157 results on '"Herkenham M"'
Search Results
2. Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress
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Schloesser, R J, Lehmann, M, Martinowich, K, Manji, H K, and Herkenham, M
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- 2010
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3. Expression of a killer cell receptor-like gene in plastic regions of the central nervous system
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Bryceson, Y.T., Foster, J.A., Kuppusamy, S.P., Herkenham, M., and Long, E.O.
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- 2005
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4. Toxicity of glucosylsphingosine (glucopsychosine) to cultured neuronal cells: a model system for assessing neuronal damage in Gaucher disease type 2 and 3
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Schueler, U.H, Kolter, T, Kaneski, C.R, Blusztajn, J.K, Herkenham, M, Sandhoff, K, and Brady, R.O
- Published
- 2003
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5. Retention of Offender DNA Samples Necessary to Ensure and Monitor Quality of Forensic DNA Efforts: Appropriate Safeguards Exist to Protect the DNA Samples from Misuse.
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Herkenham, M. Dawn
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FORENSIC sciences , *DNA data banks , *DNA fingerprinting laws , *CRIMINAL investigation , *TISSUE banks - Abstract
Analyzes the retention of offender DNA samples necessary to ensure and monitor quality of forensic DNA efforts. Background on the establishment of state and national DNA databases; Retention of offender DNA samples; Information on the limited disclosure requirements of the DNA Identification Act.
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- 2006
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6. Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism.
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Markey, S. P., Johannessen, J. N., Chiueh, C. C., Burns, R. S., and Herkenham, M. A.
- Published
- 1984
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7. Cautionary notes on the use of NF-κB p65 and p50 antibodies for CNS studies
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Listwak Samuel J, Brown Pierre, Rathore Priyanka, and Herkenham Miles
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NF-κB ,transcription factor ,immunohistochemistry ,antibody specificity ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background The characterization and cellular localization of transcription factors like NF-κB requires the use of antibodies for western blots and immunohistochemistry. However, if target protein levels are low and the antibodies not well characterized, false positive data can result. In studies of NF-κB activity in the CNS, antibodies detecting NF-κB proteins have been used to support the finding that NF-κB is constitutively active in neurons, and activity levels are further increased by neurotoxic treatments, glutamate stimulation, or elevated synaptic activity. The specificity of the antibodies used was analyzed in this study. Methods Selectivity and nonselectivity of commonly used commercial and non-commercial p50 and p65 antibodies were demonstrated in western blot assays conducted in tissues from mutant gene knockout mice lacking the target proteins. Results A few antibodies for p50 and p65 each mark a single band at the appropriate molecular weight in gels containing proteins from wildtype tissue, and this band is absent in proteins from knockout tissues. Several antibodies mark proteins that are present in knockout tissues, indicating that they are nonspecific. These include antibodies raised against the peptide sequence containing the nuclear localization signals of p65 (MAB3026; Chemicon) and p50 (sc-114; Santa Cruz). Some antibodies that recognize target proteins at the correct molecular weight still fail in western blot analysis because they also mark additional proteins and inconsistently so. We show that the criterion for validation by use of blocking peptides can still fail the test of specificity, as demonstrated for several antibodies raised against p65 phosphorylated at serine 276. Finally, even antibodies that show specificity in western blots produce nonspecific neuronal staining by immunohistochemistry. Conclusions We note that many of the findings in the literature about neuronal NF-κB are based on data garnered with antibodies that are not selective for the NF-κB subunit proteins p65 and p50. The data urge caution in interpreting studies of neuronal NF-κB activity in the brain.
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- 2011
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8. Minimal NF-κB activity in neurons.
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Listwak, S.J., Rathore, P., and Herkenham, M.
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NF-kappa B , *NEUROPHYSIOLOGY , *LIVER cells , *TUMOR necrosis factors , *BRAIN stimulation , *PHYSIOLOGICAL effects of glutamic acid , *CHEMOKINES - Abstract
Highlights: [•] In neurons, constitutive levels of the NF-κB subunit p65 were lower than in mixed brain cells or liver cells. [•] TNFα was the most effective stimulus, but levels of NF-κB activation by TNFα were far lower in neurons than in other cells. [•] Glutamate was not an effective activator of neuronal NF-κB. [•] Other reported activators did not stimulate neuronal NF-κB activity. [•] Chemokine mRNAs were the most NF-κB-responsive genes in neurons. [ABSTRACT FROM AUTHOR]
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- 2013
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9. Intracerebroventricular but not intravenous interleukin-1β induces widespread vascular-mediated leukocyte infiltration and immune signal mRNA expression followed by brain-wide glial activation
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Proescholdt, M.G., Chakravarty, S., Foster, J.A., Foti, S.B., Briley, E.M., and Herkenham, M.
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INTERLEUKIN-1 , *CYCLOOXYGENASE 2 , *MESSENGER RNA - Abstract
Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that appears in brain and cerebrospinal fluid following peripheral immune challenges and central infections or injury. We examined the consequences of i.c.v. infusion of IL-1β on mRNA expression of several immune markers and on recruitment of peripheral leukocytes. Awake rats were infused with IL-1β (100 ng/rat) into the lateral ventricle, and 0.5, 2, 4, 8, 12, or 24 h later, animals were killed and their fresh-frozen brains processed for in situ hybridization and immunohistochemistry. Widespread vascular expression of inhibitory factor κBα (IκBα, marker of nuclear factor κBα transcriptional activity) and inducible cyclooxygenase (COX-2) mRNAs at 0.5–2 h was credited to movement of IL-1β along ventricular, subarachnoid, and perivascular pathways to target endothelia that express type 1 IL-1 receptor mRNA. Induction of monocyte chemoattractant protein-1 mRNA and intercellular adhesion molecule-1 (ICAM-1) immunostaining on endothelia began at 0.5–2 h. Leukocytes (neutrophils and monocytes, recognized by morphology and CD45 and ED1 immunostaining) appeared in meninges and blood vessels at 2–4 h and diffusely penetrated the parenchyma at 8–24 h. The leukocytes strongly expressed IL-1β and inducible nitric oxide synthase mRNAs. Beginning at 4–12 h, astrocytes (glial acidic fibrillary protein mRNA and protein and c-fos mRNA) and microglia (ionized calcium-binding adaptor molecule 1 mRNA and protein) showed widespread activation. Other rats received i.v. IL-1β (6 μg/kg). Their brains showed induction of IκBα and COX-2 mRNAs in the vasculature at 2 h but none of the other sequelae.In summary, our data indicate that IL-1β in the cerebrospinal fluid reaches its target receptors on the endothelia via perivascular volume transmission, up-regulates ICAM-1, and triggers a targeted leukocyte emigration and widespread glial activation stimulated perhaps by pro-inflammatory molecules expressed by leukocytes. The dramatic difference between i.c.v. and i.v. routes of administration underscores the potency of IL-1β within the brain to dynamically affect the cellular trafficking component of ‘immune privilege’. [Copyright &y& Elsevier]
- Published
- 2002
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10. Tritiated 2-deoxy-D-glucose: a high-resolution marker for autoradiographic localization of brain metabolism
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Herkenham, M
- Published
- 1984
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11. Chronic social defeat stress induces meningeal neutrophilia via type I interferon signaling.
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Kigar SL, Lynall ME, DePuyt AE, Atkinson R, Sun VH, Samuels JD, Eassa NE, Poffenberger CN, Lehmann ML, Listwak SJ, Livak F, Elkahloun AG, Clatworthy MR, Bullmore ET, and Herkenham M
- Abstract
Animal models of stress and stress-related disorders are also associated with blood neutrophilia. The mechanistic relevance of this to symptoms or behavior is unclear. We used cytometry, immunohistochemistry, whole tissue clearing, and single-cell sequencing to characterize the meningeal immune response to chronic social defeat (CSD) stress in mice. We find that chronic, but not acute, stress causes meningeal neutrophil accumulation, and CSD increases neutrophil trafficking in vascular channels emanating from skull bone marrow (BM). Transcriptional analysis suggested CSD increases type I interferon (IFN-I) signaling in meningeal neutrophils. Blocking this pathway via the IFN-I receptor (IFNAR) protected against the anhedonic and anxiogenic effects of CSD stress, potentially through reduced infiltration of IFNAR
+ neutrophils into the meninges from skull BM. Our identification of IFN-I signaling as a putative mediator of meningeal neutrophil recruitment may facilitate development of new therapies for stress-related disorders., Competing Interests: Competing interests E.T.B. is a consultant for Sosei Heptares. M.L.L. is currently employed at AstraZeneca but was an employee at NIH at the time this work was conducted. The other authors have no conflicts to declare.- Published
- 2024
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12. Chronic social defeat alters brain vascular-associated cell gene expression patterns leading to vascular dysfunction and immune system activation.
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Samuels JD, Lotstein ML, Lehmann ML, Elkahloun AG, Banerjee S, and Herkenham M
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- Animals, Mice, Immune System, Blood-Brain Barrier, Gene Expression, Social Defeat, Brain
- Abstract
Brain vascular integrity is critical for brain health, and its disruption is implicated in many brain pathologies, including psychiatric disorders. Brain-vascular barriers are a complex cellular landscape composed of endothelial, glial, mural, and immune cells. Yet currently, little is known about these brain vascular-associated cells (BVACs) in health and disease. Previously, we demonstrated that 14 days of chronic social defeat (CSD), a mouse paradigm that produces anxiety and depressive-like behaviors, causes cerebrovascular damage in the form of scattered microbleeds. Here, we developed a technique to isolate barrier-related cells from the mouse brain and subjected the isolated cells to single-cell RNA sequencing. Using this isolation technique, we found an enrichment in BVAC populations, including distinct subsets of endothelial and microglial cells. In CSD compared to non-stress, home-cage control, differential gene expression patterns disclosed biological pathways involving vascular dysfunction, vascular healing, and immune system activation. Overall, our work demonstrates a unique technique to study BVAC populations from fresh brain tissue and suggests that neurovascular dysfunction is a key driver of psychosocial stress-induced brain pathology., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2023
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13. CCR2 monocytes repair cerebrovascular damage caused by chronic social defeat stress.
