Publications by authors named "Maria Gulinello"

61 Publications

Microglial reduction of colony stimulating factor-1 receptor expression is sufficient to confer adult onset leukodystrophy.

Glia 2021 Mar 20;69(3):779-791. Epub 2020 Oct 20.

Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.

Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a dementia resulting from dominantly inherited CSF1R inactivating mutations. The Csf1r mouse mimics ALSP symptoms and pathology. Csf1r is mainly expressed in microglia, but also in cortical layer V neurons that are gradually lost in Csf1r+/- mice with age. We therefore examined whether microglial or neuronal Csf1r loss caused neurodegeneration in Csf1r+/- mice. The behavioral deficits, pathologies and elevation of Csf2 expression contributing to disease, previously described in the Csf1r ALSP mouse, were reproduced by microglial deletion (MCsf1r mice), but not by neural deletion. Furthermore, increased Csf2 expression by callosal astrocytes, oligodendrocytes, and microglia was observed in Csf1r mice and, in MCsf1r mice, the densities of these three cell types were increased in supraventricular patches displaying activated microglia, an early site of disease pathology. These data confirm that ALSP is a primary microgliopathy and inform future therapeutic and experimental approaches.
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http://dx.doi.org/10.1002/glia.23929DOI Listing
March 2021

Nociceptors protect sickle cell disease mice from vaso-occlusive episodes and chronic organ damage.

J Exp Med 2021 Jan;218(1)

The Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY.

Sickle cell disease (SCD) is a common hereditary hematologic disorder. SCD patients suffer from acute vaso-occlusive episodes (VOEs), chronic organ damage, and premature death, with few therapeutic options. Although severe pain is a major clinical manifestation of SCD, it remains unknown whether nociception plays a role in SCD pathogenesis. To address this question, we generated nociceptor-deficient SCD mice and found, unexpectedly, that the absence of nociception led to more severe and more lethal VOE, indicating that somatosensory nerves protect SCD mice from VOE. Mechanistically, the beneficial effects of sensory nerves were induced by the neuropeptide calcitonin gene-related peptide (CGRP), which acted on hematopoietic cells. Additionally, oral capsaicin consumption, which can activate somatosensory nerves by binding to TRPV1, dramatically alleviated acute VOE and significantly prevented chronic liver and kidney damage in SCD mice. Thus, the manipulation of nociception may provide a promising approach to treat SCD.
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http://dx.doi.org/10.1084/jem.20200065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534906PMC
January 2021

Microglial Homeostasis Requires Balanced CSF-1/CSF-2 Receptor Signaling.

Cell Rep 2020 03;30(9):3004-3019.e5

Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address:

CSF-1R haploinsufficiency causes adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Previous studies in the Csf1r mouse model of ALSP hypothesized a central role of elevated cerebral Csf2 expression. Here, we show that monoallelic deletion of Csf2 rescues most behavioral deficits and histopathological changes in Csf1r mice by preventing microgliosis and eliminating most microglial transcriptomic alterations, including those indicative of oxidative stress and demyelination. We also show elevation of Csf2 transcripts and of several CSF-2 downstream targets in the brains of ALSP patients, demonstrating that the mechanisms identified in the mouse model are functional in humans. Our data provide insights into the mechanisms underlying ALSP. Because increased CSF2 levels and decreased microglial Csf1r expression have also been reported in Alzheimer's disease and multiple sclerosis, we suggest that the unbalanced CSF-1R/CSF-2 signaling we describe in the present study may contribute to the pathogenesis of other neurodegenerative conditions.
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http://dx.doi.org/10.1016/j.celrep.2020.02.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370656PMC
March 2020

Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice.

Geroscience 2019 04 10;41(2):185-208. Epub 2019 May 10.

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer Bldg, Rm 236, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.

Disruptions in growth hormone/insulin-like growth factor-1 (GH/IGF-1) signaling have been linked to improved longevity in mice and humans. Nevertheless, while IGF-1 levels are associated with increased cancer risk, they have been paradoxically implicated with protection from other age-related conditions, particularly in the brain, suggesting that strategies aimed at selectively increasing central IGF-1 action may have favorable effects on aging. To test this hypothesis, we generated inducible, brain-specific (TRE-IGF-1 × Camk2a-tTA) IGF-1 (bIGF-1) overexpression mice and studied effects on healthspan. Doxycycline was removed from the diet at 12 weeks old to permit post-development brain IGF-1 overexpression, and animals were monitored up to 24 months. Brain IGF-1 levels were increased approximately twofold in bIGF-1 mice, along with greater brain weights, volume, and myelin density (P < 0.05). Age-related changes in rotarod performance, exercise capacity, depressive-like behavior, and hippocampal gliosis were all attenuated specifically in bIGF-1 male mice (P < 0.05). However, chronic brain IGF-1 failed to prevent declines in cognitive function or neurovascular coupling. Therefore, we performed a short-term intranasal (IN) treatment of either IGF-1 or saline in 24-month-old male C57BL/6 mice and found that IN IGF-1 treatment tended to reduce depressive (P = 0.09) and anxiety-like behavior (P = 0.08) and improve motor coordination (P = 0.07) and unlike transgenic mice improved motor learning (P < 0.05) and visuospatial and working memory (P < 0.05). These data highlight important sex differences in how brain IGF-1 action impacts healthspan and suggest that translational approaches that target IGF-1 centrally can restore cognitive function, a possibility that should be explored as a strategy to combat age-related cognitive decline.
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http://dx.doi.org/10.1007/s11357-019-00065-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544744PMC
April 2019

Loss-of-Huntingtin in Medial and Lateral Ganglionic Lineages Differentially Disrupts Regional Interneuron and Projection Neuron Subtypes and Promotes Huntington's Disease-Associated Behavioral, Cellular, and Pathological Hallmarks.

J Neurosci 2019 03 9;39(10):1892-1909. Epub 2019 Jan 9.

Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine,

Emerging studies are providing compelling evidence that the pathogenesis of Huntington's disease (HD), a neurodegenerative disorder with frequent midlife onset, encompasses developmental components. Moreover, our previous studies using a hypomorphic model targeting huntingtin during the neurodevelopmental period indicated that loss-of-function mechanisms account for this pathogenic developmental component (Arteaga-Bracho et al., 2016). In the present study, we specifically ascertained the roles of subpallial lineage species in eliciting the previously observed HD-like phenotypes. Accordingly, we used the Cre-loxP system to conditionally ablate the murine huntingtin gene (Htt) in cells expressing the subpallial patterning markers Gsx2 (Gsx2-Cre) or Nkx2.1 (Nkx2.1-Cre) in Htt mice of both sexes. These genetic manipulations elicited anxiety-like behaviors, hyperkinetic locomotion, age-dependent motor deficits, and weight loss in both Htt;Gsx2-Cre and Htt;Nkx2.1-Cre mice. In addition, these strains displayed unique but complementary spatial patterns of basal ganglia degeneration that are strikingly reminiscent of those seen in human cases of HD. Furthermore, we observed early deficits of somatostatin-positive and Reelin-positive interneurons in both Htt subpallial null strains, as well as early increases of cholinergic interneurons, Foxp2 arkypallidal neurons, and incipient deficits with age-dependent loss of parvalbumin-positive neurons in Htt;Nkx2.1-Cre mice. Overall, our findings indicate that selective loss-of-huntingtin function in subpallial lineages differentially disrupts the number, complement, and survival of forebrain interneurons and globus pallidus GABAergic neurons, thereby leading to the development of key neurological hallmarks of HD during adult life. Our findings have important implications for the establishment and deployment of neural circuitries and the integrity of network reserve in health and disease. Huntington's disease (HD) is a progressive degenerative disorder caused by aberrant trinucleotide expansion in the gene. Mechanistically, this mutation involves both loss- and gain-of-function mechanisms affecting a broad array of cellular and molecular processes. Although huntingtin is widely expressed during adult life, the mutant protein only causes the demise of selective neuronal subtypes. The mechanisms accounting for this differential vulnerability remain elusive. In this study, we have demonstrated that loss-of-huntingtin function in subpallial lineages not only differentially disrupts distinct interneuron species early in life, but also leads to a pattern of neurological deficits that are reminiscent of HD. This work suggests that early disruption of selective neuronal subtypes may account for the profiles of enhanced regional cellular vulnerability to death in HD.
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http://dx.doi.org/10.1523/JNEUROSCI.2443-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407290PMC
March 2019

Neuropsychiatric Systemic Lupus Erythematosus Is Dependent on Sphingosine-1-Phosphate Signaling.

Front Immunol 2018 26;9:2189. Epub 2018 Sep 26.

Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States.

About 40% of patients with systemic lupus erythematosus experience diffuse neuropsychiatric manifestations, including impaired cognition and depression. Although the pathogenesis of diffuse neuropsychiatric SLE (NPSLE) is not fully understood, loss of brain barrier integrity, autoreactive antibodies, and pro-inflammatory cytokines are major contributors to disease development. Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, prevents lymphocyte egress from lymphoid organs through functional antagonism of S1P receptors. In addition to reducing the circulation of autoreactive lymphocytes, fingolimod has direct neuroprotective effects such as preserving brain barrier integrity and decreasing pro-inflammatory cytokine secretion by astrocytes and microglia. Given these effects, we hypothesized that fingolimod would attenuate neurobehavioral deficits in MRL-lpr/lpr (MRL/lpr) mice, a validated neuropsychiatric lupus model. Fingolimod treatment was initiated after the onset of disease, and mice were assessed for alterations in cognitive function and emotionality. We found that fingolimod significantly attenuated spatial memory deficits and depression-like behavior in MRL/lpr mice. Immunofluorescent staining demonstrated a dramatic lessening of brain T cell and macrophage infiltration, and a significant reduction in cortical leakage of serum albumin, in fingolimod treated mice. Astrocytes and endothelial cells from treated mice exhibited reduced expression of inflammatory genes, while microglia showed differential regulation of key immune pathways. Notably, cytokine levels within the cortex and hippocampus were not appreciably decreased with fingolimod despite the improved neurobehavioral profile. Furthermore, despite a reduction in splenomegaly, lymphadenopathy, and circulating autoantibody titers, IgG deposition within the brain was unaffected by treatment. These findings suggest that fingolimod mediates attenuation of NPSLE through a mechanism that is not dependent on reduction of autoantibodies or cytokines, and highlight modulation of the S1P signaling pathway as a novel therapeutic target in lupus involving the central nervous system.
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http://dx.doi.org/10.3389/fimmu.2018.02189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168636PMC
October 2019

Lipocalin-2 is a pathogenic determinant and biomarker of neuropsychiatric lupus.

J Autoimmun 2019 01 30;96:59-73. Epub 2018 Aug 30.

Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA; Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address:

Neuropsychiatric manifestations in lupus (NPSLE) affect ∼20-40% of patients. In the central nervous system, lipocalin-2 (LCN2) can promote injury through mechanisms directly linked to NPSLE, including brain barrier disruption, neurotoxicity, and glial activation. Since LCN2 is elevated in lupus and has been implicated in neuroinflammation, we investigated whether LCN2 is required for the pathogenesis of NPSLE. Here, we investigated the effects of LCN2 deficiency on the development of neurobehavioral deficits in the B6.Sle1.Sle3 (Sle1,3) mouse lupus model. Sle1,3 mice exhibited depression-like behavior and impaired spatial and recognition memory, and these deficits were attenuated in Sle1,3-LCN2KO mice. Whole-brain flow cytometry showed a significant increase in brain infiltrating leukocytes in Sle1,3 mice that was not reduced by LCN2 deficiency. RNA sequencing on sorted microglia revealed that several genes differentially expressed between B6 and Sle1,3 mice were regulated by LCN2, and that these genes are key mediators of the neuroinflammatory cascade. Importantly, LCN2 is upregulated in the cerebrospinal fluid of NPSLE patients across 2 different ethnicities. Our findings establish the Sle1,3 strain as an NPSLE model, demonstrate that LCN2 is a major regulator of the detrimental neuroimmune response in NPSLE, and identify CSF LCN2 as a novel biomarker for NPSLE.
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http://dx.doi.org/10.1016/j.jaut.2018.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310639PMC
January 2019

Methotrexate causes persistent deficits in memory and executive function in a juvenile animal model.

Neuropharmacology 2018 09 7;139:76-84. Epub 2018 Jul 7.

Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA; Rutgers Cancer Institute of New Jersey, Division of Pediatric Hematology/Oncology, New Brunswick, NJ, USA. Electronic address:

Methotrexate is a dihydrofolate reductase inhibitor widely employed in curative treatment for children with acute lymphoblastic leukemia (ALL). However, methotrexate administration is also associated with persistent cognitive deficits among long-term childhood cancer survivors. Animal models of methotrexate-induced cognitive deficits have primarily utilized adult animals. The purpose of present study is to investigate the neurotoxicity of methotrexate in juvenile rats and its relevant mechanisms. The doses and schedule of systemic and intrathecal methotrexate, given from post-natal age 3-7 weeks, were chosen to model the effects of repeated methotrexate dosing on the developing brains of young children with ALL. This methotrexate regimen had no visible acute toxicity and no effect on growth. At 15 weeks of age (8 weeks after the last methotrexate dose) both spatial pattern memory and visual recognition memory were impaired. In addition, methotrexate-treated animals demonstrated impaired performance in the set-shifting assay, indicating decreased cognitive flexibility. Histopathological analysis demonstrated decreased cell proliferation in methotrexate-treated animals compared to controls, as well as changes in length and thickness of the corpus callosum. Moreover, methotrexate suppressed microglia activation and RANTES production. In conclusion, our study demonstrated that a clinically relevant regimen of systemic and intrathecal methotrexate induces persistent deficits in spatial pattern memory, visual recognition memory and executive function, lasting at least 8 weeks after the last injection. The mechanisms behind methotrexate-induced deficits are likely multifactorial and may relate to suppression of neurogenesis, alterations in neuroinflammation and microglial activation, and structural changes in the corpus callosum.
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http://dx.doi.org/10.1016/j.neuropharm.2018.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089371PMC
September 2018

Pathobiology of Christianson syndrome: Linking disrupted endosomal-lysosomal function with intellectual disability and sensory impairments.

Neurobiol Learn Mem 2019 11 14;165:106867. Epub 2018 May 14.

Dominick P. Purpura Dept. of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Christianson syndrome (CS) is a recently described rare neurogenetic disorder presenting early in life with a broad range of neurological symptoms, including severe intellectual disability with nonverbal status, hyperactivity, epilepsy, and progressive ataxia due to cerebellar atrophy. CS is due to loss-of-function mutations in SLC9A6, encoding NHE6, a sodium-hydrogen exchanger involved in the regulation of early endosomal pH. Here we review what is currently known about the neuropathogenesis of CS, based on insights from experimental models, which to date have focused on mechanisms that affect the CNS, specifically the brain. In addition, parental reports of sensory disturbances in their children with CS, including an apparent insensitivity to pain, led us to explore sensory function and related neuropathology in Slc9a6 KO mice. We present new data showing sensory deficits in Slc9a6 KO mice, which had reduced behavioral responses to noxious thermal and mechanical stimuli (Hargreaves and Von Frey assays, respectively) compared to wild type (WT) littermates. Immunohistochemical and ultrastructural analysis of the spinal cord and peripheral nervous system revealed intracellular accumulation of the glycosphingolipid GM2 ganglioside in KO but not WT mice. This cellular storage phenotype was most abundant in neurons of lamina I-II of the dorsal horn, a major relay site in the processing of painful stimuli. Spinal cords of KO mice also exhibited changes in astroglial and microglial populations throughout the gray matter suggestive of a neuroinflammatory process. Our findings establish the Slc9a6 KO mouse as a relevant tool for studying the sensory deficits in CS, and highlight selective vulnerabilities in relevant cell populations that may contribute to this phenotype. How NHE6 loss of function leads to such a multifaceted neurological syndrome is still undefined, and it is likely that NHE6 is involved with many cellular processes critical to normal nervous system development and function. In addition, the sensory issues exhibited by Slc9a6 KO mice, in combination with our neuropathological findings, are consistent with NHE6 loss of function impacting the entire nervous system. Sensory dysfunction in intellectually disabled individuals is challenging to assess and may impair patient safety and quality of life. Further mechanistic studies of the neurological impairments underlying CS and other genetic intellectual disability disorders must also take into account mechanisms affecting broader nervous system function in order to understand the full range of associated disabilities.
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http://dx.doi.org/10.1016/j.nlm.2018.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235725PMC
November 2019

Rigor and reproducibility in rodent behavioral research.

Neurobiol Learn Mem 2019 11 4;165:106780. Epub 2018 Jan 4.

IDDRC Rodent Behavior Core, MIND Institute, University of California Davis School of Medicine, Sacramento, CA 95817, USA. Electronic address:

Behavioral neuroscience research incorporates the identical high level of meticulous methodologies and exacting attention to detail as all other scientific disciplines. To achieve maximal rigor and reproducibility of findings, well-trained investigators employ a variety of established best practices. Here we explicate some of the requirements for rigorous experimental design and accurate data analysis in conducting mouse and rat behavioral tests. Novel object recognition is used as an example of a cognitive assay which has been conducted successfully with a range of methods, all based on common principles of appropriate procedures, controls, and statistics. Directors of Rodent Core facilities within Intellectual and Developmental Disabilities Research Centers contribute key aspects of their own novel object recognition protocols, offering insights into essential similarities and less-critical differences. Literature cited in this review article will lead the interested reader to source papers that provide step-by-step protocols which illustrate optimized methods for many standard rodent behavioral assays. Adhering to best practices in behavioral neuroscience will enhance the value of animal models for the multiple goals of understanding biological mechanisms, evaluating consequences of genetic mutations, and discovering efficacious therapeutics.
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http://dx.doi.org/10.1016/j.nlm.2018.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034984PMC
November 2019

Loss of Gas6 and Axl signaling results in extensive axonal damage, motor deficits, prolonged neuroinflammation, and less remyelination following cuprizone exposure.

Glia 2017 12 19;65(12):2051-2069. Epub 2017 Sep 19.

Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, 10461.

