sensory root of the trigeminal nerve, and spinal trigeminal tract (sp5). Furthermore, TRPM8-expressing nerve fibers surrounded the somata of HuC/D-positive neurons in the sp5. Moreover, the distribution of TRPM8-expressing fibers from rostral to caudal was visualized in sagittal sections of the mouse brain. The present results also revealed that a high number of TRPM8-expressing fibers colocalized with CTB-labeled fibers in the sp5 following an injection of CTB into the whisker compared to mice's eye and ear. These results show the distribution pathway of TRPM8-expressing fibers in the pons and medulla oblongata and possible involvement in peripheral signaling from the trigeminal nerve.
Subject(s)
TRPM Cation Channels , Animals , Medulla Oblongata/metabolism , Mice , Neurons/metabolism , Pons/metabolism , TRPM Cation Channels/metabolism , Trigeminal Nerve/metabolismABSTRACT
Brain injury leads to an excitatory phase followed by an inhibitory phase in the brain. The clinical sequelae caused by cerebral injury seem to be a response to remote functional inhibition of cerebral nuclei located far from the motor cortex but anatomically related to the injury site. It appears that such functional inhibition is mediated by an increase in lipid peroxidation (LP). To test this hypothesis, we report data from 80 rats that were allocated to the following groups: the sham group (n = 40), in which rats received an intracortical infusion of artificial cerebrospinal fluid (CSF); the injury group (n = 20), in which rats received CSF containing ferrous chloride (FeCl2, 50 mM); and the recovery group (n = 20), in which rats were injured and allowed to recover. Beam-walking, sensorimotor and spontaneous motor activity tests were performed to evaluate motor performance after injury. Lipid fluorescent products (LFPs) were measured in the pons. The total pontine contents of glutamate (GLU), glutamine (GLN) and gamma-aminobutyric acid (GABA) were also measured. In injured rats, the motor deficits, LFPs and total GABA and GLN contents in the pons were increased, while the GLU level was decreased. In contrast, in recovering rats, none of the studied variables were significantly different from those in sham rats. Thus, motor impairment after cortical injury seems to be mediated by an inhibitory pontine response, and functional recovery may result from a pontine restoration of the GLN-GLU-GABA cycle, while LP may be a primary mechanism leading to remote pontine inhibition after cortical injury.
Subject(s)
Brain Injuries/physiopathology , Glutamic Acid/metabolism , Glutamine/metabolism , Motor Cortex/physiology , Pons/metabolism , Recovery of Function , gamma-Aminobutyric Acid/metabolism , Animals , Lipid Peroxidation , Male , Motor Disorders/physiopathology , Oxidative Stress , Rats , Rats, WistarABSTRACT
Locus coeruleus (LC) neurodegeneration is associated with cognitive deterioration during the transition from normal cognition to mild cognitive impairment (MCI) and Alzheimer disease (AD). However, the extent to which LC degenerative processes differentiate cognitively normal, "resilient" subjects bearing a high AD pathological burden from those with MCI or AD remains unclear. We approached this problem by quantifying the number of LC neurons and the percentage of LC neurons bearing AT8 tau pathology, TDP-43 pathology, or a marker for DNA/RNA oxidative damage, in well-characterized subjects diagnosed as normal cognition-low AD pathology (NC-LP), NC-high AD pathology (NC-HP), MCI, or mild/moderate AD. In addition, the severity of pontine arteriolosclerosis in each subject was compared across the groups. There was a trend for a step-wise â¼20% loss of LC neuron number between the NC-LP, NC-HP and MCI subjects despite a successive, significant â¼80%-100% increase in tau pathology between these groups. In contrast, increasing pontine arteriolosclerosis severity scores and LC oxidative stress burden significantly separated the NC-LP/HP and MCI/AD groups via comparative, correlation, and regression analysis. Pontine perfusion, as well as LC neuronal metabolic and redox function, may impact noradrenergic LC modulation of cognition during the preclinical and prodromal stages of AD.