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Lehmann ML, Samuels JD, Kigar SL, Poffenberger CN, Lotstein ML, and Herkenham M
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- Animals, Chemokine CCL2 metabolism, Endothelial Cells metabolism, Fibrinogen metabolism, Mice, Mice, Inbred C57BL, Social Defeat, Monocytes metabolism, Receptors, CCR2 metabolism
- Abstract
Immune surveillance of the brain plays an important role in health and disease. Peripheral leukocytes patrol blood-brain barrier interfaces, and after injury, monocytes cross the cerebrovasculature and follow a pattern of pro- and anti-inflammatory activity leading to tissue repair. We have shown that chronic social defeat (CSD) causes scattered vasculature disruptions. Here, we assessed CCR2
+ monocyte trafficking to the vascular injury sites in Ccr2wt/rfp reporter mice both during CSD and one week following CSD cessation. We found that CSD for 14 days induced microhemorrhages where plasma fibrinogen leaked into perivascular spaces, but it did not affect the distribution or density of CCR2rfp+ monocytes in the brain. However, after recovery from CSD, many vascularly adhered CCR2+ cells were detected, and gene expression of the CCR2 chemokine receptor ligands CCL7 and CCL12, but not CCL2, was elevated in endothelial cells. Adhered CCR2+ cells were mostly the non-classical, anti-inflammatory Ly6Clo type, and they phagocytosed fibrinogen in perivascular spaces. In CCR2-deficient Ccr2rfp/rfp mice, fibrinogen levels remained elevated in recovery. Fibrinogen infused intracerebroventricularly induced CCR2+ cells to adhere to the vasculature and phagocytose perivascular fibrinogen in Ccr2wt/rfp but not Ccr2rfp/rfp mice. Depletion of monocytes with clodronate liposomes during CSD recovery prevented fibrinogen clearance and blocked behavioral recovery. We hypothesize that peripheral CCR2+ monocytes are not elevated in the brain on day 14 at the end of CSD and do not contribute to its behavioral effects at that time, but in recovery following cessation of stress, they enter the brain and exert restorative functions mediating vascular repair and normalization of behavior., (Copyright © 2022. Published by Elsevier Inc.)- Published
- 2022
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14. B-cells are abnormal in psychosocial stress and regulate meningeal myeloid cell activation.
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Lynall ME, Kigar SL, Lehmann ML, DePuyt AE, Tuong ZK, Listwak SJ, Elkahloun AG, Bullmore ET, Herkenham M, and Clatworthy MR
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- Animals, Antigen Presentation, Mice, Mice, Inbred C57BL, Myeloid Cells, Stress, Psychological, B-Lymphocytes, Meninges
- Abstract
There is increasing interest in how immune cells, including those within the meninges at the blood-brain interface, influence brain function and mood disorders, but little data on humoral immunity in this context. Here, we show that in mice exposed to psychosocial stress, there is increased splenic B cell activation and secretion of the immunoregulatory cytokine interleukin (IL)-10. Meningeal B cells were prevalent in homeostasis but substantially decreased following stress, whereas Ly6C
hi monocytes increased, and meningeal myeloid cells showed augmented expression of activation markers. Single-cell RNA sequencing of meningeal B cells demonstrated the induction of innate immune transcriptional programmes following stress, including genes encoding antimicrobial peptides that are known to alter myeloid cell activation. Cd19-/- mice, that have reduced B cells, showed baseline meningeal myeloid cell activation and decreased exploratory behaviour. Together, these data suggest that B cells may influence behaviour by regulating meningeal myeloid cell activation., (Copyright © 2021. Published by Elsevier Inc.)- Published
- 2021
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15. Analysis of cerebrovascular dysfunction caused by chronic social defeat in mice.
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Lehmann ML, Poffenberger CN, Elkahloun AG, and Herkenham M
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- Animals, Blood-Brain Barrier, Brain blood supply, Endothelial Cells, Male, Mice, Mice, Inbred C57BL, Stress, Psychological, Social Defeat
- Abstract
Psychological stress and affective disorders are clinically associated with hypertension and vascular disease, but the biological links between the conditions have not been fully explored. To examine this relationship, we used chronic social defeat (CSD) stress, which produces anxiety-like and depressive-like behavioral declines in susceptible mice. In such mice, CSD also produces cerebrovascular microbleeds in scattered locations. Here, we showed further evidence of vascular pathology and blood-brain barrier breakdown by visualizing plasma immunoglobulins and erythrocytes within the parenchyma and perivascular spaces of CSD brains. To further characterize the impact of stress on the cerebrovasculature, brain endothelial cells (bECs) were isolated, and global gene expression profiles were generated. Bioinformatic analysis of CSD-induced transcriptional changes in bECs showed enrichment in pathways that delineate the vascular response to injury. These pathways followed a temporal sequence of inflammation, oxidative stress, growth factor signaling, and wound healing (i.e., platelet aggregation, hemostasis, fibrinogen deposition, and angiogenesis). Immunohistochemical staining for markers of fibrinogen deposition and angiogenesis confirmed the existence of the markers at the sites of vascular disruptions. Recovery after CSD cessation was marked by recruitment of leukocytes perhaps participating in vascular repair. The data suggest that co-morbidity of affective disorders and vascular diseases may be attributed in part to a common link in altered endothelial cell function., (Published by Elsevier Inc.)
- Published
- 2020
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16. The Behavioral Sequelae of Social Defeat Require Microglia and Are Driven by Oxidative Stress in Mice.
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Lehmann ML, Weigel TK, Poffenberger CN, and Herkenham M
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- Acetylcysteine pharmacology, Animals, Antioxidants pharmacology, Male, Mice, Mice, Inbred C57BL, Microglia drug effects, Organic Chemicals toxicity, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor antagonists & inhibitors, Microglia metabolism, Oxidative Stress, Social Behavior, Stress, Psychological metabolism
- Abstract
Chronic social defeat (CSD) in male mice can produce anxiety and aberrant socialization. Animals susceptible to CSD show activation of microglia, which have elevated levels of oxidative stress markers. We hypothesized that microglia and reactive oxygen species (ROS) production contribute to the CSD stress-induced changes in affective behavior. First, we selectively depleted microglia (99%) by administering the CSF1R (colony-stimulating factor 1 receptor) antagonist PLX5622 before and during the 14 d CSD procedure. Microglia-depleted mice in contrast to nondepleted mice were protected from the stress effects measured by light/dark and social interaction tests. ROS production, measured histochemically following dihydroethidium administration, was elevated by CSD, and the production was reduced to basal levels in mice lacking microglia. The deleterious stress effects were also blocked in nondepleted mice by continuous intracerebral administration of N -acetylcysteine (NAC), a ROS inhibitor. In a second experiment, at the end of the CSD period, PLX5622 was discontinued to allow microglial repopulation. After 14 d, the brain had a full complement of newly generated microglia. At this time, the mice that had previously been protected now showed behavioral deficits, and their brain ROS production was elevated, both in all brain cells and in repopulated microglia. NAC administration during repopulation prevented the behavioral decline in the repopulated mice, and it supported behavioral recovery in nondepleted stressed mice. The data suggest that microglia drive elevated ROS production during and after stress exposure. This elevated ROS activity generates a central state supporting dysregulated affect, and it hinders the restoration of behavioral and neurochemical homeostasis after stress cessation. SIGNIFICANCE STATEMENT Chronic psychosocial stress is associated with psychiatric disorders such as depression and anxiety. Understanding the details of CNS cellular contributions to stress effects could lead to the development of intervention strategies. Inflammation and oxidative stress are positively linked to depression severity, but the cellular nature of these processes is not clear. The chronic social defeat (CSD) paradigm in mice produces mood alterations and microglial activation characterized by elevated reactive oxygen species (ROS) production. The depletion of microglia or ROS inhibition prevented adverse stress effects. Microglial repopulation of the brain post-CSD reintroduced adverse stress effects, and ROS inhibition in this phase protected against the effects. The results suggest that stress-induced microglial ROS production drives a central state that supports dysregulated affective behavior., (Copyright © 2019 the authors.)
- Published
- 2019
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17. The contribution of microglia to "immunization against stress".
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Herkenham M
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- Alarmins, Anti-Inflammatory Agents, Anxiety, Immunization, Microglia immunology, Mycobacterium
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- 2018
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18. Decoding microglia responses to psychosocial stress reveals blood-brain barrier breakdown that may drive stress susceptibility.
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Lehmann ML, Weigel TK, Cooper HA, Elkahloun AG, Kigar SL, and Herkenham M
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- Animals, Behavior, Animal, Gene Expression Profiling, Immunohistochemistry, Mice, Microarray Analysis, Blood-Brain Barrier physiopathology, Microglia immunology, Microglia pathology, Stress, Psychological physiopathology
- Abstract
An animal's ability to cope with or succumb to deleterious effects of chronic psychological stress may be rooted in the brain's immune responses manifested in microglial activity. Mice subjected to chronic social defeat (CSD) were categorized as susceptible (CSD-S) or resilient (CSD-R) based on behavioral phenotyping, and their microglia were isolated and analyzed by microarray. Microglia transcriptomes from CSD-S mice were enriched for pathways associated with inflammation, phagocytosis, oxidative stress, and extracellular matrix remodeling. Histochemical experiments confirmed the array predictions: CSD-S microglia showed elevated phagocytosis and oxidative stress, and the brains of CSD-S but not CSD-R or non-stressed control mice showed vascular leakage of intravenously injected fluorescent tracers. The results suggest that the inflammatory profile of CSD-S microglia may be precipitated by extracellular matrix degradation, oxidative stress, microbleeds, and entry and phagocytosis of blood-borne substances into brain parenchyma. We hypothesize that these CNS-centric responses contribute to the stress-susceptible behavioral phenotype.
- Published
- 2018
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19. Contributions of the adaptive immune system to mood regulation: Mechanisms and pathways of neuroimmune interactions.
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Herkenham M and Kigar SL
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- Animals, Brain cytology, Cytokines metabolism, Humans, Lymphocytes metabolism, Adaptive Immunity physiology, Affect physiology, Brain immunology
- Abstract
Clinical and basic studies of functional interactions between adaptive immunity, affective states, and brain function are reviewed, and the neural, humoral, and cellular routes of bidirectional communication between the brain and the adaptive immune system are evaluated. In clinical studies of depressed populations, lymphocytes-the principal cells of the adaptive immune system-exhibit altered T cell subtype ratios and CD4
+ helper T cell polarization profiles. In basic studies using psychological stress to model depression, T cell profiles are altered as well, consistent with stress effects conveyed by the hypothalamic-pituitary-adrenal axis and sympathetic nervous system. Lymphocytes in turn have effects on behavior and CNS structure and function. CD4+ T cells in particular appear to modify affective behavior and rates of hippocampal dentate gyrus neurogenesis. These observations force the question of how such actions are carried out. CNS effects may occur via cellular and molecular mechanisms whereby effector memory T cells and the cytokine profiles they produce in the blood interact with the blood-brain barrier in ways that remain to be clarified. Understanding the mechanisms by which T cells polarize and interact with the brain to alter mood states is key to advances in the field, and may permit development of therapies that target cells in the periphery, thus bypassing problems associated with bioavailability of drugs within the brain., (Published by Elsevier Inc.)- Published
- 2017
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20. Chronic social defeat reduces myelination in the mouse medial prefrontal cortex.
