Louise D McCullough

University of Connecticut, Сторс, Connecticut, United States

Are you Louise D McCullough?

Claim your profile

Publications (143)597.85 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neonatal hypoxic-ischemic encephalopathy (HIE) is an important cause of motor and cognitive impairment in children. Clinically, male infants are more vulnerable to ischemic insults and suffer more long-term deficits than females; however, the mechanisms underlying this sex difference remain elusive. Inflammatory processes initiated by microglial activation are fundamental in the pathophysiology of ischemia. Recent studies report a sexual dimorphism in microglia numbers and expression of activation markers in the neonatal brain under normal conditions. How these basal sex differences in microglia affect HIE remains largely unexplored. This study investigated sex differences in ischemic outcomes and inflammation triggered by HIE. We hypothesize that ischemia induces sex-specific brain injury in male and female neonates and that microglial activation and inflammatory responses play an important role in this sexual dimorphism. Male and female C57BL6 mice were subjected to 60-min Rice-Vanucci modeling (RVM) at post-natal day 10 (P10) to induce HIE. Stroke outcomes were measured 1, 3, 7, and 30 days after stroke. Microglial activation and inflammatory responses were evaluated by flow cytometry and cytokine analysis. On day 1 of HIE, no difference in infarct volumes or seizure scores was seen between male and female neonates. However, female neonates exhibited significantly smaller infarct size and fewer seizures compared to males 3 days after HIE. Females also had less brain tissue loss and behavioral deficits compared to males at the chronic stage of HIE. Male animals demonstrated increased microglial activation and up-regulated inflammatory response compared to females at day 3. HIE leads to an equivalent primary brain injury in male and female neonates at the acute stage that develops into sexually dimorphic outcomes at later time points. An innate immune response secondary to the primary injury may contribute to sexual dimorphism in HIE.
    Journal of Neuroinflammation 12/2015; 12(1). DOI:10.1186/s12974-015-0251-6 · 4.90 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Memory deficits are common among stroke survivors. Identifying neuroprotective agents that can prevent memory impairment or improve memory recovery is a vital area of research. Glycogen synthase kinase-3β (GSK-3β) is involved in several essential intracellular signaling pathways. Unlike many other kinases, GSK-3β is active only when dephosphorylated and activation promotes inflammation and apoptosis. In contrast, increased phosphorylation leads to reduced GSK-3β (pGSK-3β) activity. GSK-3β inhibition has beneficial effects on memory in other disease models. GSK-3β regulates both the 5'AMP-activated kinase (AMPK) and transforming growth factor-β-activated kinase (TAK1) pathways. In this work, we examined the effect of GSK-3β inhibition, both independently, in conjunction with a TAK inhibitor, and in AMPK-α2 deficient mice, after stroke to investigate mechanistic interactions between these pathways. GSK-3β inhibition was neuroprotective and ameliorated stroke-induced cognitive impairments. This was independent of AMPK signaling as the protective effects of GSK-3β inhibition were seen in AMPK deficient mice. However, GSK-3β inhibition provided no additive protection in mice treated with a TAK inhibitor suggesting that TAK1 is an upstream regulator of GSK-3β. Targeting GSK-3β could be a novel therapeutic strategy for post-stroke cognitive deficits. © 2015 Venna et al.; Published by Cold Spring Harbor Laboratory Press.
    Learning & memory (Cold Spring Harbor, N.Y.) 06/2015; 22(7). DOI:10.1101/lm.038083.115 · 4.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The brain's initial innate response to stroke is primarily mediated by microglia, the resident macrophage of the CNS. However, as early as 4 h after stroke, the blood-brain barrier is compromised and monocyte infiltration occurs. The lack of discriminating markers between these two myeloid populations has led many studies to generate conclusions based on the grouping of these two populations. A growing body of evidence now supports the distinct roles played by microglia and monocytes in many disease models. Using a flow cytometry approach, combined with ex-vivo functional assays, we were able to distinguish microglia from monocytes using the relative expression of CD45 and assess the function of each cell type following stroke over the course of 7 days. We found that at 72 h after a 90-min middle cerebral artery occlusion (MCAO), microglia populations decrease whereas monocytes significantly increase in the stroke brain compared to sham. After stroke, BRDU incorporation into monocytes in the bone marrow increased. After recruitment to the ischemic brain, these monocytes accounted for nearly all BRDU-positive macrophages. Inflammatory activity peaked at 72 h. Microglia produced relatively higher reactive oxygen species and TNF, whereas monocytes were the predominant IL-1β producer. Although microglia showed enhanced phagocytic activity after stroke, monocytes had significantly higher phagocytic capacity at 72 h. Interestingly, we found a positive correlation between TNF expression levels and phagocytic activity of microglia after stroke. In summary, the resident microglia population is vulnerable to the effects of severe ischemia, show compromised cell cycle progression, and adopt a largely pro-inflammatory phenotype after stroke. Infiltrating monocytes are primarily involved with early debris clearance of dying cells. These findings suggest that the early wave of infiltrating monocytes may be beneficial to stroke repair and future therapies aimed at mitigating microglia cell death may prove more effective than attempting to elicit targeted anti-inflammatory responses from damaged cells.