Subject(s)
Arteriolosclerosis/pathology , Cognitive Dysfunction/pathology , Locus Coeruleus/pathology , Oxidative Stress/physiology , Pons/pathology , Resilience, Psychological/physiology , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/psychology , Arteriolosclerosis/metabolism , Arteriolosclerosis/psychology , Brief Psychiatric Rating Scale , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/psychology , Cohort Studies , Diagnosis, Differential , Female , Humans , Locus Coeruleus/metabolism , Male , Pons/metabolismABSTRACT
BACKGROUND AND PURPOSE: Studies associate repeat gadolinium-based contrast agent administration with T1 shortening in the dentate nucleus and globus pallidus, indicating CNS gadolinium deposition, most strongly with linear agents but also reportedly with macrocyclics. Renal impairment effects on long-term CNS gadolinium deposition remain underexplored. We investigated the relationship between signal intensity changes and renal function in patients who received ≥10 administrations of the macrocyclic agent gadobutrol. MATERIALS AND METHODS: Patients who underwent ≥10 brain MR imaging examinations with administration of intravenous gadobutrol between February 1, 2014, and January 1, 2018, were included in this retrospective study. Dentate nucleus-to-pons and globus pallidus-to-thalamus signal intensity ratios were calculated, and correlations were calculated between the estimated glomerular filtration rate (minimum and mean) and the percentage change in signal intensity ratios from the first to last scan. Partial correlations were calculated to control for potential confounders. RESULTS: One hundred thirty-one patients (73 women; mean age at last scan, 55.9 years) showed a mean percentage change of the dentate nucleus-to-pons of 0.31%, a mean percentage change of the globus pallidus-to-thalamus of 0.15%, a mean minimum estimated glomerular filtration rate of 69.65 (range, 10.16-132.26), and a mean average estimated glomerular filtration rate at 89.48 (range, 38.24-145.93). No significant association was found between the estimated glomerular filtration rate and percentage change of the dentate nucleus-to-pons (minimum estimated glomerular filtration rate, r = -0.09, P = .28; average estimated glomerular filtration rate, r = -0.09, P = .30,) or percentage change of the globus pallidus-to-thalamus (r = 0.07, P = .43; r = 0.07, P = .40). When we controlled for age, sex, number of scans, and total dose, there were no significant associations between the estimated glomerular filtration rate and the percentage change of the dentate nucleus-to-pons (r = 0.16, P = .07; r = 0.15, P = .08) or percentage change of the globus pallidus-to-thalamus (r = -0.14, P = .12; r = -0.15, P = .09). CONCLUSIONS: In patients receiving an average of 12 intravenous gadobutrol administrations, no correlation was found between renal function and signal intensity ratio changes, even in those with mild or moderate renal impairment.
Subject(s)
Central Nervous System/metabolism , Contrast Media/adverse effects , Gadolinium/metabolism , Kidney/metabolism , Organometallic Compounds/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Cerebellar Nuclei/metabolism , Child , Child, Preschool , Contrast Media/pharmacokinetics , Female , Glomerular Filtration Rate , Humans , Kidney Diseases/metabolism , Kidney Function Tests , Magnetic Resonance Imaging/adverse effects , Magnetic Resonance Imaging/methods , Male , Middle Aged , Organometallic Compounds/pharmacokinetics , Pons/metabolism , Retrospective Studies , Young AdultABSTRACT
BACKGROUND: Cannabidiol (CBD), a non-psychotropic constituent of Cannabis sativa, has shown therapeutic promises by modulating several pathological conditions, including pain, epilepsy autism, among others. However, the molecular mechanism of action of CBD remains unknown and recent data suggest the engagement on CBD´s effects of nuclear elements, such as histone activity. AIM: This study assessed the changes in the post-translational modification (PTM) on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions of rats after the administration of CBD (20 mg/Kg/i.p.). OBJECTIVE: To evaluate the effects on the PTM of histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels in the cerebral cortex, hypothalamus and pons of CBD-treated rats. METHODS: Ten adult rats were randomly assigned into 2 groups: Control or CBD (20 mg/Kg/i.p). Animals were sacrificed after treatments and brains were collected for dissections of the cerebral cortex, hypothalamus and pons. Samples were analyzed for PTM on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels by Western blot procedure. RESULTS: CBD increased the PTM levels on the histones H3K4Me3, H3K9ac, and H3K27Me3 in the cerebral cortex whereas no significant differences were found in H3K9Me2 and H3K36Me2. In addition, in the hypothalamus, CBD decreased the contents of H3K9ac while no significant effects were observed in H3K4Me3, H3K9Me2, H3K27Me3, and H3K36Me2. Lastly, in the pons, CBD- treated rats showed a significant decline on the PTM levels of H3K4Me3 whereas no statistical differences were found in H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2. CONCLUSION: The study showed that CBD induced differential effects in levels of PTM on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions.