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Lehmann ML, Weigel TK, Elkahloun AG, and Herkenham M
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- Animals, Male, Mice, Myelin Sheath metabolism, Myelin Sheath pathology, Prefrontal Cortex metabolism, Prefrontal Cortex pathology, Stress, Psychological metabolism, Stress, Psychological pathology
- Abstract
The medial prefrontal cortex (mPFC) plays a key role in top-down control of the brain's stress axis, and its structure and function are particularly vulnerable to stress effects, which can lead to depression in humans and depressive-like states in animals. We tested whether chronic social defeat produces structural alterations in the mPFC in mice. We first performed a microarray analysis of mPFC gene expression changes induced by defeat, and biological pathway analysis revealed a dominant pattern of down-regulation of myelin-associated genes. Indeed, 69% of the most significantly down-regulated genes were myelin-related. The down regulation was confirmed by in situ hybridization histochemistry for two strongly down-regulated genes, myelin oligodendrocyte glycoprotein (Mog) and ermin (Ermn), and by immunohistochemistry for myelin basic protein. To test for stress-induced changes in myelin integrity, aurophosphate (Black Gold) myelin staining was performed on mPFC sections. Quantitative stereologic analysis showed reduced myelinated fiber length and density. Behavioral analysis confirmed that the 14-day social defeat sessions resulted in induction of depressive-like states measured in social interaction and light/dark tests. The combined data suggest that chronic social defeat induces molecular changes that reduce myelination of the prefrontal cortex, which may be an underlying basis for stress-induced depressive states.
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- 2017
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21. Therapeutic effects of stress-programmed lymphocytes transferred to chronically stressed mice.
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Scheinert RB, Haeri MH, Lehmann ML, and Herkenham M
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- Animals, Anxiety, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Disease Models, Animal, Exploratory Behavior physiology, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Hippocampus immunology, Hippocampus pathology, Lymph Nodes immunology, Lymph Nodes pathology, Lymphocytes pathology, Male, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity physiology, Neurogenesis physiology, Neurons immunology, Neurons pathology, Restraint, Physical, Spleen immunology, Spleen pathology, Stress, Psychological pathology, Lymphocyte Transfusion methods, Lymphocytes physiology, Stress, Psychological immunology, Stress, Psychological therapy
- Abstract
Our group has recently provided novel insights into a poorly understood component of intercommunication between the brain and the immune system by showing that psychological stress can modify lymphocytes in a manner that may boost resilience to psychological stress. To demonstrate the influence of the adaptive immune system on mood states, we previously showed that cells from lymph nodes of socially defeated mice, but not from unstressed mice, conferred anxiolytic and antidepressant-like effects and elevated hippocampal cell proliferation when transferred into naïve lymphopenic Rag2(-/-) mice. In the present study, we asked whether similar transfer could be anxiolytic and antidepressant when done in animals that had been rendered anxious and depressed by chronic psychological stress. First, we demonstrated that lymphopenic Rag2(-/-) mice and their wild-type C57BL/6 mouse counterparts had similar levels of affect normally. Second, we found that following chronic (14days) restraint stress, both groups displayed an anxious and depressive-like phenotype and decreased hippocampal cell proliferation. Third, we showed that behavior in the open field test and light/dark box was normalized in the restraint-stressed Rag2(-/-) mice following adoptive transfer of lymph node cells from green fluorescent protein (GFP) expressing donor mice previously exposed to chronic (14days) of social defeat stress. Cells transferred from unstressed donor mice had no effect on behavior. Immunolabeling of GFP+ cells confirmed that tissue engraftment had occurred at 14days after transfer. We found GFP+ lymphocytes in the spleen, lymph nodes, blood, choroid plexus, and meninges of the recipient Rag2(-/-) mice. The findings suggest that the adaptive immune system may play a key role in promoting recovery from chronic stress. The data support using lymphocytes as a novel therapeutic target for anxiety states., (Published by Elsevier Inc.)
- Published
- 2016
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22. Social defeat induces depressive-like states and microglial activation without involvement of peripheral macrophages.
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Lehmann ML, Cooper HA, Maric D, and Herkenham M
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- Animals, Depression immunology, Depression metabolism, Female, Macrophages immunology, Macrophages metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microglia immunology, Microglia metabolism, Stress, Psychological metabolism, Stress, Psychological psychology, Depression pathology, Macrophages pathology, Microglia pathology, Social Behavior, Stress, Psychological pathology
- Abstract
Background: We are interested in the causal interactions between psychological stress and activity within different compartments of the immune system. Psychosocial stress has been reported to not only alter microglia morphology but also produce anxiety-like and depressive-like effects by triggering CNS infiltration of macrophages from the periphery. We sought to test these phenomena in a somewhat different but standardized model of chronic social defeat (SD) stress., Methods: We used a paradigm of dyadic home pairing of dominant and subordinate mice that has been validated to induce powerful anxiety-like and depressive-like effects manifested by behavior assessed in social tasks. We administered the SD stress for 3 days (acute SD) or 14 days (chronic SD) and looked for monocyte entry into the brain by three independent means, including CD45 activation states assessed by flow cytometry and tracking fluorescently tagged peripheral cells from Ccr2 (wt/rfp) and Ubc (gfp/gfp) reporter mice. We further characterized the effects of SD stress on microglia using quantitative morphometric analysis, ex vivo phagocytosis assays, flow cytometry, and immunochemistry., Results: We saw no evidence of stress-induced macrophage entry after acute or chronic defeat stress. In comparison, brain infiltration of peripheral cells did occur after endotoxin administration. Furthermore, mutant mice lacking infiltrating macrophages due to CCR2 knockout developed the same degree of chronic SD-induced depressive behavior as wildtype mice. We therefore focused more closely on the intrinsic immune cells, the microglia. Using Cx3cr1 (wt/gpf) microglial reporter mice, we saw by quantitative methods that microglial morphology was not altered by stress at either time point. However, chronic SD mice had elevated numbers of CD68(hi) microglia examined by flow cytometry. CD68 is a marker for phagocytic activity. Indeed, these cells ex vivo showed elevated phagocytosis, confirming the increased activation status of chronic SD microglia. Finally, acute SD but not chronic SD increased microglial proliferation, which occurred selectively in telencephalic stress-related brain areas., Conclusions: In the SD paradigm, changes in CNS-resident microglia numbers and activation states might represent the main immunological component of the psychosocial stress-induced depressive state.
- Published
- 2016
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23. Lymphocytes from chronically stressed mice confer antidepressant-like effects to naive mice.
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Brachman RA, Lehmann ML, Maric D, and Herkenham M
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- Animals, Antidepressive Agents pharmacology, Cell Proliferation drug effects, Chronic Disease, Corticosterone blood, Cytokines blood, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, Dark Adaptation drug effects, Disease Models, Animal, Exploratory Behavior drug effects, Exploratory Behavior physiology, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, Hippocampus drug effects, Hippocampus physiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Stress, Psychological blood, Stress, Psychological psychology, Urine chemistry, Adoptive Transfer, Antidepressive Agents therapeutic use, Lymphocytes physiology, Stress, Psychological immunology, Stress, Psychological therapy
- Abstract
We examined whether cells of the adaptive immune system retain the memory of psychosocial stress and thereby alter mood states and CNS function in the host. Lymphocytes from mice undergoing chronic social defeat stress or from unstressed control mice were isolated and adoptively transferred into naive lymphopenic Rag2(-/-) mice. Changes in affective behavior, hippocampal cell proliferation, microglial activation states, and blood cytokine levels were examined in reconstituted stress-naive mice. The mice receiving lymphocytes from defeated donors showed less anxiety, more social behavior, and increased hippocampal cell proliferation compared with those receiving no cells or cells from unstressed donors. Mice receiving stressed immune cells had reduced pro-inflammatory cytokine levels in the blood relative to the other groups, an effect opposite to the elevated donor pro-inflammatory cytokine profile. Furthermore, mice receiving stressed immune cells had microglia skewed toward an anti-inflammatory, neuroprotective M2-like phenotype, an effect opposite the stressed donors' M1-like pro-inflammatory profile. However, stress had no effect on lymphocyte surface marker profiles in both donor and recipient mice. The data suggest that chronic stress-induced changes in the adaptive immune system, contrary to conferring anxiety and depressive behavior, protect against the deleterious effects of stress. Improvement in affective behavior is potentially mediated by reduced peripheral pro-inflammatory cytokine load, protective microglial activity, and increased hippocampal cell proliferation. The data identify the peripheral adaptive immune system as putatively involved in the mechanisms underlying stress resilience and a potential basis for developing novel rapid-acting antidepressant therapies., (Copyright © 2015 the authors 0270-6474/15/351530-09$15.00/0.)
- Published
- 2015
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24. Urine scent marking (USM): a novel test for depressive-like behavior and a predictor of stress resiliency in mice.
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Lehmann ML, Geddes CE, Lee JL, and Herkenham M
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- Animals, Female, Male, Mice, Mice, Inbred C57BL, Territoriality, Behavior, Animal physiology, Depression urine, Stress, Psychological urine
- Abstract
Decreased interest in pleasurable stimuli including social withdrawal and reduced libido are some of the key symptomatic criteria for major depression, and thus assays that measure social and sexual behavior in rodents may be highly appropriate for modeling depressive states. Here we present a novel approach for validating rodent models of depression by assessing male urine scent marking (USM) made in consequence to a spot of urine from a proestrous female. USM is an ethologically important form of sexual communication expressed by males to attract females. The expression of this behavior is highly sensitive and adaptive to environmental cues and social status. We hypothesized that male USM behavior offers a naturalistic measure of social motivation that can be used to evaluate hedonic behaviors relevant to the study of mood disorders. We demonstrated that 1) adult male mice displayed a strong preference for marking proestrous female urine with a high degree of specificity, 2) exposure to chronic social defeat profoundly decreased USM whereas exposure to environmental enrichment increased USM, 3) the standard antidepressant fluoxetine reversed declines in USM induced by social defeat, 4) USM behavior closely correlated with other hedonic measures, and 5) USM scores in non-stressed mice predicted behavioral outcomes after defeat exposure such that mice displaying high preference for marking female urine prior to social defeat showed behavioral resiliency after social defeat. The findings indicate that the USM test is a sensitive, validated measure of psychosocial stress effects that has high predictive value for examination of stress resiliency and vulnerability and their neurobiological substrates.
- Published
- 2013
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25. PACAP-deficient mice show attenuated corticosterone secretion and fail to develop depressive behavior during chronic social defeat stress.