The TAM (Tyro3, Axl, and MerTK) family of receptor tyrosine kinases (RTKs) and their ligands, Gas6 and ProS1, are important for innate immune responses and central nervous system (CNS) homeostasis. While only Gas6 directly activates Axl, ProS1 activation of Tyro3/MerTK can indirectly activate Axl through receptor heterodimerization. Therefore, we generated Gas6 Axl double knockout (DKO) mice to specifically examine the contribution of this signaling axis while retaining ProS1 signaling through Tyro3 and MerTK. We found that naïve young adult DKO and WT mice have comparable myelination and equal numbers of axons and oligodendrocytes in the corpus callosum. Using the cuprizone model of demyelination/remyelination, transmission electron microscopy revealed extensive axonal swellings containing autophagolysosomes and multivesicular bodies, and fewer myelinated axons in brains of DKO mice at 3-weeks recovery from a 6-week cuprizone diet. Analysis of immunofluorescent staining demonstrated more SMI32+ and APP+ axons and less myelin in the DKO mice. There were no significant differences in the number of GFAP+ astrocytes or Iba1+ microglia/macrophages between the groups of mice. However, at 6-weeks cuprizone and recovery, DKO mice had increased proinflammatory cytokine and altered suppressor of cytokine signaling (SOCS) mRNA expression supporting a role for Gas6-Axl signaling in proinflammatory cytokine suppression. Significant motor deficits in DKO mice relative to WT mice on cuprizone were also observed. These data suggest that Gas6-Axl signaling plays an important role in maintaining axonal integrity and regulating and reducing CNS inflammation that cannot be compensated for by ProS1/Tyro3/MerTK signaling.
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http://dx.doi.org/10.1002/glia.23214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643251PMC
December 2017

Liposomal Cytarabine Induces Less Neurocognitive Dysfunction Than Intrathecal Methotrexate in an Animal Model.

J Pediatr Hematol Oncol 2018 03;40(2):e91-e96

Departments of Pediatrics.

Liposomal cytarabine is currently being tested clinically as an alternative to intrathecal (IT) methotrexate (MTX) for preventing relapse within the central nervous system among patients with acute lymphoblastic leukemia. To compare the toxicity and cognitive deficits caused by IT MTX versus liposomal cytarabine, juvenile Long Evans rats were treated with IT injections of MTX 1 mg/kg×4 doses over 8 days, or liposomal cytarabine 0.8 mg once. Mean concentrations of free cytarabine in cerebrospinal fluid remained above the cytotoxic threshold of 0.4 μM for 2 weeks after dosing. Animals treated with liposomal cytarabine exhibited normal recognition and spatial memory 4 weeks after injection. In contrast, exposure to IT MTX led to impaired cognitive function. In addition, mean hematocrit on day 11 was significantly lower in the MTX-treated animals (30.8%; 95% confidence interval, 27.0%-34.7%; n=6) compared with that in the liposomal cytarabine-treated animals (39.5%; 95% confidence interval, 38.4%-40.6%; n=6; P<0.0001). Our data suggest that liposomal cytarabine induces fewer neurocognitive deficits and less acute hematologic toxicity compared with IT MTX. Liposomal cytarabine may therefore have therapeutic advantages over IT MTX, if it is equally effective in preventing relapse.
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http://dx.doi.org/10.1097/MPH.0000000000000888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743776PMC
March 2018

A study of time- and sex-dependent effects of vortioxetine on rat sexual behavior: Possible roles of direct receptor modulation.

Neuropharmacology 2017 Jul 13;121:89-99. Epub 2017 Apr 13.

Lundbeck Research USA, Paramus, NJ, USA.

Treatment-related sexual dysfunction is a common side effect of antidepressants and contributes to patient non-compliance or treatment cessation. However, the multimodal antidepressant, vortioxetine, demonstrates low sexual side effects in depressed patients. To investigate the mechanisms involved, sexual behavior was assessed in male and female rats after acute, and repeated (7 and 14 days) treatment with vortioxetine, flesinoxan (a 5-HT receptor agonist), CP-94253 (a 5-HT receptor agonist), or ondansetron (a 5-HT receptor antagonist). These selective ligands were chosen to simulate vortioxetine's direct modulation of these receptors. Paroxetine was also included in the male study. Acute and repeated treatment with vortioxetine at doses corresponding to clinical levels (based on serotonin transporter occupancy) had minimal effects on sexual behavior in male and female rats. High dose vortioxetine plus flesinoxan (to mimic predicted clinical levels of 5-HT receptor occupancy by vortioxetine) facilitated male rat sexual behavior (acutely) while inhibiting female rat proceptive behavior (both acutely and after 14 days treatment). The selective serotonin reuptake inhibitor, paroxetine, inhibited male sexual behavior after repeated administration (7 and 14 days). Flesinoxan alone facilitated male sexual behavior acutely while inhibiting female rat proceptive behavior after repeated administration (7 and 14 days). CP-94253 inhibited sexual behavior in both male and female rats after repeated administration. Ondansetron had no effect on sexual behavior. These findings underline the complex serotonergic regulation of sexual behavior and indicate that the low sexual side effects of vortioxetine found in clinical studies are likely associated with its direct modulation of serotonin receptors.
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http://dx.doi.org/10.1016/j.neuropharm.2017.04.017DOI Listing
July 2017

Drugs with antidepressant properties affect tryptophan metabolites differently in rodent models with depression-like behavior.

J Neurochem 2017 07 16;142(1):118-131. Epub 2017 May 16.

Translational Neuropsychiatry Unit, Risskov, Denmark.

The metabolism of tryptophan through kynurenine and serotonin pathways is linked to depression. Here, effects of different drugs with antidepressant properties (vortioxetine, fluoxetine, and ketamine) on various tryptophan metabolites in different brain regions and plasma were examined using tandem mass spectrometry (LC-MS/MS), in Flinders Sensitive Line rats, a genetic rat model of depression, and its controls: Flinders Sensitive Line and Sprague-Dawley rats. Protein levels of kynurenine pathway enzymes were measured in the brains and livers of these rat strains. Furthermore, effects of vortioxetine on tryptophan metabolites were assessed in the cortical regions of lupus mice (MRL/MpJ-Fas ), a murine model of increased depression-like behavior associated with inflammation. Sustained vortioxetine or fluoxetine (at doses aimed to fully occupy serotonin transporter via food or drinking water for at least 14 days) reduced levels of the excitotoxin quinolinic acid (QUIN) in various brain regions in all rats. Furthermore, chronic vortioxetine reduced levels of QUIN in MRL/MpJ-Fas mice. Acute i.p. administration of fluoxetine (10 mg/kg) or vortioxetine (10 mg/kg) led to reduced brain 5-hydroxyindoleacetic acid in Sprague-Dawley rats (2, 4, 6, and 8 h) and a similar trend was evident in Flinders Sensitive Line and Flinders Sensitive Line rats after 4 h. In contrast, single or repeated administration of ketamine (15 mg/kg i.p.) did not induce significant changes in metabolite levels. In conclusion, sustained vortioxetine and fluoxetine administration decreased QUIN independent of species, while ketamine was ineffective. These results support the hypothesis that modulating tryptophan metabolism may be part of the mechanism of action for some antidepressants.
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http://dx.doi.org/10.1111/jnc.14043DOI Listing
July 2017

BXD recombinant inbred strains participate in social preference, anxiety and depression behaviors along sex-differences in cytokines and tactile allodynia.