Subject(s)
Cannabidiol , Histones , Animals , Cannabidiol/pharmacology , Cerebral Cortex/metabolism , Histones/genetics , Histones/metabolism , Hypothalamus/metabolism , Pons/metabolism , Protein Processing, Post-Translational , RatsABSTRACT
Migraine is a complex disorder, involving peripheral and central brain structures, where mechanisms and site of attack initiation are an unresolved puzzle. While abnormal pontine neuronal activation during migraine attacks has been reported, exact implication of this finding is unknown. Evidence suggests an important role of glutamate in migraine, implying a possible association of pontine hyperactivity to increased glutamate levels. Migraine without aura patients were scanned during attacks after calcitonin gene-related peptide and sildenafil in a double-blind, randomized, double-dummy, cross-over design, on two separate study days, by proton magnetic resonance spectroscopy and pseudo-continuous arterial spin labeling at 3T. Headache characteristics were recorded until 24 h after drug administrations. Twenty-six patients were scanned during migraine, yielding a total of 41 attacks. Cerebral blood flow increased in dorsolateral pons, ipsilateral to pain side during attacks, compared to outside attacks (13.6%, p = 0.009). Glutamate levels in the same area remained unchanged during attacks (p = 0.873), while total creatine levels increased (3.5%, p = 0.041). In conclusion, dorsolateral pontine activation during migraine was not associated with higher glutamate levels. However, the concurrently increased total creatine levels may suggest an altered energy metabolism, which should be investigated in future studies to elucidate the role of pons in acute migraine.
Subject(s)
Glutamic Acid/metabolism , Magnetic Resonance Imaging , Migraine Disorders/pathology , Pons/metabolism , Proton Magnetic Resonance Spectroscopy , Adult , Arteries/chemistry , Arteries/physiopathology , Calcitonin Gene-Related Peptide/pharmacology , Calcitonin Gene-Related Peptide/therapeutic use , Cerebrovascular Circulation/drug effects , Cerebrovascular Circulation/physiology , Creatine/metabolism , Double-Blind Method , Energy Metabolism/drug effects , Female , Humans , Male , Middle Aged , Migraine Disorders/drug therapy , Pons/blood supply , Pons/physiopathology , Sildenafil Citrate/pharmacology , Sildenafil Citrate/therapeutic use , Spin Labels , Vasodilator Agents/pharmacology , Vasodilator Agents/therapeutic use , Young AdultABSTRACT
BACKGROUND: Recent studies have demonstrated a complex and dynamic neural crosstalk between the heart and brain. A heart-brain interaction has been described regarding cardiac ischemia, but the cerebral metabolic mechanisms involved are unknown. METHODS: Male Sprague Dawley rats were randomly allocated into 2 groups: those receiving myocardial ischemia-reperfusion surgery (IR group, n =10) and surgical controls (Con group, n=10). These patterns of metabolic abnormalities in different brain regions were assessed using proton magnetic resonance spectroscopy (PMRS). RESULTS: Results assessed by echocardiography showed resultant cardiac dysfunction following heart ischemia-reperfusion. Compared with the control group, the altered metabolites in the IR group were taurine and choline, and differences mainly occurred in the thalamus and brainstem. CONCLUSIONS: Alterations in cerebral taurine and choline are important findings offering new avenues to explore neuroprotective strategies for myocardial ischemia-reperfusion injury. These results provide preliminary evidence for understanding the cerebral metabolic process underlying myocardial ischemia-reperfusion injury in rats.
Subject(s)
Brain/metabolism , Myocardial Reperfusion Injury/metabolism , Animals , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Choline , Chytridiomycota/metabolism , Corpus Striatum/metabolism , Echocardiography , Inositol/metabolism , Male , Medulla Oblongata/metabolism , Myocardial Reperfusion Injury/diagnostic imaging , Parietal Lobe/metabolism , Pons/metabolism , Proton Magnetic Resonance Spectroscopy , Rats , Rats, Sprague-Dawley , Taurine , Thalamus/metabolism , gamma-Aminobutyric Acid/metabolismABSTRACT
INTRODUCTION: To investigate whether neurodegeneration underlying Parkinson's disease (PD) accounts for a substantial proportion of cases of minimal parkinsonism in the elderly. METHODS: We recruited 48 consecutive subjects with minimal parkinsonism who visited the clinic with cognitive complaints. All subjects did not show findings compatible with PD on 18F-FP-CIT PET scans, and had no evidence of other neurodegenerative disorders. Striatal dopamine transporter (DAT) availability was quantified, and mean diffusivity (MD) values in the pons were calculated to characterize structural damage using diffusion tensor imaging. Additionally, 35 patients with PD and 21 healthy controls were included as reference groups. RESULTS: Individuals with minimal parkinsonism (mean age, 73.23 ± 7.03 years) exhibited mild decrease in DAT availability in the posterior putamen, which was at a level between that of healthy controls and patients with PD. DAT availability in the caudate and anterior putamen was also mildly decreased in the minimal parkinsonism group. Individuals with minimal parkinsonism also tended to have higher MD values in the pons compared to healthy controls. CONCLUSIONS: Our results suggest that a substantial proportion of minimal parkinsonism is associated with nigrostriatal dopamine depletion and pontine structural damage, which may be related to the disease process of prodromal PD.