- Author
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Lehmann ML, Mustafa T, Eiden AM, Herkenham M, and Eiden LE
- Subjects
- Animals, Behavior, Animal physiology, Chronic Disease, Corticosterone blood, Depressive Disorder physiopathology, Hierarchy, Social, Hypothalamo-Hypophyseal System metabolism, Hypothalamo-Hypophyseal System physiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pituitary-Adrenal System metabolism, Pituitary-Adrenal System physiology, Stress, Psychological blood, Stress, Psychological metabolism, Stress, Psychological physiopathology, Corticosterone metabolism, Depressive Disorder genetics, Dominance-Subordination, Pituitary Adenylate Cyclase-Activating Polypeptide genetics, Stress, Psychological genetics
- Abstract
The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) regulates activation of the hypothalamic-pituitary-adrenal (HPA) axis and the adrenal gland in response to various stressors. We previously found that in response to acute psychological stress (restraint), elevated corticotrophin-releasing hormone (CRH) mRNA levels in the hypothalamic paraventricular nucleus (PVN) as well as elevated plasma corticosterone (CORT) were profoundly attenuated in PACAP-deficient mice. To determine whether HPA axis responses and stress-induced depressive-like behaviors in a chronic stress paradigm are affected by PACAP deficiency, we subjected mice to 14 days of social defeat stress. Defeat-exposed PACAP-/- mice showed a marked attenuation of stress-induced increases in serum CORT levels, cellular PVN ΔFosB immunostaining, and depressive-like behaviors (social interaction and forced swim tests) compared to wild-type control mice. The PACAP-/- mice showed reduced PVN FosB-positive cell numbers, but relatively elevated cell counts in several forebrain areas including the medial prefrontal cortex, after social stress. PACAP appears to be specific for mediating HPA activation only in psychological stress because marked elevations in plasma CORT after a systemic stressor (lipopolysaccharide administration) occurred regardless of genotype. We conclude that chronically elevated CORT is a key component of depressive effects of social defeat, and that attenuation of the CORT response at the level of the PVN, as well as extrahypothalamic forebrain regions, in PACAP-deficient mice protects from development of depressive behavior., (Published by Elsevier Ltd.)
- Published
- 2013
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26. Glucocorticoids orchestrate divergent effects on mood through adult neurogenesis.
- Author
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Lehmann ML, Brachman RA, Martinowich K, Schloesser RJ, and Herkenham M
- Subjects
- Adaptation, Psychological physiology, Adrenalectomy, Animals, Antimetabolites, Behavior, Animal physiology, Bromodeoxyuridine, Corticosterone metabolism, Corticosterone pharmacology, Depression psychology, Environment, Housing, Animal, Mice, Mice, Inbred C57BL, Resilience, Psychological, Social Behavior, Social Dominance, Stress, Psychological psychology, Affect physiology, Glucocorticoids physiology, Neurogenesis physiology
- Abstract
Both social defeat stress and environmental enrichment stimulate adrenal glucocorticoid secretion, but they have opposing effects on hippocampal neurogenesis and mood. Hypothalamic-pituitary-adrenal axis dysregulation and decreased neurogenesis are consequences of social defeat. These outcomes are correlated with depressive states, but a causal role in the etiology of depression remains elusive. The antidepressant actions of environmental enrichment are neurogenesis-dependent, but the contribution of enrichment-elevated glucocorticoids is unexplored. Importantly, for both social defeat and environmental enrichment, how glucocorticoids interact with neurogenesis to alter mood is unknown. Here, we investigate causal roles of glucocorticoids and neurogenesis in induction of depressive-like behavior and its amelioration by environmental enrichment in mice. By blocking neurogenesis and surgically clamping adrenal hormone secretions, we showed that neurogenesis, via hypothalamic-pituitary-adrenal axis interactions, is directly involved in precipitating the depressive phenotype after social defeat. Mice adrenalectomized before social defeat showed enhanced behavioral resiliency and increased survival of adult-born hippocampal neurons compared with sham-operated defeated mice. However, mice lacking hippocampal neurogenesis did not show protective effects of adrenalectomy. Moreover, glucocorticoids secreted during environmental enrichment promoted neurogenesis and were required for restoration of normal behavior after social defeat. The data demonstrate that glucocorticoid-dependent declines in neurogenesis drive changes in mood after social defeat and that glucocorticoids secreted during enrichment promote neurogenesis and restore normal behavior after defeat. These data provide new evidence for direct involvement of neurogenesis in the etiology of depression, suggesting that treatments promoting neurogenesis can enhance stress resilience.
- Published
- 2013
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27. Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response.
- Author
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Oskvig DB, Elkahloun AG, Johnson KR, Phillips TM, and Herkenham M
- Subjects
- Amniotic Fluid immunology, Animals, Autistic Disorder immunology, Brain immunology, Cytokines analysis, Exploratory Behavior, Female, Fetus embryology, Gene Expression Profiling, Lipopolysaccharides administration & dosage, Lipopolysaccharides immunology, Oxidative Stress, Pregnancy, Pregnancy Complications, Infectious immunology, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Social Behavior, Transcription Factors metabolism, Brain embryology, Cell Movement immunology, Down-Regulation immunology, Fetus immunology, Interneurons immunology, Prenatal Exposure Delayed Effects immunology
- Abstract
Maternal immune activation (MIA) is a risk factor for the development of schizophrenia and autism. Infections during pregnancy activate the mother's immune system and alter the fetal environment, with consequential effects on CNS function and behavior in the offspring, but the cellular and molecular links between infection-induced altered fetal development and risk for neuropsychiatric disorders are unknown. We investigated the immunological, molecular, and behavioral effects of MIA in the offspring of pregnant Sprague-Dawley rats given an intraperitoneal (0.25 mg/kg) injection of lipopolysaccharide (LPS) on gestational day 15. LPS significantly elevated pro-inflammatory cytokine levels in maternal serum, amniotic fluid, and fetal brain at 4 h, and levels decreased but remained elevated at 24 h. Offspring born to LPS-treated dams exhibited reduced social preference and exploration behaviors as juveniles and young adults. Whole genome microarray analysis of the fetal brain at 4 h post maternal LPS was performed to elucidate the possible molecular mechanisms by which MIA affects the fetal brain. We observed dysregulation of 3285 genes in restricted functional categories, with increased mRNA expression of cellular stress and cell death genes and reduced expression of developmentally-regulated and brain-specific genes, specifically those that regulate neuronal migration of GABAergic interneurons, including the Distal-less (Dlx) family of transcription factors required for tangential migration from progenitor pools within the ganglionic eminences into the cerebral cortex. Our results provide a novel mechanism by which MIA induces the widespread down-regulation of critical neurodevelopmental genes, including those previously associated with autism., (Published by Elsevier Inc.)
- Published
- 2012
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28. Cautionary notes on the use of NF-κB p65 and p50 antibodies for CNS studies.
- Author
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Herkenham M, Rathore P, Brown P, and Listwak SJ
- Subjects
- Animals, Hippocampus cytology, Hippocampus metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B p50 Subunit genetics, Neurons cytology, Neurons metabolism, Transcription Factor RelA genetics, Antibodies metabolism, Antibody Specificity, Immunohistochemistry methods, NF-kappa B p50 Subunit metabolism, Transcription Factor RelA metabolism
- Abstract
Background: The characterization and cellular localization of transcription factors like NF-κB requires the use of antibodies for western blots and immunohistochemistry. However, if target protein levels are low and the antibodies not well characterized, false positive data can result. In studies of NF-κB activity in the CNS, antibodies detecting NF-κB proteins have been used to support the finding that NF-κB is constitutively active in neurons, and activity levels are further increased by neurotoxic treatments, glutamate stimulation, or elevated synaptic activity. The specificity of the antibodies used was analyzed in this study., Methods: Selectivity and nonselectivity of commonly used commercial and non-commercial p50 and p65 antibodies were demonstrated in western blot assays conducted in tissues from mutant gene knockout mice lacking the target proteins., Results: A few antibodies for p50 and p65 each mark a single band at the appropriate molecular weight in gels containing proteins from wildtype tissue, and this band is absent in proteins from knockout tissues. Several antibodies mark proteins that are present in knockout tissues, indicating that they are nonspecific. These include antibodies raised against the peptide sequence containing the nuclear localization signals of p65 (MAB3026; Chemicon) and p50 (sc-114; Santa Cruz). Some antibodies that recognize target proteins at the correct molecular weight still fail in western blot analysis because they also mark additional proteins and inconsistently so. We show that the criterion for validation by use of blocking peptides can still fail the test of specificity, as demonstrated for several antibodies raised against p65 phosphorylated at serine 276. Finally, even antibodies that show specificity in western blots produce nonspecific neuronal staining by immunohistochemistry., Conclusions: We note that many of the findings in the literature about neuronal NF-κB are based on data garnered with antibodies that are not selective for the NF-κB subunit proteins p65 and p50. The data urge caution in interpreting studies of neuronal NF-κB activity in the brain.
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- 2011
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29. Environmental enrichment confers stress resiliency to social defeat through an infralimbic cortex-dependent neuroanatomical pathway.
- Author
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Lehmann ML and Herkenham M
- Subjects
- Analysis of Variance, Animals, Housing, Animal, Immunohistochemistry, Male, Mice, Proto-Oncogene Proteins c-fos metabolism, Stress, Psychological physiopathology, Cerebral Cortex physiology, Dominance-Subordination, Environment, Limbic System physiology, Nerve Net physiology, Resilience, Psychological
- Abstract
Enriched environmental (EE) housing dampens stress-induced alterations in neurobiological systems, promotes adaptability, and extinguishes submissive behavioral traits developed during social defeat stress (SD). In the present study, we hypothesized that enrichment before SD can confer stress resiliency and, furthermore, that neuronal activity in the prefrontal cortex (PFC) is requisite for this resiliency. To test these hypotheses, mice were housed in EE, standard (SE), or impoverished (IE) housing and then exposed to SD. EE conferred resilience to SD as measured in several behavioral tasks. EE-housed mice expressed elevated FosB/ΔFosB immunostaining in areas associated with emotional regulation and reward processing, i.e., infralimbic, prelimbic, and anterior cingulate cortices, amygdala, and nucleus accumbens, and this expression was mostly preserved in mice receiving EE followed by SD. In contrast, in SE- or IE-housed animals, SD increased maladaptive behaviors and greatly reduced FosB/ΔFosB staining in the forebrain. We tested the putative involvement of the PFC in mediating resilience by lesioning individual regions of the PFC either before or after EE housing and then exposing the mice to SD. We found that discrete lesions of the infralimbic but not prelimbic or cingulate cortex made before but not after EE abolished the behavioral resiliency to stress afforded by EE and attenuated FosB/ΔFosB expression in the accumbens and amygdala while increasing it in the paraventricular hypothalamic nucleus. These data suggest that pathological ventromedial PFC outputs to downstream limbic targets could predispose an individual to anxiety disorders in stressful situations, whereas enhanced ventromedial PFC outputs could convey stress resilience.
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- 2011
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30. NF-kappaB activity affects learning in aversive tasks: possible actions via modulation of the stress axis.