Psychoneuroendocrinology 2017 Jun 6;80:92-98. Epub 2017 Mar 6.

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address:

Depression and anxiety are the most common psychiatric disorders, representing a major public health concern. Dysregulation of oxidative and inflammatory systems may be associated with psychiatric disorders, such as depression and anxiety. Due to the need to find appropriate animal models to the understanding of such disorders, we queried whether 2 BXD recombinant inbred (RI) mice strains (BXD21/TyJ RI and BXD84/RwwJ RI mice) and C57BL/6 wild-type mice show differential performance in depression and anxiety related behaviors and biomarkers. Specifically, we assessed social preference, elevated plus maze, forced swim, and Von Frey tests at 3-4 months-of-age, as well as activation of cytokines and antioxidant mRNA levels in the cortex at 7 months-of-age. We report that (1) the BXD84/RwwJ RI strain exhibits anxiety disorder and social avoidance-like behavior (2) BXD21/TyJ RI strain shows a resistance to depression illness, and (3) sex-dependent cytokine profiles and allodynia with elevated inflammatory activity were inherent to male BXD21/TyJ RI mice. In conclusion, we provide novel data in favor of the use of BXD recombinant inbred mice to further understand anxiety and depression disorders.
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http://dx.doi.org/10.1016/j.psyneuen.2017.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985819PMC
June 2017

Distinct Antidepressant-Like and Cognitive Effects of Antidepressants with Different Mechanisms of Action in Middle-Aged Female Mice.

Int J Neuropsychopharmacol 2017 06;20(6):510-515

Lundbeck Research USA, Paramus, New Jersey (Drs Li and Sanchez); Behavioral Core Facility, Neuroscience Dept., Albert Einstein College of Medicine (Dr Gulinello).

Background: Cognitive dysfunction is among the key symptoms of major depressive disorder and can be affected by antidepressants. Cognitive decline also occurs in normal aging. The effects of different antidepressants on affective and cognitive domains in older subjects are seldom assessed simultaneously.

Methods: Healthy middle-aged female mice received vehicle or antidepressant (vortioxetine, vilazodone, duloxetine, or fluoxetine) at therapeutic doses. After 1 month treatment, mice were accessed for visuospatial memory and depression-like behavior. A separate cohort of mice received 3 months of treatment and was test for recognition memory and depression-like behavior.

Results: After 1 month treatment, vortioxetine improved visuospatial memory and reduced depression-like behavior. Vilazodone reduced depression-like behavior. Duloxetine and fluoxetine were ineffective in both tests. After 3 months treatment, vortioxetine reduced depression-like behavior without affecting recognition memory, while fluoxetine impaired recognition memory. Duloxetine and vilazodone had no effect in both tests.

Conclusion: Different antidepressants have distinct effects in middle-aged female mice.
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http://dx.doi.org/10.1093/ijnp/pyx004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458342PMC
June 2017

Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington's disease.

Neurobiol Dis 2016 Dec 10;96:144-155. Epub 2016 Sep 10.

Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY, USA; The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address:

The mutation in huntingtin (mHtt) leads to a spectrum of impairments in the developing forebrain of Huntington's disease (HD) mouse models. Whether these developmental alterations are due to loss- or gain-of-function mechanisms and contribute to HD pathogenesis is unknown. We examined the role of selective loss of huntingtin (Htt) function during development on postnatal vulnerability to cell death. We employed mice expressing very low levels of Htt throughout embryonic life to postnatal day 21 (Hdh). We demonstrated that Hdh mice exhibit: (1) late-life striatal and cortical neuronal degeneration; (2) neurological and skeletal muscle alterations; and (3) white matter tract impairments and axonal degeneration. Hdh embryos also exhibited subpallial heterotopias, aberrant striatal maturation and deregulation of gliogenesis. These results indicate that developmental deficits associated with Htt functions render cells present at discrete neural foci increasingly susceptible to cell death, thus implying the potential existence of a loss-of-function developmental component to HD pathogenesis.
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http://dx.doi.org/10.1016/j.nbd.2016.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102778PMC
December 2016

In vivo and in vitro effects of vortioxetine on molecules associated with neuroplasticity.

J Psychopharmacol 2017 03 28;31(3):365-376. Epub 2016 Sep 28.

1 Lundbeck Research, Paramus, NJ, USA.

Neuroplasticity is fundamental for brain functions, abnormal changes of which are associated with mood disorders and cognitive impairment. Neuroplasticity can be affected by neuroactive medications and by aging. Vortioxetine, a multimodal antidepressant, has shown positive effects on cognitive functions in both pre-clinical and clinical studies. In rodent studies, vortioxetine increases glutamate neurotransmission, promotes dendritic branching and spine maturation, and elevates hippocampal expression of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) at the transcript level. The present study aims to assess the effects of vortioxetine on several neuroplasticity-related molecules in different experimental systems. Chronic (1 month) vortioxetine increased Arc/Arg3.1 protein levels in the cortical synaptosomes of young and middle-aged mice. In young mice, this was accompanied by an increase in actin-depolymerizing factor (ADF)/cofilin serine 3 phosphorylation without altering the total ADF/cofilin protein level, and an increase in the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor phosphorylation at serine 845 (S845) without altering serine 831 (S831) GluA1 phosphorylation nor the total GluA1 protein level. Similar effects were detected in cultured rat hippocampal neurons: Acute vortioxetine increased S845 GluA1 phosphorylation without changing S831 GluA1 phosphorylation or the total GluA1 protein level. These changes were accompanied by an increase in α subunit of Ca/calmodulin-dependent kinase (CaMKIIα) phosphorylation (at threonine 286) without changing the total CaMKIIα protein level in cultured neurons. In addition, chronic (1 month) vortioxetine, but not fluoxetine, restored the age-associated reduction in Arc/Arg3.1 and c-Fos transcripts in the frontal cortex of middle-aged mice. Taken together, these results demonstrated that vortioxetine modulates molecular targets that are related to neuroplasticity.
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http://dx.doi.org/10.1177/0269881116667710DOI Listing
March 2017

Selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington's disease.

Proc Natl Acad Sci U S A 2016 May 2;113(20):5736-41. Epub 2016 May 2.

Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY 10461; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY 10461; The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY 10461; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461; Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY 10461; Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461; Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY 10461; Center for Epigenomics, Albert Einstein College of Medicine, Bronx, NY 10461; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461

Recent studies have identified impairments in neural induction and in striatal and cortical neurogenesis in Huntington's disease (HD) knock-in mouse models and associated embryonic stem cell lines. However, the potential role of these developmental alterations for HD pathogenesis and progression is currently unknown. To address this issue, we used BACHD:CAG-Cre(ERT2) mice, which carry mutant huntingtin (mHtt) modified to harbor a floxed exon 1 containing the pathogenic polyglutamine expansion (Q97). Upon tamoxifen administration at postnatal day 21, the floxed mHtt-exon1 was removed and mHtt expression was terminated (Q97(CRE)). These conditional mice displayed similar profiles of impairments to those mice expressing mHtt throughout life: (i) striatal neurodegeneration, (ii) early vulnerability to NMDA-mediated excitotoxicity, (iii) impairments in motor coordination, (iv) temporally distinct abnormalities in striatal electrophysiological activity, and (v) altered corticostriatal functional connectivity and plasticity. These findings strongly suggest that developmental aberrations may play important roles in HD pathogenesis and progression.
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http://dx.doi.org/10.1073/pnas.1603871113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878495PMC
May 2016

Sleep duration, depression, and oxytocinergic genotype influence prepulse inhibition of the startle reflex in postpartum women.

Eur Neuropsychopharmacol 2016 Apr 22;26(4):767-76. Epub 2016 Jan 22.

Department of Women's and Children׳s Health, Uppsala University, Uppsala, Sweden.

The postpartum period is characterized by a post-withdrawal hormonal status, sleep deprivation, and susceptibility to affective disorders. Postpartum mothering involves automatic and attentional processes to screen out new external as well as internal stimuli. The present study investigated sensorimotor gating in relation to sleep duration, depression, as well as catecholaminergic and oxytocinergic genotypes in postpartum women. Prepulse inhibition (PPI) of the startle reflex and startle reactivity were assessed two months postpartum in 141 healthy and 29 depressed women. The catechol-O-methyltransferase (COMT) Val158Met, and oxytocin receptor (OXTR) rs237885 and rs53576 polymorphisms were genotyped, and data on sleep duration were collected. Short sleep duration (less than four hours in the preceding night) and postpartum depression were independently associated with lower PPI. Also, women with postpartum depression had higher startle reactivity in comparison with controls. The OXTR rs237885 genotype was related to PPI in an allele dose-dependent mode, with T/T healthy postpartum women carriers displaying the lowest PPI. Reduced sensorimotor gating was associated with sleep deprivation and depressive symptoms during the postpartum period. Individual neurophysiological vulnerability might be mediated by oxytocinergic genotype which relates to bonding and stress response. These findings implicate the putative relevance of lower PPI of the startle response as an objective physiological correlate of liability to postpartum depression.
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http://dx.doi.org/10.1016/j.euroneuro.2016.01.002DOI Listing
April 2016

Intracerebroventricular administration of TNF-like weak inducer of apoptosis induces depression-like behavior and cognitive dysfunction in non-autoimmune mice.

Brain Behav Immun 2016 May 23;54:27-37. Epub 2015 Dec 23.

The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA; Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address:

Fn14, the sole known signaling receptor for the TNF family member TWEAK, is inducibly expressed in the central nervous system (CNS) in endothelial cells, astrocytes, microglia, and neurons. There is increasing recognition of the importance of the TWEAK/Fn14 pathway in autoimmune neurologic conditions, including experimental autoimmune encephalomyelitis and neuropsychiatric lupus. Previously, we had found that Fn14 knockout lupus-prone MRL/lpr mice display significantly attenuated neuropsychiatric manifestations. To investigate whether this improvement in disease is secondary to inhibition of TWEAK/Fn14 signaling within the CNS or the periphery, and determine whether TWEAK-mediated neuropsychiatric effects are strain dependent, we performed intracerebroventricular (ICV) injection of Fc-TWEAK or an isotype matched control protein to C57Bl6/J non-autoimmune mice. We found that Fc-TWEAK injected C57Bl6/J mice developed significant depression-like behavior and cognitive dysfunction. Inflammatory mediators associated with lupus brain disease, including CCL2, C3, and iNOS, were significantly elevated in the brains of Fc-TWEAK treated mice. Furthermore, Fc-TWEAK directly increased blood brain barrier (BBB) permeability, as demonstrated by increased IgG deposition in the brain and reduced aquaporin-4 expression. Finally, Fc-TWEAK increased apoptotic cell death in the cortex and hippocampus. In conclusion, TWEAK can contribute to lupus-associated neurobehavioral deficits including depression and cognitive dysfunction by acting within the CNS to enhance production of inflammatory mediators, promote disruption of the BBB, and induce apoptosis in resident brain cells. Our study provides further support that the TWEAK/Fn14 signaling pathway may be a potential therapeutic target for inflammatory diseases involving the CNS.
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http://dx.doi.org/10.1016/j.bbi.2015.12.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828298PMC
May 2016

Neuropsychiatric systemic lupus erythematosus persists despite attenuation of systemic disease in MRL/lpr mice.

J Neuroinflammation 2015 Nov 6;12:205. Epub 2015 Nov 6.

The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.

Background: Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease marked by both B and T cell hyperactivity which commonly affects the joints, skin, kidneys, and brain. Neuropsychiatric disease affects about 40 % of SLE patients, most frequently manifesting as depression, memory deficits, and general cognitive decline. One important and yet unresolved question is whether neuropsychiatric SLE (NPSLE) is a complication of systemic autoimmunity or whether it is primarily driven by brain-intrinsic factors.

Methods: To dissect the relative contributions of the central nervous system from those of the hematopoietic compartment, we generated bone marrow chimeras between healthy control (MRL/+) and lupus-prone MRL/Tnfrsf6 (lpr/lpr) mice (MRL/+ → MRL/lpr), as well as control chimeras. After bone marrow reconstitution, mice underwent extensive behavioral testing, analysis of brain tissue, and histological assessment.

Results: Despite transfer of healthy MRL/+ bone marrow and marked attenuation of systemic disease, we found that MRL/+ → MRL/lpr mice had a behavioral phenotype consisting of depressive-like behavior and visuospatial memory deficits, comparable to MRL/lpr → MRL/lpr control transplanted mice and the behavioral profile previously established in MRL/lpr mice. Moreover, MRL/+ → MRL/lpr chimeric mice displayed increased brain RANTES expression, neurodegeneration, and cellular infiltration in the choroid plexus, as well as blood brain barrier disruption, all in the absence of significant systemic autoimmunity.