    Journal of Neuroinflammation 05/2015; 12(1):106. DOI:10.1186/s12974-015-0329-1 · 4.90 Impact Factor
  • Matthew D Howe, Louise D McCullough
    [Show abstract] [Hide abstract]
    ABSTRACT: Stroke is the leading cause of acquired disability and the third leading cause of death in women worldwide. Sex differences in risk factors, treatment response and quality of life after stroke complicate stroke management in women. Women have an increased lifetime incidence of stroke compared to men, largely due to a sharp increase in stroke risk in older postmenopausal women. Women also have an increased lifetime prevalence of stroke risk factors, including hypertension and atrial fibrillation in postmenopausal women, as well as abdominal obesity and metabolic syndrome in middle-aged women. Controversy continues over the risks of oral contraceptives, hormone therapy and surgical intervention for carotid stenosis in women. Pregnancy and the postpartum period represent a time of increased risk, presenting challenges to stroke management. Recognition of these issues is critical to improving acute care and functional recovery after stroke in women.
    Expert Review of Cardiovascular Therapy 03/2015; 13(4):1-13. DOI:10.1586/14779072.2015.1020300
  • [Show abstract] [Hide abstract]
    ABSTRACT: Inflammation in the central nervous system (CNS) is primarily regulated by microglia. No longer considered a homogenous population, microglia display a high degree of heterogeneity, immunological diversity and regional variability in function. Given their low rate of self-renewal, the microenvironment in which microglia reside may play an important role in microglial senescence. This study examines age-related changes in microglia in the brain and spinal cord. Using ex-vivo flow cytometry analyses, functional assays were performed to assess changes in microglial morphology, oxidative stress, cytokine production, and phagocytic activity with age in both the brain and spinal cord. The regional CNS environment had a significant effect on microglial activity with age. Blood-CNS barrier permeability was greater in the aging spinal cord compared with aging brain; this was associated with increased tissue cytokine levels. Aged microglia had deficits in phagocytosis at baseline and after stimulus-induced activation. The identification of age-specific, high scatter microglia together with the use of ex-vivo functional analyses provides the first functional characterization of senescent microglia. Age and regional-specificity of CNS disease should be taken into consideration when developing immune-modulatory treatments. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of aging 02/2015; 36(6). DOI:10.1016/j.neurobiolaging.2015.02.016 · 4.85 Impact Factor
  • Mehwish A. Mirza, Yan Xu, Louise D. McCullough, Fudong Liu
    American-Heart-Association/American Stroke Association International; 02/2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Speech impairments affect one in four stroke survivors. However, animal models of post-ischemic vocalization deficits are limited. Male mice vocalize at ultrasonic frequencies when exposed to an estrous female mouse. In this study we assessed vocalization patterns and quantity in male mice after cerebral ischemia. FOXP2, a gene associated with verbal dyspraxia in humans, with known roles in neurogenesis and synaptic plasticity, was also examined after injury. Using a transient middle cerebral artery occlusion (MCAO) model, we assessed correlates of vocal impairment at several time-points after stroke. Further, to identify possible lateralization of vocalization deficits induced by left and right hemispheric strokes were compared. Significant differences in vocalization quantity were observed between stroke and sham animals that persisted for a month after injury. Injury to the left hemisphere reduced early vocalizations more profoundly than those to the right hemisphere. Nuclear expression of Foxp2 was elevated early after stroke (at 6hours), but significantly decreased 24hours after injury in both the nucleus and the cytoplasm. Neuronal Foxp2 expression increased in stroke mice compared to sham animals 4 weeks after injury. This study demonstrates that quantifiable deficits in ultrasonic vocalizations (USVs) are seen after stroke. USV may be a useful tool to assess chronic behavioral recovery in murine models of stroke. Copyright © 2015 Elsevier B.V. All rights reserved.