- Author
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Lehmann ML, Brachman RA, Listwak SJ, and Herkenham M
- Subjects
- Adrenalectomy, Animals, Anxiety genetics, Anxiety psychology, Avoidance Learning drug effects, Chemokine CXCL1 biosynthesis, Corticosterone blood, Electrophoretic Mobility Shift Assay, Exploratory Behavior physiology, Genes, Immediate-Early physiology, Hippocampus drug effects, Hippocampus metabolism, Hypothalamo-Hypophyseal System drug effects, Maze Learning physiology, Memory drug effects, Memory physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B biosynthesis, NF-kappa B physiology, NF-kappa B p50 Subunit biosynthesis, NF-kappa B p50 Subunit genetics, NF-kappa B p50 Subunit physiology, Pituitary-Adrenal System drug effects, RNA, Messenger biosynthesis, RNA, Messenger genetics, Stress, Psychological genetics, Avoidance Learning physiology, NF-kappa B genetics, Stress, Psychological metabolism, Stress, Psychological psychology
- Abstract
The role of altered activity of nuclear factor kappaB (NF-kappaB) in specific aspects of motivated behavior and learning and memory was examined in mice lacking the p50 subunit of the NF-kappaB/rel transcription factor family. Nfkb1-deficient mice are unable to produce p50 and show specific susceptibilities to infections and inflammatory challenges, but the behavioral phenotype of such mice has been largely unexamined, owing in large part to the lack of understanding of the role of NF-kappaB in nervous system function. Here we show that Nfkb1 (p50) knockout mice more rapidly learned to find the hidden platform in the Morris water maze than did wildtype mice. The rise in plasma corticosterone levels after the maze test was greater in p50 knockout than in wildtype mice. In the less stressful Barnes maze, which tests similar kinds of spatial learning, the p50 knockout mice performed similarly to control mice. Adrenalectomy with corticosterone replacement eliminated the differences between p50 knockout and wildtype mice in the water maze. Knockout mice showed increased levels of basal anxiety in the open-field and light/dark box tests, suggesting that their enhanced escape latency in the water maze was due to activation of the stress (hypothalamic-pituitary-adrenal) axis leading to elevated corticosterone production by strongly but not mildly anxiogenic stimuli. The results suggest that, as in the immune system, p50 in the nervous system normally serves to dampen NF-kappaB-mediated intracellular activities, which are manifested physiologically through elevated stress responses to aversive stimuli and behaviorally in the facilitated escape performance in learning tasks., (Published by Elsevier Inc.)
- Published
- 2010
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31. Three Promoters Regulate Tissue- and Cell Type-specific Expression of Murine Interleukin-1 Receptor Type I.
- Author
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Chen Q, Zhang H, Li Q, An Y, Herkenham M, Lai W, Popovich P, Agarwal S, and Quan N
- Subjects
- Animals, DNA, Complementary genetics, Gene Library, Glucocorticoids genetics, Glucocorticoids metabolism, Interleukin-1 genetics, Mice, Organ Specificity physiology, RNA, Messenger biosynthesis, RNA, Messenger genetics, Receptors, Interleukin-1 genetics, Gene Expression Regulation physiology, Interleukin-1 metabolism, Promoter Regions, Genetic physiology, Receptors, Interleukin-1 biosynthesis
- Abstract
The type 1 interleukin-1 receptor (IL-1R1) mediates diverse functions of interleukin-1 (IL-1) in the nervous, immune, and neuroendocrine systems. It has been suggested previously that the versatile functions of IL-1 may in part be conferred by the multiple promoters of IL-1R1 that have been identified for the human IL-1R1 gene. Promoters for murine IL-1R1 (mIL-1R1) gene have not been studied in detail. We performed 5'-rapid amplification of cDNA ends to determine the transcription start sites (TSS) in mIL-1R1, using mRNAs derived from 24 different tissues. The results revealed three putative TSSs of mIL-1R1. Three full-length cDNAs containing these distinct TSSs were recovered in screens of cloned cDNA libraries. Translation of these cDNAs produced IL-1R1 proteins that were verified by Western blot analysis. IL-1 stimulation of the individual IL-1R1 proteins resulted in the activation of NF-kappaB. Promoter-reporter assay for genomic DNA sequences immediately upstream of the three TSSs validated that the sequences possess promoter activity in a cell type-specific manner. These promoters are termed P1, P2, and P3 of the mIL-1R1, in 5' to 3' order. Quantitative PCR analysis of P1-, P2-, and P3-specific mIL-1R1 mRNAs showed that there is tissue-specific distribution of these mRNAs in vivo, and there are distinct patterns of P1, P2, and P3 mRNA expression in different cell lines. In the brain, P3 mRNA is expressed preferentially in the dentate gyrus. Further, glucocorticoids differentially regulate these promoters in a cell type-specific manner. Together, these results suggest that the different IL-1R1 promoters contribute to the discrete and diverse actions of IL-1.
- Published
- 2009
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32. Induction of IDO by bacille Calmette-Guérin is responsible for development of murine depressive-like behavior.
- Author
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O'Connor JC, Lawson MA, André C, Briley EM, Szegedi SS, Lestage J, Castanon N, Herkenham M, Dantzer R, and Kelley KW
- Subjects
- Animals, BCG Vaccine administration & dosage, BCG Vaccine adverse effects, Chronic Disease, Depression genetics, Enzyme Induction genetics, Enzyme Induction immunology, Indoleamine-Pyrrole 2,3,-Dioxygenase deficiency, Indoleamine-Pyrrole 2,3,-Dioxygenase genetics, Indoleamine-Pyrrole 2,3,-Dioxygenase physiology, Inflammation enzymology, Inflammation genetics, Inflammation immunology, Male, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Mice, Knockout, Mice, Transgenic, Motor Activity genetics, Motor Activity immunology, Transcriptional Activation immunology, Up-Regulation genetics, Up-Regulation immunology, BCG Vaccine immunology, Depression enzymology, Depression immunology, Indoleamine-Pyrrole 2,3,-Dioxygenase biosynthesis
- Abstract
Chronic inflammation activates the tryptophan-degrading enzyme IDO, which is well known to impair T cell proliferation. We have previously established that bacille Calmette-Guérin (BCG), an attenuated form of Mycobacterium bovis, is associated with persistent activation of IDO in the brain and chronic depressive-like behavior, but a causative role has not been established. In these experiments we used both pharmacologic and genetic approaches to test the hypothesis that IDO activation is responsible for the development of chronic depression that follows BCG infection. BCG induced TNF-alpha, IFN-gamma, and IDO mRNA steady-state transcripts in the brain as well as the enzyme 3-hydroxyanthranilic acid oxygenase (3-HAO) that lies downstream of IDO and generates the neuroactive metabolite, quinolinic acid. Behaviors characteristic of depression were apparent 1 wk after BCG infection. Pretreatment with the competitive IDO inhibitor 1-methyltryptophan fully blocked BCG-induced depressive-like behaviors. Importantly, IDO-deficient mice were completely resistant to BCG-induced depressive-like behavior but responded normally to BCG induction of proinflammatory cytokines. These results are the first to prove that the BCG-induced persistent activation of IDO is accompanied by the induction of 3-hydroxyanthranilic acid oxygenase and that IDO is required as an initial step for the subsequent development of chronic depressive-like behavior.
- Published
- 2009
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33. Insidious adrenocortical insufficiency underlies neuroendocrine dysregulation in TIF-2 deficient mice.
- Author
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Patchev AV, Fischer D, Wolf SS, Herkenham M, Götz F, Gehin M, Chambon P, Patchev VK, and Almeida OF
- Subjects
- 3-Hydroxysteroid Dehydrogenases metabolism, Animals, Base Sequence, Corticosterone blood, DNA Primers, Female, Hypothalamo-Hypophyseal System, In Situ Hybridization, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nuclear Receptor Coactivator 2, Phosphoproteins metabolism, Pituitary-Adrenal System, Receptors, Glucocorticoid genetics, Reverse Transcriptase Polymerase Chain Reaction, Steroidogenic Factor 1, Transcription Factors genetics, Adrenal Cortex physiopathology, Receptors, Glucocorticoid physiology, Transcription Factors physiology
- Abstract
The transcription-intermediary-factor-2 (TIF-2) is a coactivator of the glucocorticoid receptor (GR), and its disruption would be expected to influence glucocorticoid-mediated control of the hypothalamo-pituitary-adrenal (HPA) axis. Here, we show that its targeted deletion in mice is associated with altered expression of several glucocorticoid-dependent components of HPA regulation (e.g., corticotropin-releasing hormone, vasopressin, ACTH, glucocorticoid receptors), suggestive of hyperactivity under basal conditions. At the same time, TIF-2(-/-) mice display significantly lower basal corticosterone levels and a sluggish and blunted initial secretory response to brief emotional and prolonged physical stress. Subsequent analysis revealed this discrepancy to result from pronounced aberrations in the structure and function of the adrenal gland, including the cytoarchitectural organization of the zona fasciculata and basal and stress-induced expression of key elements of steroid hormone synthesis, such as the steroidogenic acute regulatory (StAR) protein and 3beta-hydroxysteroid dehydrogenase (3beta-HSD). In addition, altered expression levels of two nuclear receptors, DAX-1 and steroidogenic factor 1 (SF-1), in the adrenal cortex strengthen the view that TIF-2 deletion disrupts adrenocortical development and steroid biosynthesis. Thus, hyperactivity of the hypothalamo-pituitary unit is ascribed to insidious adrenal insufficiency and impaired glucocorticoid feedback.
- Published
- 2007
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34. Bacterial lipopolysaccharide fever is initiated via Toll-like receptor 4 on hematopoietic cells.
- Author
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Steiner AA, Chakravarty S, Rudaya AY, Herkenham M, and Romanovsky AA
- Subjects
- Animals, Bone Marrow Cells cytology, Bone Marrow Cells physiology, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells immunology, Mice, Signal Transduction, Fever physiopathology, Hematopoietic Stem Cells physiology, Lipopolysaccharides toxicity, Toll-Like Receptor 4 physiology
- Abstract
Lipopolysaccharide (LPS), a well-known bacterial pyrogen, is recognized by several receptors, including the Toll-like receptor 4 (TLR4), on various cells. Which of these receptors and cells are linked to fever production is unknown. By constructing 4 mouse chimeras and studying their thermoregulatory responses, we found that all 3 phases of the typical LPS fever depend on TLR4 signaling. The first phase is triggered via the TLR4 on hematopoietic cells. The second and third phases involve TLR4 signaling in both hematopoietic and nonhematopoietic cells.
- Published
- 2006
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35. Thermoregulatory responses of rats to conventional preparations of lipopolysaccharide are caused by lipopolysaccharide per se-- not by lipoprotein contaminants.