Subject(s)
Aging , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine/metabolism , Neostriatum , Parkinsonian Disorders , Pons , Substantia Nigra , Aged , Aged, 80 and over , Aging/metabolism , Aging/pathology , Diffusion Tensor Imaging , Female , Humans , Male , Neostriatum/diagnostic imaging , Neostriatum/metabolism , Neostriatum/pathology , Parkinsonian Disorders/diagnostic imaging , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/pathology , Pons/diagnostic imaging , Pons/metabolism , Pons/pathology , Positron-Emission Tomography , Substantia Nigra/diagnostic imaging , Substantia Nigra/metabolism , Substantia Nigra/pathologyABSTRACT
Accumulating evidence indicates that disruption of galanin signaling is associated with neuropsychiatric disease, but the precise functions of this neuropeptide remain largely unresolved due to lack of tools for experimentally disrupting its transmission in a cell type-specific manner. To examine the function of galanin in the noradrenergic system, we generated and crossed two novel knock-in mouse lines to create animals lacking galanin specifically in noradrenergic neurons (GalcKO-Dbh). We observed reduced levels of galanin peptide in pons, hippocampus, and prefrontal cortex of GalcKO-Dbh mice, indicating that noradrenergic neurons are a significant source of galanin to those brain regions, while midbrain and hypothalamic galanin levels were comparable to littermate controls. In these same brain regions, we observed no change in levels of norepinephrine or its major metabolite at baseline or after an acute stressor, suggesting that loss of galanin does not affect noradrenergic synthesis or turnover. GalcKO-Dbh mice had normal performance in tests of depression, learning, and motor-related behavior, but had an altered response in some anxiety-related tasks. Specifically, GalcKO-Dbh mice showed increased marble and shock probe burying and had a reduced latency to eat in a novel environment, indicative of a more proactive coping strategy. Together, these findings indicate that noradrenergic neurons provide a significant source of galanin to discrete brain areas, and noradrenergic-specific galanin opposes adaptive coping responses.
Subject(s)
Adaptation, Psychological/physiology , Adrenergic Neurons/metabolism , Brain/metabolism , Galanin/metabolism , Animals , Female , Galanin/genetics , Gene Knock-In Techniques , Hippocampus/metabolism , Male , Mice, Knockout , Pons/metabolism , Prefrontal Cortex/metabolismABSTRACT
BACKGROUND: Canavan disease is a genetic neurodegenerative leukodystrophy that results in the spongy degeneration of the white matter. Its key clinical features in the infantile form are developmental delay, visual problems and macrocephaly. Congenital and juvenile forms have also been described. PATIENT DESCRIPTION: We report on a 13-year-old boy who is a high school student in a public school. He was diagnosed with juvenile Canavan disease, presenting with intentional tremor as the only clinical finding. RESULTS: Magnetic resonance imaging revealed mainly the involvement of the caudate nucleus and pons extending to the mesencephalon and also the putamen and the thalamus, with no apparent signal increase in the cerebral white matter. A homozygous p.Gly274Arg (c.820A>G) missense mutation was identified. CONCLUSION: Juvenile Canavan disease with mainly pons involvement has not been published before. Pons, caudate nucleus and basal ganglia involvement without any white matter being involved could be expected in juvenile Canavan disease as a rare form of the disease.