Conclusions: Chimeric MRL/+ → MRL/lpr mice displayed no attenuation of the behavioral phenotype found in MRL/lpr mice, despite normalized serum autoantibodies and conserved renal function. Therefore, neuropsychiatric disease in the MRL/lpr lupus-prone strain of mice can occur absent any major contributions from systemic autoimmunity.
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http://dx.doi.org/10.1186/s12974-015-0423-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636802PMC
November 2015

X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities.

Dis Model Mech 2016 Jan 29;9(1):13-23. Epub 2015 Oct 29.

Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA

Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/β-galactosidase (β-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, β-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.
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http://dx.doi.org/10.1242/dmm.022780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728337PMC
January 2016

Hippocampal-dependent neurocognitive impairment following cranial irradiation observed in pre-clinical models: current knowledge and possible future directions.

Br J Radiol 2016 30;89(1057):20150762. Epub 2015 Oct 30.

1 Institute for Onco-Physics, Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY, USA.

We reviewed the literature for studies pertaining to impaired adult neurogenesis leading to neurocognitive impairment following cranial irradiation in rodent models. This compendium was compared with respect to radiation dose, converted to equivalent dose in 2 Gy fractions (EQD2) to allow for direct comparison between studies. The effects of differences between animal species and the dependence on animal age as well as for time after irradiation were also considered. One of the major sites of de novo adult neurogenesis is the hippocampus, and as such, this review also focuses on assessing evidence related to the expression and potential effects of inflammatory cytokines on neural stem cells in the subgranular zone of the dentate gyrus and whether this correlates with neurocognitive impairment. This review also discusses potential strategies to mitigate the detrimental effects on neurogenesis and neurocognition resulting from cranial irradiation, and how the rationale for these strategies compares with the current outcome of pre-clinical studies.
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http://dx.doi.org/10.1259/bjr.20150762DOI Listing
May 2016

A mouse model replicating hippocampal sparing cranial irradiation in humans: A tool for identifying new strategies to limit neurocognitive decline.

Sci Rep 2015 Sep 24;5:14384. Epub 2015 Sep 24.

Institute for Onco-Physics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Cancer patients undergoing cranial irradiation are at risk of developing neurocognitive impairments. Recent evidence suggests that radiation-induced injury to the hippocampi could play an important role in this cognitive decline. As a tool for studying the mechanisms of hippocampal-dependent cognitive decline, we developed a mouse model replicating the results of the recent clinical RTOG 0933 study of hippocampal sparing whole-brain irradiation. We irradiated 16-week-old female C57BL/6J mice to a single dose of 10 Gy using either whole-brain irradiation (WBRT) or hippocampal sparing irradiation (HSI). These animals, as well as sham-irradiated controls, were subjected to behavioral/cognitive assessments distinguishing between hippocampal-dependent and hippocampal-independent functions. Irradiation was well tolerated by all animals and only limited cell death of proliferating cells was found within the generative zones. Animals exposed to WBRT showed significant deficits compared to sham-irradiated controls in the hippocampal-dependent behavioral task. In contrast, HSI mice did not perform significantly different from sham-irradiated mice (control group) and performed significantly better when compared to WBRT mice. This is consistent with the results from the RTOG 0933 clinical trial, and as such this animal model could prove a helpful tool for exploring new strategies for mitigating cognitive decline in cancer patients receiving cranial irradiation.
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http://dx.doi.org/10.1038/srep14384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585869PMC
September 2015

A critical evaluation of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1)'s putative role in regulating dendritic plasticity, cognitive processes, and mood in animal models of depression.

Front Neurosci 2015 10;9:279. Epub 2015 Aug 10.

Behavioral Core Facility, Department of Neuroscience, Albert Einstein College of Medicine Bronx, NY, USA.

Major depressive disorder (MDD) is primarily conceptualized as a mood disorder but cognitive dysfunction is also prevalent, and may limit the daily function of MDD patients. Current theories on MDD highlight disturbances in dendritic plasticity in its pathophysiology, which could conceivably play a role in the production of both MDD-related mood and cognitive symptoms. This paper attempts to review the accumulated knowledge on the basic biology of the activity-regulated cytoskeleton-associated protein (Arc or Arg3.1), its effects on neural plasticity, and how these may be related to mood or cognitive dysfunction in animal models of MDD. On a cellular level, Arc plays an important role in modulating dendritic spine density and remodeling. Arc also has a close, bidirectional relationship with postsynaptic glutamate neurotransmission, since it is stimulated by multiple glutamatergic receptor mechanisms but also modulates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor internalization. The effects on AMPA receptor trafficking are likely related to Arc's ability to modulate phenomena such as long-term potentiation, long-term depression, and synaptic scaling, each of which are important for maintaining proper cognitive function. Chronic stress models of MDD in animals show suppressed Arc expression in the frontal cortex but elevation in the amygdala. Interestingly, cognitive tasks depending on the frontal cortex are generally impaired by chronic stress, while those depending on the amygdala are enhanced, and antidepressant treatments stimulate cortical Arc expression with a timeline that is reminiscent of the treatment efficacy lag observed in the clinic or in preclinical models. However, pharmacological treatments that stimulate regional Arc expression do not universally improve relevant cognitive functions, and this highlights a need to further refine our understanding of Arc on a subcellular and network level.
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http://dx.doi.org/10.3389/fnins.2015.00279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530346PMC
August 2015

Behavioral Deficits Are Accompanied by Immunological and Neurochemical Changes in a Mouse Model for Neuropsychiatric Lupus (NP-SLE).

Int J Mol Sci 2015 Jul 3;16(7):15150-71. Epub 2015 Jul 3.