- Author
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Steiner AA, Chakravarty S, Robbins JR, Dragic AS, Pan J, Herkenham M, and Romanovsky AA
- Subjects
- Animals, Body Temperature drug effects, Drug Contamination, Escherichia coli, Interleukin-1 blood, Interleukin-1 metabolism, Lipoproteins pharmacology, Male, Mice, Mice, Inbred C3H, Rats, Rats, Wistar, Receptors, Immunologic metabolism, Spleen drug effects, Spleen metabolism, Toll-Like Receptor 4, Tumor Necrosis Factor-alpha metabolism, Body Temperature Regulation drug effects, Drug Compounding, Lipopolysaccharides chemistry, Lipopolysaccharides pharmacology
- Abstract
LPS preparations cause a variety of body temperature (T(b)) responses: monophasic fever, different phases of polyphasic fever, and hypothermia. Conventional (c) LPS preparations contain highly active lipoprotein contaminants (endotoxin proteins). Whereas LPS signals predominantly via the Toll-like receptor (TLR) 4, endotoxin proteins signal via TLR2. Several TLR2-dependent responses of immunocytes to cLPS in vitro are triggered by endotoxin proteins and not by LPS itself. We tested whether any T(b) response to cLPS from Escherichia coli 055:B5 is triggered by non-TLR4-signaling contaminants. A decontaminated (d) LPS preparation (free of endotoxin proteins) was produced by subjecting cLPS to phenol-water reextraction. The presence of non-TLR4-signaling contaminants in cLPS (and their absence in dLPS) was confirmed by showing that cLPS (but not dLPS) induced IL-1beta expression in the spleen and increased serum levels of TNF-alpha and IL-1beta of C3H/HeJ mice; these mice bear a nonfunctional TLR4. Yet, both cLPS and dLPS caused cytokine responses in C3H/HeOuJ mice; these mice bear a fully functional TLR4. We then studied the T(b) responses to cLPS and dLPS in Wistar rats preimplanted with jugular catheters. At a neutral ambient temperature (30 degrees C), a low (0.1 microg/kg iv) dose of cLPS caused a monophasic fever, whereas a moderate (10 microg/kg iv) dose produced a polyphasic fever. In the cold (20 degrees C), a high (500 microg/kg iv) dose of cLPS caused hypothermia. All T(b) responses to dLPS were identical to those of cLPS. We conclude that all known T(b) responses to LPS preparations are triggered by LPS per se and not by non-TLR4-signaling contaminants of such preparations.
- Published
- 2005
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36. Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines.
- Author
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Chakravarty S and Herkenham M
- Subjects
- Animals, Bone Marrow Transplantation, CX3C Chemokine Receptor 1, Cell Lineage, Choroid Plexus metabolism, Corticosterone blood, Cytokines physiology, Encephalitis metabolism, Encephalitis pathology, Endotoxemia metabolism, Endotoxemia pathology, Gene Expression Regulation, Hypothalamo-Hypophyseal System physiopathology, I-kappa B Proteins biosynthesis, I-kappa B Proteins genetics, Lipopolysaccharides toxicity, Male, Meninges metabolism, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, NF-KappaB Inhibitor alpha, Pituitary-Adrenal System physiopathology, RNA, Messenger biosynthesis, RNA, Messenger genetics, Radiation Chimera, Receptors, Chemokine biosynthesis, Receptors, Chemokine genetics, Receptors, Immunologic biosynthesis, Receptors, Immunologic deficiency, Receptors, Immunologic genetics, Spleen metabolism, Toll-Like Receptor 4, Brain metabolism, Encephalitis etiology, Endotoxemia complications, Receptors, Immunologic physiology
- Abstract
Inflammatory agonists such as lipopolysaccharide (LPS) induce robust systemic as well as CNS responses after peripheral administration. Responses in the innate immune system require triggering of toll-like receptor 4 (TLR4), but the origin of CNS sequelas has been controversial. We demonstrate expression of TLR4 transcripts in mouse brain in the meninges, ventricular ependyma, circumventricular organs, along the vasculature, and in parenchymal microglia. The contribution of TLR4 expressed in CNS resident versus hematopoietic cells to the development of CNS inflammation was examined using chimeric mice. Reciprocal bone marrow chimeras between wild-type and TLR4 mutant mice show that TLR4 on CNS resident cells is critically required for sustained inflammation in the brain after systemic LPS administration. Hematopoietic TLR4 alone supported the systemic release of acute phase cytokines, but transcription of proinflammatory genes in the CNS was reduced in duration. In contrast, TLR4 function in radiation-resistant cells was sufficient for inflammatory progression in the brains of chimeric mice, despite the striking absence of cytokine elevations in serum. Surprisingly, a temporal rise in serum corticosterone was also dependent on TLR4 signaling in nonhematopoietic cells. Our findings demonstrate a requirement for TLR4 function in CNS-resident cells, independent of systemic cytokine effects, for sustained CNS-specific inflammation and corticosterone rise during endotoxemia.
- Published
- 2005
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37. Folliculo-stellate (FS) cells of the anterior pituitary mediate interactions between the endocrine and immune systems.
- Author
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Herkenham M
- Subjects
- Animals, Macrophage Migration-Inhibitory Factors physiology, Pituitary Gland, Anterior cytology, Endocrine Glands physiology, Immune System physiology, Pituitary Gland, Anterior physiology
- Published
- 2005
- Full Text
- View/download PDF
38. NF-kappaB p50-deficient mice show reduced anxiety-like behaviors in tests of exploratory drive and anxiety.
- Author
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Kassed CA and Herkenham M
- Subjects
- Animals, Anxiety genetics, Behavior, Animal physiology, Circadian Rhythm genetics, Gene Expression Regulation, Habituation, Psychophysiologic physiology, Male, Maze Learning, Mice, Mice, Knockout, Motor Activity physiology, NF-kappa B genetics, NF-kappa B p50 Subunit, Psychomotor Performance, Statistics, Nonparametric, Time Factors, Anxiety physiopathology, Drive, Exploratory Behavior physiology, NF-kappa B deficiency
- Abstract
The ubiquitous transcription factor nuclear factor (NF)-kappaB plays a prominent role in regulation of inflammatory immune responses and in cell survival. Recently, it has been found to be active in neurons, and mice lacking NF-kappaB subunits p50 or p65 show deficits in specific cognitive tasks. Here we demonstrate a strikingly low level of anxiety-like behavior in the p50(-/-) mouse. In an open field, the mutant mice showed significantly less defecation, more rearing, and more time spent in the center compartment relative to wild type control mice. The p50(-/-) mice also spent more time investigating a novel object placed in the open field. On the elevated plus maze, p50(-/-) mice spent more time on the open arms and had increased numbers of open arm entries relative to wild type. In group housing conditions, they did not establish dominant-subordinate hierarchies, whereas wild type control animals did so, in part, by whisker barbering and conspecific allogrooming. In tests of general health, sensorimotor function, and daily activity on a circadian rhythm, p50(-/-) mice were normal. Thus, absence of the p50 subunit of the NF-kappaB transcription factor, which results in altered NF-kappaB transcriptional activity in cells throughout the body and brain, alters neuronal circuitry underlying manifestation of emotional behavior. The p50 subunit appears to play a role in normal expression of certain forms of anxiety.
- Published
- 2004
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39. Activin mRNA induced during amygdala kindling shows a spatiotemporal progression that tracks the spread of seizures.
- Author
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Foster JA, Puchowicz MJ, McIntyre DC, and Herkenham M
- Subjects
- Amygdala physiopathology, Animals, Brain-Derived Neurotrophic Factor genetics, Cerebral Cortex metabolism, Cerebral Cortex physiopathology, Disease Models, Animal, Disease Progression, Epilepsy, Temporal Lobe genetics, Epilepsy, Temporal Lobe physiopathology, Functional Laterality physiology, Glutamate Decarboxylase genetics, Isoenzymes genetics, Kindling, Neurologic genetics, Neurons cytology, Neurons metabolism, RNA, Messenger biosynthesis, Rats, Rats, Long-Evans, Reaction Time genetics, Seizures genetics, Time Factors, Transcriptional Activation genetics, Up-Regulation genetics, Activins genetics, Amygdala metabolism, Epilepsy, Temporal Lobe metabolism, Kindling, Neurologic metabolism, RNA, Messenger metabolism, Seizures metabolism
- Abstract
The progressive development of seizures in rats by amygdala kindling, which models temporal lobe epilepsy, allows the study of molecular regulators of enduring synaptic changes. Neurotrophins play important roles in synaptic plasticity and neuroprotection. Activin, a member of the transforming growth factor-beta superfamily of growth and differentiation factors, has recently been added to the list of candidate synaptic regulators. We mapped the induction of activin betaA mRNA in amygdala and cortex at several stages of seizure development. Strong induction, measured 2 hours after the first stage 2 (partial) seizure, appeared in neurons of the ipsilateral amygdala (confined to the lateral, basal, and posterior cortical nuclei) and insular, piriform, orbital, and infralimbic cortices. Activin betaA mRNA induction, after the first stage 5 (generalized) seizure, had spread to the contralateral amygdala (same nuclear distribution) and cortex, and the induced labeling covered much of the convexity of neocortex as well as piriform, perirhinal, and entorhinal cortices in a nearly bilaterally symmetrical pattern. This pattern had filled in by the sixth stage 5 seizure. Induced labeling in cortical neurons was confined mainly to layer II. A similar temporal and spatial pattern of increased mRNA expression of brain-derived neurotrophic factor (BDNF) was found in the amygdala and cortex. Activin betaA and BDNF expression patterns were similar at 1, 2, and 6 hours after the last seizure, subsiding at 24 hours; in contrast, c-fos mRNA induction appeared only at 1 hour throughout cortex and then subsided. In double-label studies, activin betaA mRNA-positive neurons were also BDNF mRNA positive, and they did not colocalize with GAD67 mRNA (a marker of gamma-aminobutyric acidergic neurons). The data suggest that activin and BDNF transcriptional activities accurately mark excitatory neurons participating in seizure-induced synaptic alterations and may contribute to the enduring changes that underlie the kindled state., (Published 2004 Wiley-Liss, Inc.)
- Published
- 2004
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40. Hyperforin-containing extracts of St John's wort fail to alter gene transcription in brain areas involved in HPA axis control in a long-term treatment regimen in rats.