Subject(s)
Canavan Disease/genetics , Canavan Disease/pathology , Pons/pathology , Adolescent , Amidohydrolases/genetics , Basal Ganglia/pathology , Brain/pathology , Canavan Disease/diagnosis , Developmental Disabilities/pathology , Humans , Magnetic Resonance Imaging , Male , Megalencephaly , Pons/metabolism , White Matter/pathologyABSTRACT
OBJECTIVE: We aimed to evaluate the association between the availability of serotonin transporter (SERT) measured by ioflupane-DaTSCAN (123I-FP-CIT) and imaged by single photon emission tomography (SPET) and memory function in healthy subjects. SUBJECTS AND METHODS: Specific binding of 123I-FP-CIT indicating SERT was achieved using a region of interest analysis. Spherical volumes of interest for midbrain and pons were defined. The cerebellum was chosen as a reference region. Specific binding ratios (SBR) in midbrain and pons representing SERT availability were measured as follows: SBR=(target-cerebellum)/cerebellum. A hundred and eighty-one healthy subjects (117 male, 64 female) were included in this study. RESULTS: Specific binding ratios of both midbrain (P=0.025) and pons (P=0.006) of males was higher than that of females. None of the SBR showed a correlation with age both in males: (midbrain; P=0.736, pons; P=0.875) and in females (midbrain; P=0.294, pons; P=0.170). In all our cases, SERT availability of midbrain correlated positively with total recall score (rho=0.159, P=0.033), and delayed recall score (rho=0.149, P=0.046). In females, the correlation between SERT availability in midbrain and delayed recall score was significant (rho=0.320, P=0.010), however, not in males (rho=0.112, P=0.229). CONCLUSION: In conclusion, we demonstrated that SERT availability was associated with memory function in healthy females from the PPMI database. Further studies are needed to clarify underlying mechanisms of this phenomenon.
Subject(s)
Healthy Volunteers , Memory , Mesencephalon/physiology , Pons/physiology , Serotonin Plasma Membrane Transport Proteins/metabolism , Female , Humans , Male , Mesencephalon/diagnostic imaging , Mesencephalon/metabolism , Middle Aged , Pons/diagnostic imaging , Pons/metabolism , Tomography, Emission-Computed, Single-Photon , TropanesABSTRACT
Development of effective targeted cancer therapies is fundamentally limited by our molecular understanding of disease pathogenesis. Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy of the childhood pons characterized by a unique substitution to methionine in histone H3 at lysine 27 (H3K27M) that results in globally altered epigenetic marks and oncogenic transcription. Through primary DIPG tumor characterization and isogenic oncohistone expression, we show that the same H3K27M mutation displays distinct modes of oncogenic reprogramming and establishes distinct enhancer architecture depending upon both the variant of histone H3 and the cell context in which the mutation occurs. Compared with non-malignant pediatric pontine tissue, we identify and functionally validate both shared and variant-specific pathophysiology. Altogether, we provide a powerful resource of epigenomic data in 25 primary DIPG samples and 5 rare normal pediatric pontine tissue samples, revealing clinically relevant functional distinctions previously unidentified in DIPG.
Subject(s)
Diffuse Intrinsic Pontine Glioma/genetics , Histones/genetics , Brain/pathology , Brain Neoplasms/genetics , Cellular Reprogramming/genetics , Diffuse Intrinsic Pontine Glioma/metabolism , Enhancer Elements, Genetic/genetics , Epigenesis, Genetic/genetics , Epigenomics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/genetics , Glioma/genetics , Glioma/metabolism , Humans , Lysine/genetics , Mutation/genetics , Pons/metabolism , Signal Transduction , Transcriptome/physiologyABSTRACT
Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumor-related death among children. Until now, there is still a lack of effective therapy with prolonged overall survival for this disease. A typical strategy for preclinical cancer research is to find out the molecular differences between tumor tissue and para-tumor normal tissue, in order to identify potential therapeutic targets. Unfortunately, it is impossible to obtain normal tissue for DIPG because of the vital functions of the pons. Here we report the human fetal hindbrain-derived neural progenitor cells (pontine progenitor cells, PPCs) as normal control cells for DIPG. The PPCs not only harbored similar cell biological and molecular signatures as DIPG glioma stem cells, but also had the potential to be immortalized by the DIPG-specific mutation H3K27M in vitro. These findings provide researchers with a candidate normal control and a potential medicine carrier for preclinical research on DIPG.