Behavioral Core Facility, Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology. Neuropsychiatric symptoms, particularly affective and cognitive indications, may be among the earliest manifestations of SLE. Among the potential pathophysiological mechanisms responsible for NP-SLE are increased peripheral pro-inflammatory cytokines, subsequent induction of indoleamine-2,3-dioxygenase (IDO) and activation of the kynurenine pathway. In the MRL/MpJ-Faslpr (MRL/lpr) murine model of lupus, depression-like behavior and cognitive dysfunction is evident before significant levels of autoantibody titers and nephritis are present. We examined the behavioral profile of MRL/lpr mice and their congenic controls, a comprehensive plasma cytokine and chemokine profile, and brain levels of serotonin and kynurenine pathway metabolites. Consistent with previous studies, MRL/lpr mice had increased depression-like behavior and visuospatial memory impairment. Plasma levels of different inflammatory molecules (Haptoglobin, interleukin 10 (IL-10), interferon γ-inducible protein 10 (IP-10/CXCL10), lymphotactin, macrophage inhibitory protein 3β (MIP-3β/CCL19), monocyte chemotactic protein 1, 3 and 5 (MCP-1/CCL2, MCP-3/CCL7, MCP-5/CCL12), vascular cell adhesion molecule 1 (VCAM-1), lymphotactin and interferon γ (IFN-γ)) were increased in MRL/lpr mice. In cortex and hippocampus, MRL/lpr mice had increased levels of kynurenine pathway metabolites (kynurenine, 3-hydroxykynurenine, 3-hydroxynthranilic acid and quinolinic acid). Therefore, our study suggests that increased cytokine expression may be critical in the regulation subtle aspects of brain function in NP-SLE via induction of IDO and tryptophan/kynurenine metabolism.
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http://dx.doi.org/10.3390/ijms160715150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519892PMC
July 2015

Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice.

Pharmacol Biochem Behav 2015 Aug 2;135:70-82. Epub 2015 Jun 2.

Behavioral Core Facility, Department of Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Pkwy S., Bronx, NY 10461, United States. Electronic address:

Cognitive decline occurs during healthy aging, even in middle-aged subjects, via mechanisms that could include reduced stem cell proliferation, changed growth factor expression and/or reduced expression of synaptic plasticity genes. Although antidepressants alter these mechanisms in young rodents, their effects in older animals are unclear. In middle-aged mice, we examined the effects of a selective serotonin reuptake inhibitor (fluoxetine) and a multimodal antidepressant (vortioxetine) on cognitive and affective behaviors, brain stem cell proliferation, growth factor and gene expression. Twelve-month-old female C57BL/6 mice exhibited impaired visuospatial memory in the novel object placement (location) task associated with reduced expression of several plasticity-related genes. Chronic treatment with vortioxetine, but not fluoxetine, improved visuospatial memory and reduced depression-like behavior in the forced swim test in middle-aged mice. Vortioxetine, but not fluoxetine, increased hippocampal expression of several neuroplasticity-related genes in middle-aged mice (e.g., Nfkb1, Fos, Fmr1, Camk2a, Arc, Shank1, Nlgn2, and Rab3a). Neither drug reversed the age-associated decrease in stem cell proliferation. Hippocampal growth factor levels were not consistent with behavioral outcomes. Thus, a change in the expression of multiple genes involved in neuronal plasticity by antidepressant treatment was associated with improved cognitive function and a reduction in depression-like behavior in middle-aged mice.
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http://dx.doi.org/10.1016/j.pbb.2015.05.013DOI Listing
August 2015

TNF-like weak inducer of apoptosis promotes blood brain barrier disruption and increases neuronal cell death in MRL/lpr mice.

J Autoimmun 2015 Jun 22;60:40-50. Epub 2015 Apr 22.

Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Division of Rheumatology and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address:

Neuropsychiatric disease is one of the most common manifestations of human systemic lupus erythematosus, but the mechanisms remain poorly understood. In human brain microvascular endothelial cells in vitro, TNF-like weak inducer of apoptosis (TWEAK) decreases tight junction ZO-1 expression and increases the permeability of monolayer cell cultures. Furthermore, knockout (KO) of the TWEAK receptor, Fn14, in the MRL/lpr lupus mouse strain markedly attenuates neuropsychiatric disease, as demonstrated by significant reductions in depressive-like behavior and improved cognitive function. The purpose of the present study was to determine the mechanisms by which TWEAK signaling is instrumental in the pathogenesis of neuropsychiatric lupus (NPSLE). Evaluating brain sections of MRL/lpr Fn14WT and Fn14KO mice, we found that Fn14KO mice displayed significantly decreased cellular infiltrates in the choroid plexus. To evaluate the integrity of the blood brain barrier (BBB) in MRL/lpr mice, Western blot for fibronectin, qPCR for iNOS, and immunohistochemical staining for VCAM-1/ICAM-1 were performed. We found preserved BBB permeability in MRL/lpr Fn14KO mice, attributable to reduced brain expression of VCAM-1/ICAM-1 and iNOS. Additionally, administration of Fc-TWEAK intravenously directly increased the leakage of a tracer (dextran-FITC) into brain tissue. Furthermore, MRL/lpr Fn14KO mice displayed reduced antibody (IgG) and complement (C3, C6, and C4a) deposition in the brain. Finally, we found that MRL/lpr Fn14KO mice manifested reduced neuron degeneration and hippocampal gliosis. Our studies indicate that TWEAK/Fn14 interactions play an important role in the pathogenesis of NPSLE by increasing the accumulation of inflammatory cells in the choroid plexus, disrupting BBB integrity, and increasing neuronal damage, suggesting a novel target for therapy in this disease.
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http://dx.doi.org/10.1016/j.jaut.2015.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457585PMC
June 2015

Rescue of homeostatic regulation of striatal excitability and locomotor activity in a mouse model of Huntington's disease.

Proc Natl Acad Sci U S A 2015 Feb 2;112(7):2239-44. Epub 2015 Feb 2.

Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461

We describe a fast activity-dependent homeostatic regulation of intrinsic excitability of identified neurons in mouse dorsal striatum, the striatal output neurons. It can be induced by brief bursts of activity, is expressed on a time scale of seconds, limits repetitive firing, and can convert regular firing patterns to irregular ones. We show it is due to progressive recruitment of the KCNQ2/3 channels that generate the M current. This homeostatic mechanism is significantly reduced in striatal output neurons of the R6/2 transgenic mouse model of Huntington's disease, at an age when the neurons are hyperactive in vivo and the mice begin to exhibit locomotor impairment. Furthermore, it can be rescued by bath perfusion with retigabine, a KCNQ channel activator, and chronic treatment improves locomotor performance. Thus, M-current dysfunction may contribute to the hyperactivity and network dysregulation characteristic of this neurodegenerative disease, and KCNQ2/3 channel regulation may be a target for therapeutic intervention.
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http://dx.doi.org/10.1073/pnas.1405748112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343133PMC
February 2015