- Author
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Butterweck V, Winterhoff H, and Herkenham M
- Subjects
- Adrenal Glands drug effects, Adrenocorticotropic Hormone blood, Animals, Body Weight drug effects, Brain anatomy & histology, Brain metabolism, Bridged Bicyclo Compounds, Corticosterone blood, Drug Interactions, Hypothalamo-Hypophyseal System metabolism, Immunohistochemistry, In Situ Hybridization methods, Male, Organ Size drug effects, Phloroglucinol analogs & derivatives, Phosphoproteins genetics, Phosphoproteins metabolism, Pituitary-Adrenal System metabolism, Plant Extracts pharmacology, Pro-Opiomelanocortin genetics, Pro-Opiomelanocortin metabolism, RNA, Messenger metabolism, Radioimmunoassay methods, Rats, Receptor, Serotonin, 5-HT1A metabolism, Receptors, Glucocorticoid metabolism, Receptors, Mineralocorticoid metabolism, Time Factors, Tyrosine 3-Monooxygenase metabolism, Anti-Bacterial Agents pharmacology, Antidepressive Agents pharmacology, Brain drug effects, Hypericum chemistry, Hypothalamo-Hypophyseal System drug effects, Pituitary-Adrenal System drug effects, Terpenes pharmacology, Transcription, Genetic drug effects
- Abstract
We previously showed that a methanolic extract of St John's wort (SJW) (Hypericum) and hypericin, one of its active constituents, both have delayed regulation of genes that are involved in the control of the hypothalamic-pituitary-adrenal (HPA) axis. Hyperforin, another constituent of SJW, is active in vitro and has been proposed to be the active constituent for therapeutic efficacy in depression. We therefore examined if hyperforin has delayed effects on HPA axis control centers similar to those of Hypericum and hypericin. We used in situ hybridization histochemistry to examine in rats the effects of short-term (2 weeks) and long-term (8 weeks) oral administration of two hyperforin preparations, fluoxetine (positive control), and haloperidol (negative control) on the expression of genes involved in the regulation of the HPA axis. Fluoxetine (10 mg/kg) given daily for 8 weeks, but not 2 weeks, significantly decreased levels of corticotropin-releasing hormone (CRH) mRNA by 22% in the paraventricular nucleus (PVN) of the hypothalamus and tyrosine hydroxylase (TH) mRNA by 23% in the locus coeruleus. Fluoxetine increased levels of mineralocorticoid (MR) (17%), glucocorticoid (GR) (18%), and 5-HT(1A) receptor (21%) mRNAs in the hippocampus at 8, but not 2, weeks. Comparable to haloperidol (1 mg/kg), neither the hyperforin-rich CO(2) extract (27 mg/kg) nor hyperforin-trimethoxybenzoate (8 mg/kg) altered mRNA levels in brain structures relevant for HPA axis control at either time point. These data suggest that hyperforin and hyperforin derivatives are not involved in the regulation of genes that control HPA axis function.
- Published
- 2003
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41. Immunization with a cannabinoid receptor type 1 peptide results in experimental allergic meningocerebellitis in the Lewis rat: a model for cell-mediated autoimmune neuropathology.
- Author
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Proescholdt MG, Quigley L, Martin R, and Herkenham M
- Subjects
- Amino Acid Sequence, Animals, Apoptosis, Autoimmunity immunology, Behavior, Animal, Cerebellar Diseases complications, Cerebellar Diseases immunology, Cerebellar Diseases pathology, Disease Models, Animal, Disease Progression, Encephalitis complications, Encephalitis pathology, Female, Immunity, Cellular immunology, Immunohistochemistry, In Situ Hybridization, In Situ Nick-End Labeling, Lymph Nodes pathology, Meningitis complications, Meningitis pathology, Molecular Sequence Data, Nervous System Autoimmune Disease, Experimental chemically induced, Nervous System Autoimmune Disease, Experimental complications, Nervous System Autoimmune Disease, Experimental pathology, Peptide Fragments administration & dosage, RNA, Messenger biosynthesis, Rats, Rats, Inbred Lew, Receptors, Cannabinoid, Receptors, Drug genetics, Receptors, Drug metabolism, Reproducibility of Results, Encephalitis immunology, Meningitis immunology, Nervous System Autoimmune Disease, Experimental immunology, Peptide Fragments immunology, Receptors, Drug immunology
- Abstract
Neuronal elements are increasingly suggested as primary targets of an autoimmune attack in certain neurological and neuropsychiatric diseases. Type 1 cannabinoid receptors (CB1) were selected as autoimmune targets because they are predominantly expressed on neuronal surfaces in brain and display strikingly high protein levels in striatum, hippocampus, and cerebellum. Female Lewis rats were immunized with N-terminally acetylated peptides (50 or 400 microg per rat) of the extracellular domains of the rat CB1 and killed at various time points. Subsequent evaluation using immunohistochemistry and in situ hybridization showed dense infiltration of immune cells exclusively within the cerebellum, peaking 12-16 days after immunization with the CB1 peptide containing amino acids 9-25. The infiltrates clustered in meninges and perivascular locations in molecular and granular cell layers and were also scattered throughout the CB1-rich neuropil. They consisted primarily of CD4(+) and ED1(+) cells, suggestive of cell-mediated autoimmune pathology. There were no inflammatory infiltrates elsewhere in the brain or spinal cord. The results show that neuronal elements, such as neuronal cell-surface receptors, may be recognized as antigenic targets in a cell-mediated autoimmune attack and, therefore, support the hypothesis of cell-mediated antineuronal autoimmune pathology in certain brain disorders.
- Published
- 2002
- Full Text
- View/download PDF
42. Induced neuronal expression of class I major histocompatibility complex mRNA in acute and chronic inflammation models.
- Author
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Foster JA, Quan N, Stern EL, Kristensson K, and Herkenham M
- Subjects
- Acute Disease, Animals, Chronic Disease, Gene Expression Regulation, Histocompatibility Antigens Class I biosynthesis, In Situ Hybridization, Inflammation etiology, Inflammation genetics, Kinetics, Lipopolysaccharides, Male, Neuroimmunomodulation, Paraventricular Hypothalamic Nucleus cytology, Paraventricular Hypothalamic Nucleus metabolism, Rats, Rats, Sprague-Dawley, Transcription, Genetic, Trypanosomiasis genetics, Trypanosomiasis immunology, Histocompatibility Antigens Class I genetics, Inflammation immunology, Neurons metabolism, RNA, Messenger biosynthesis
- Abstract
Studies have demonstrated neuronal expression of class I major histocompatibility complex (MHC) mRNA and protein in normal and developing brain and in response to injury or viral infection. We report neuronal expression of class I MHC mRNA in hypothalamic paraventricular nucleus (PVN) neurons in rats following systemic infection with Trypanosoma brucei brucei parasites (chronic) and in response to intravenous 1 mg/kg lipopolysaccharide administration (acute peripheral) and in striatal neurons following intrastriatal 5 microg lipopolysaccharide injection (acute central). These results demonstrate that neurons can be a source of immune signaling molecules and establish class I MHC as part of the neuronal component of immune responses.
- Published
- 2002
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43. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors.
- Author
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Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, and Pertwee RG
- Subjects
- Animals, Cannabinoids chemistry, Humans, International Agencies, Receptors, Cannabinoid, Receptors, Drug chemistry, Cannabinoids metabolism, Receptors, Drug classification, Receptors, Drug metabolism, Terminology as Topic
- Abstract
Two types of cannabinoid receptor have been discovered so far, CB(1) (2.1: CBD:1:CB1:), cloned in 1990, and CB(2) (2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB(1) and CB(2) exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB(1) receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB(1) agonists probably serve as retrograde synaptic messengers. CB(2) receptors are present mainly on immune cells. Such cells also express CB(1) receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.
- Published
- 2002
- Full Text
- View/download PDF
44. Connecting cytokines and brain: a review of current issues.
- Author
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Quan N and Herkenham M
- Subjects
- Animals, Blood-Brain Barrier physiology, Humans, Nerve Degeneration etiology, Nerve Degeneration pathology, Nerve Net physiology, Nervous System Diseases physiopathology, Signal Transduction physiology, Brain Chemistry physiology, Cytokines physiology
- Abstract
Cytokines have been a multi-disciplinary research focus for over 2 decades. To date, there have been more than 15,000 articles published concerning the relationship between cytokines and the central nervous system (CNS). Over half of these articles have been published in the last 5 years. From such vast number of studies, two major topics emerge as the critical issues: 1) how do cytokines modulate the functions of the CNS? 2) what is the role of cytokines in the pathogenesis of neurological diseases? Thus far, it has been clearly established that cytokines can alter the functions of the CNS in specific manners, invoking CNS-controlled autonomic, neuroendocrine, and behavioral responses. Induced expression of cytokines has also been found in the CNS during brain injury and infection, contributing to the immunological processes at this "immunologically privileged" site. Furthermore, increasing evidence points to the potential involvement of cytokines in the induction and modulation of an array of neurological diseases ranging from Alzheimer's disease to chronic fatigue syndrome. Despite such progress, however, substantial obstacles remain for both the basic understanding and the potential clinical exploitation of how cytokines interact with CNS. In this review, we will attempt to synopsize the current theories and evidence regarding the answers to the above-mentioned critical questions. These issues will be reviewed not only in isolation, as most of the original reports focused on only one of the questions, but also in parallel such that inter-issue insights may be gained.
- Published
- 2002
- Full Text
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45. Spatiotemporal induction patterns of cytokine and related immune signal molecule mRNAs in response to intrastriatal injection of lipopolysaccharide.
- Author
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Stern EL, Quan N, Proescholdt MG, and Herkenham M
- Subjects
- Animals, Autoradiography, DNA-Binding Proteins genetics, DNA-Binding Proteins immunology, Gene Expression drug effects, Gene Expression immunology, In Situ Hybridization, Interleukin 1 Receptor Antagonist Protein, Interleukin-1 genetics, Interleukin-1 immunology, Interleukin-12 genetics, Interleukin-12 immunology, Interleukin-6 genetics, Interleukin-6 immunology, Lipopolysaccharides pharmacology, Male, Microinjections, NF-KappaB Inhibitor alpha, Nitric Oxide Synthase genetics, Nitric Oxide Synthase Type II, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Receptors, Interleukin-1 genetics, Receptors, Interleukin-1 immunology, Sialoglycoproteins genetics, Sialoglycoproteins immunology, Transcription, Genetic immunology, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha immunology, Corpus Striatum immunology, Cytokines genetics, Cytokines immunology, I-kappa B Proteins, Signal Transduction immunology
- Abstract
The brain's response to a direct immune challenge was examined by in situ hybridization histochemistry. Lipopolysaccharide (bacterial endotoxin) injected acutely into rat striatum induced mRNA expression for inhibitory factor kappaBalpha, interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-6, IL-12 p35, inducible nitric oxide synthase, IL-1 receptor antagonist, and the type 1 IL-1 receptor. Expression patterns were evaluated at select time points ranging from 15 min to 3 days post-injection. Rats injected with vehicle alone were used to control for mechanical effects. Following lipopolysaccharide administration, a wave of mRNA induction within brain parenchyma radiated outward from the injection site, generally peaking in intensity at the 16-h time point. The individual profiles of cytokine mRNA induction patterns reveal that the brain's immune response to local inflammatory stimulation is quite elaborate and in many ways resembles the progression of cytokine induction customary of localized inflammation in peripheral tissues.
- Published
- 2000
- Full Text
- View/download PDF
46. Induction of IkappaBalpha mRNA expression in the brain by glucocorticoids: a negative feedback mechanism for immune-to-brain signaling.