Subject(s)
Brain Stem Neoplasms/metabolism , Glioma/metabolism , Neural Stem Cells/metabolism , Pons/metabolism , Animals , Brain Stem Neoplasms/genetics , Brain Stem Neoplasms/pathology , Cell Line, Tumor , Cellular Senescence , Female , Glioma/genetics , Glioma/pathology , Histones/genetics , Humans , Mice, Inbred NOD , Mice, SCID , Neoplasm Transplantation , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Neural Stem Cells/drug effects , Neural Stem Cells/pathology , Pons/embryology , Pons/pathology , Primary Cell CultureABSTRACT
OBJECTIVE: To determine whether proton magnetic resonance spectroscopy (1H-MRS) can detect neurochemical changes in amyotrophic lateral sclerosis (ALS) associated with heterogeneous functional decline. METHODS: Nineteen participants with early-stage ALS and 18 age-matched and sex ratio-matched controls underwent ultra-high field 1H-MRS scans of the upper limb motor cortex and pons, ALS Functional Rating Scale-Revised (ALSFRS-R total, upper limb and bulbar) and upper motor neuron burden assessments in a longitudinal observational study design with follow-up assessments at 6 and 12 months. Slopes of neurochemical levels over time were compared between patient subgroups classified by the rate of upper limb or bulbar functional decline. 1H-MRS and clinical ratings at baseline were assessed for ability to predict study withdrawal due to disease progression. RESULTS: Motor cortex total N-acetylaspartate to myo-inositol ratio (tNAA:mIns) significantly declined in patients who worsened in upper limb function over the follow-up period (n=9, p=0.002). Pons glutamate + glutamine significantly increased in patients who worsened in bulbar function (n=6, p<0.0001). Neurochemical levels did not change in patients with stable function (n=5-6) or in healthy controls (n=14-16) over time. Motor cortex tNAA:mIns and ALSFRS-R at baseline were significantly lower in patients who withdrew from follow-up due to disease progression (n=6) compared with patients who completed the 12-month scan (n=10) (p<0.001 for tNAA:mIns; p<0.01 for ALSFRS-R), with a substantially larger overlap in ALSFRS-R between groups. CONCLUSION: Neurochemical changes in motor areas of the brain are associated with functional decline in corresponding body regions. 1H-MRS was a better predictor of study withdrawal due to ALS progression than ALSFRS-R.
Subject(s)
Amyotrophic Lateral Sclerosis/etiology , Amyotrophic Lateral Sclerosis/metabolism , Adult , Aged , Amyotrophic Lateral Sclerosis/diagnosis , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Case-Control Studies , Disease Progression , Female , Glutamic Acid/metabolism , Humans , Longitudinal Studies , Male , Middle Aged , Motor Cortex/metabolism , Motor Neurons/metabolism , Pons/metabolism , Prognosis , Proton Magnetic Resonance Spectroscopy , Upper ExtremityABSTRACT
The deposition of the amyloid ß-protein (Aß) in senile plaques is one of the histopathological hallmarks of Alzheimer's disease (AD). Aß-plaques arise first in neocortical areas and, then, expand into further brain regions in a process described by 5 phases. Since it is possible to identify amyloid pathology with radioactive-labeled tracers by positron emission tomography (PET) the question arises whether it is possible to distinguish the neuropathological Aß-phases with amyloid PET imaging. To address this question we reassessed 97 cases of the end-of-life study cohort of the phase 3 [18F]flutemetamol trial (ClinicalTrials.gov identifiers NCT01165554, and NCT02090855) by combining the standardized uptake value ratios (SUVRs) with pons as reference region for cortical and caudate nucleus-related [18F]flutemetamol-retention. We tested them for their prediction of the neuropathological pattern found at autopsy. By defining threshold levels for cortical and caudate nucleus SUVRs we could distinguish different levels of [18F]flutemetamol uptake termed PET-Aß phase estimates. When comparing these PET-Aß phase estimates with the neuropathological Aß-phases we found that PET-Aß phase estimate 0 corresponded with Aß-phases 0-2, 1 with Aß-phase 3, 2 with Aß-phase 4, and 3 with Aß-phase 5. Classification using the PET-Aß phase estimates predicted the correct Aß-phase in 72.16% of the cases studied here. Bootstrap analysis was used to confirm the robustness of the estimates around this association. When allowing a range of ± 1 phase for a given Aß-phase correct classification was given in 96.91% of the cases. In doing so, we provide a novel method to convert SUVR-levels into PET-Aß phase estimates that can be easily translated into neuropathological phases of Aß-deposition. This method allows direct conclusions about the pathological distribution of amyloid plaques (Aß-phases) in vivo. Accordingly, this method may be ideally suited to detect early preclinical AD-patients, to follow them with disease progression, and to provide a more precise prognosis for them based on the knowledge about the underlying pathological phase of the disease.