- Author
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Quan N, He L, Lai W, Shen T, and Herkenham M
- Subjects
- Animals, Brain drug effects, Brain immunology, Feedback, Gene Expression Regulation physiology, Glucocorticoids pharmacology, Immune System physiology, Lipopolysaccharides pharmacology, Male, NF-KappaB Inhibitor alpha, NF-kappa B antagonists & inhibitors, RNA, Messenger genetics, Rats, Rats, Sprague-Dawley, Signal Transduction, Transcription, Genetic physiology, Brain physiology, DNA-Binding Proteins genetics, Dexamethasone pharmacology, Gene Expression Regulation drug effects, I-kappa B Proteins, Interleukin-1 genetics, Transcription, Genetic drug effects
- Abstract
Peripheral injection of bacterial endotoxin lipopolysaccharide (LPS) induces brain mRNA expression of the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha and the cytokine-responsive immediate-early gene IkappaBalpha. Peripheral LPS also increases levels of plasma glucocorticoids. Whether the induction of IkappaBalpha mRNA in the brain after peripheral LPS injection is caused by the feedback action of glucocorticoids has not been determined. In this study, we examined the mRNA expression of IkappaBalpha and IL-1beta in the rat brain by in situ hybridization histochemistry. Injection of the glucocorticoid agonist dexamethasone induced IkappaBalpha mRNA expression in the brain in a pattern identical to that of LPS injection. LPS but not dexamethasone also induced IL-1beta mRNA expression. Pretreatment with dexamethasone 30 min before LPS injection enhanced the expression of IkappaBalpha mRNA in the brain in a dose-dependent manner. Immobilization of rats for 2 hr (which raises glucocorticoid levels) also induced IkappaBalpha mRNA expression without inducing the expression of IL-1beta. Brain IkappaBalpha expression induced by peripheral LPS injection was attenuated by pretreatment of rats with the glucocorticoid antagonist RU-486. Finally, increased expression of IL-1beta mRNA in the brain was observed at 4 hr after peripheral LPS injection in adrenalectomized rats compared with sham-operated rats. These results reveal that in the brain glucocorticoids selectively induce IkappaBalpha mRNA expression, which serves as a negative feedback mechanism for peripheral LPS-induced synthesis of proinflammatory cytokines. Such an inhibitory control mechanism may be important for preventing prolonged expression of proinflammatory cytokines in the brain after peripheral immune challenge.
- Published
- 2000
47. Localization of cannabinoid CB(1) receptor mRNA in neuronal subpopulations of rat striatum: a double-label in situ hybridization study.
- Author
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Hohmann AG and Herkenham M
- Subjects
- Animals, Arachidonic Acids pharmacology, Calcium Channel Blockers pharmacology, Choline O-Acetyltransferase analysis, Choline O-Acetyltransferase genetics, Endocannabinoids, Gene Expression physiology, In Situ Hybridization, Interneurons enzymology, Male, Polyunsaturated Alkamides, Protein Precursors analysis, Protein Precursors genetics, RNA, Messenger analysis, Rats, Rats, Sprague-Dawley, Receptors, Cannabinoid, Receptors, Drug analysis, Somatostatin analysis, Somatostatin genetics, Sulfur Radioisotopes, Corpus Striatum cytology, Interneurons chemistry, Receptors, Drug genetics
- Abstract
Double-label in situ hybridization was used to identify the phenotypes of striatal neurons that express mRNA for cannabinoid CB(1) receptors. Simultaneous detection of multiple mRNAs was performed by combining a (35)S-labeled ribonucleotide probe for CB(1) mRNA with digoxigenin-labeled riboprobes for striatal projection neurons (preprotachykinin A, prodynorphin, and preproenkephalin mRNAs) and interneurons (vesicular acetylcholine transporter (VAChT), choline acetyltransferase (ChAT), somatostatin, and glutamic acid decarboxylase (Mr 67,000; GAD67) mRNAs). To ascertain whether CB(1) mRNA was a marker for striatal efferents, digoxigenin-labeled probes for mRNA markers of both striatonigral (prodynorphin or preprotachykinin A mRNAs), and striatopallidal (proenkephalin mRNAs) projection neurons were combined with the (35)S-labeled probe for CB(1). A mediolateral gradient in CB(1) mRNA expression was observed at rostral and mid-striatal levels; in the same coronal sections the number of silver grains per cell ranged from below the threshold of detectability at the medial and ventral poles to saturation at the dorsolateral boundary bordered by the corpus callosum. At the caudal level examined, CB(1) mRNA was denser in the ventral sector relative to the dorsal sector. Virtually all neurons expressing mRNA markers for striatal projection neurons colocalized CB(1) mRNA. Combining a (35)S-labeled riboprobe for CB(1) with digoxigenin-labeled riboprobes for both preproenkephalin and prodynorphin confirmed localization of CB(1) mRNA to striatonigral and striatopallidal neurons expressing prodynorphin and preproenkephalin mRNAs, respectively. However, CB(1) mRNA-positive cells that failed to coexpress the other markers were also apparent. CB(1) mRNA was localized to putative GABAergic interneurons that express high levels of GAD67 mRNA. These interneurons enable functional interactions between the direct and indirect striatal output pathways. By contrast, aspiny interneurons that express preprosomatostatin mRNA and cholinergic interneurons that coexpress ChAT and VAChT mRNAs were CB(1) mRNA-negative. The present data provide direct evidence that cannabinoid receptors are synthesized in striatonigral neurons that contain dynorphin and substance P and striatopallidal neurons that contain enkephalin. By contrast, local circuit neurons in striatum that contain somatostatin or acetylcholine do not synthesize cannabinoid receptors. Published 2000 Wiley-Liss, Inc.
- Published
- 2000
- Full Text
- View/download PDF
48. Fragile X (fmr1) mRNA expression is differentially regulated in two adult models of activity-dependent gene expression.
- Author
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Valentine G, Chakravarty S, Sarvey J, Bramham C, and Herkenham M
- Subjects
- Analysis of Variance, Animals, Dentate Gyrus chemistry, Electroshock, Fragile X Mental Retardation Protein, Immunohistochemistry, In Situ Hybridization, Nerve Tissue Proteins analysis, RNA, Messenger analysis, Rats, Rats, Sprague-Dawley, Dentate Gyrus metabolism, Gene Expression Regulation, Long-Term Potentiation genetics, Nerve Tissue Proteins genetics, RNA-Binding Proteins
- Abstract
We sought to determine whether the fragile X mental retardation gene fmr1 is regulated in long-term potentiation (LTP) and electroconvulsive shock (ECS). In situ hybridization of fmr1 mRNA in hippocampus of rats given LTP in vivo showed no change in fmr1 mRNA levels relative to control. However, ECS induced a selective increase in fmr1 mRNA expression in the dentate gyrus (DG) granule cell layer at 6 h post-ECS. The ECS paradigm may unmask relevant activity-dependent regulatory mechanisms that modulate fmr1 gene transcription in vivo.
- Published
- 2000
- Full Text
- View/download PDF
49. Chronic sodium salicylate treatment exacerbates brain neurodegeneration in rats infected with Trypanosoma brucei.
- Author
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Quan N, Mhlanga JD, Whiteside MB, Kristensson K, and Herkenham M
- Subjects
- Animals, Blood-Brain Barrier drug effects, Brain metabolism, Cytokines genetics, In Situ Hybridization, Male, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Time Factors, Trypanosomiasis, African metabolism, Brain drug effects, Brain pathology, Nerve Degeneration pathology, Sodium Salicylate pharmacology, Trypanosoma brucei brucei, Trypanosomiasis, African pathology
- Abstract
We have reported previously that axonal degeneration in specific brain regions occurs in rats infected with the parasite Trypanosoma brucei. These degenerative changes occur in spatiotemporal association with over-expression of pro-inflammatory cytokine messenger RNAs in the brain. To test how aspirin-like anti-inflammatory drugs might alter the disease process, we fed trypanosome-infected rats with 200mg/kg of sodium salicylate (the first metabolite of aspirin) daily in their drinking water. Sodium salicylate treatment in uninfected rats did not cause any neural damage. However, sodium salicylate treatment greatly exacerbated neurodegeneration in trypanosome-infected rats, resulting in extensive terminal and neuronal cell body degeneration in the cortex, hippocampus, striatum, thalamus, and anterior olfactory nucleus. The exaggerated neurodegeneration, which occurred in late stages of infection, was temporally and somewhat spatially associated with a late-appearing enhancement of messenger RNA expression of interleukin-1beta, interleukin-1beta converting enzyme, tumor necrosis factor-alpha, and inhibitory factor kappaBalpha in the brain parenchyma. Restricted areas showed elevations in messenger RNA expression of interleukin-1 receptor antagonist, interleukin-6, inducible nitric oxide synthase, interferon-gamma, and inducible cyclooxygenase. The association suggests that increased production of pro-inflammatory cytokines in the brain may be an underlying mechanism for neural damage induced by the chronic sodium salicylate treatment. Furthermore, the results reveal a serious complication in using aspirin-like drugs for the treatment of trypanosome infection.
- Published
- 2000
- Full Text
- View/download PDF
50. Studies of cerebrospinal fluid flow and penetration into brain following lateral ventricle and cisterna magna injections of the tracer [14C]inulin in rat.
- Author
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Proescholdt MG, Hutto B, Brady LS, and Herkenham M
- Subjects
- Animals, Autoradiography, Brain physiology, Carbon Radioisotopes, Injections, Intraventricular, Male, Rats, Rats, Sprague-Dawley, Subarachnoid Space physiology, Time Factors, Tissue Distribution, Cerebrospinal Fluid physiology, Cisterna Magna physiology, Inulin pharmacokinetics, Lateral Ventricles physiology
- Abstract
Parasynaptic communication, also termed volume transmission, has been suggested as an important means to mediate information transfer within the central nervous system. The purpose of the present study was to visualize by autoradiography the available channels for fluid movement within the extracellular space following injection of the inert extracellular marker [14C]inulin into the lateral ventricle or cisterna magna. Bolus injections of 5 microl of 1 microCi of [14C]inulin were made in awake rats via chronically implanted cannulae. After survival times ranging from 5 min to 4 h, brains were processed for in vivo autoradiography. At 5 min the tracer distributed throughout the ventricles, subarachnoid spaces and cisterns "downstream" of the injection sites. Penetration into the brain from these sites was complex with preferential entry along the ventral side of the brain, especially into the hypothalamus and brainstem. By 4 h virtually the entire brain was labeled irrespective of the site of tracer application. Sustained tracer entry from subarachnoid spaces suggests that some areas act as depots to trap circulating material. This mechanism may contribute to the pattern of deep penetration at later time-points. The spatial and temporal characteristics of fluid movement throughout the brain are instructive in the interpretation of many experimental procedures involving injection of molecules into the cerebrospinal fluid.
- Published
- 2000
- Full Text
- View/download PDF
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