    Behavioural Brain Research 01/2015; 283. DOI:10.1016/j.bbr.2015.01.035 · 3.39 Impact Factor
  • Violiza Inoa, Louise D McCullough
    [Show abstract] [Hide abstract]
    ABSTRACT: Movement disorders have been reported as rare complications of stroke. The basal ganglia have been implicated in the pathophysiology of most post-stroke dyskinesias. We outline different types of post-stroke myoclonus and their possible pathophysiology. A middle-aged man developed generalized myoclonus after an ischemic stroke in the superior midbrain and subthalamic nuclei. Spontaneous resolution was seen by 72 hours. A lesion to the subthalamic nuclei disrupted the normal thalamic inhibition, which likely led to the involuntary movements seen in our patient. In this case, myoclonus was generalized, which, to the best of our knowledge, has not been reported in the literature as a direct consequence of focal stroke.
    01/2015; 5(1):28-31. DOI:10.1177/1941874413515679
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Stroke is the fifth leading cause of death and the primary cause of long-term adult disability in the United States. Increasing evidence suggests that low T3 levels immediately following acute ischemic stroke are associated with greater stroke severity, higher mortality rates, and poorer functional outcomes. Prognosis is also poor in critically ill hospitalized patients who have non-thyroidal illness syndrome (NTIS), where T3 levels are low, but TSH is normal. However, data regarding the association between TSH levels and functional outcomes are contradictory. Thus, this study investigated the role of TSH on stroke outcomes, concomitantly with T3 and T4. In this work, blood was collected from patients with radiologically confirmed acute ischemic stroke at 24±6 hours post-symptom onset and serum levels of TSH, free T3, and free T4 were measured. Stroke outcomes were measured at discharge, 3 and 12 months using the modified Rankin scale and modified Barthel Index as markers of disability. Though we found that lower levels of free T3 were associated with worse prognosis at hospital discharge, and at 3 and 12 months post-stroke, none of these outcomes held after multivariate analysis. Thus, it is likely that thyroid hormones are associated with other factors that impact stroke outcomes, such as sex, age and stroke etiology. This study found that lower levels of free T3 were associated with poorer outcomes at hospital discharge, and at 3 and 12 months post stroke, however, these associations diminished after correction for other known predictors of stroke outcome. Thyroid hormones have a complex relationship with ischemic stroke and stroke recovery, which merits further larger investigations.
    Thyroid Research 01/2015; 8:9. DOI:10.1186/s13044-015-0021-7
  • Brett Friedler, Joshua Crapser, Louise McCullough
    [Show abstract] [Hide abstract]
    ABSTRACT: The deleterious effects of chronic social isolation (SI) have been recognized for several decades. Isolation is a major source of psychosocial stress and is associated with an increased prevalence of vascular and neurological diseases. In addition, isolation exacerbates morbidity and mortality following acute injuries such as stroke or myocardial infarction. In contrast, affiliative social interactions can improve organismal function and health. The molecular mechanisms underlying these effects are unknown. Recently, results from large epidemiological trials and pre-clinical studies have revealed several potential mediators of the detrimental effects of isolation. At least three major biological systems have been implicated: the neuroendocrine (HPA) axis, the immune system, and the autonomic nervous system. This review summarizes studies examining the relationship between isolation and mortality and the pathophysiological mechanisms underlying SI. Cardiovascular, cerebrovascular, and neurological diseases including atherosclerosis, myocardial infarction, ischemic stroke and Alzheimer's disease are given special emphasis in the context of SI. Sex differences are highlighted and studies are separated into clinical and basic science for clarity.
    Acta Neuropathologica 12/2014; 129(4). DOI:10.1007/s00401-014-1377-9 · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Substantial evidence from both experimental and clinical studies has demonstrated that social isolation can increase stroke incidence and impair recovery. Social isolation leads to higher rates of recurrent stroke but is often not reported as a risk factor. We examined prospectively collected stroke center database variables, which included prestroke living situation, to determine if social isolation could be determined from existing data using living arrangement as a proxy. Patients were categorized into 4 groups hypothesized to represent increasing levels of social isolation: living with spouse, living with family, living alone with visiting services, and living alone. Initial stroke severity and recovery were measured using the National Institutes of Health Stroke Scale and Barthel Index, respectively. A multivariate model was used to determine the relationship among prestroke living situation, stroke severity, and functional outcome. Patients living alone had less severe strokes on admission and better recovery at 3 months compared with the other cohorts. Patients living alone or those who lived with a spouse had less severe strokes on presentation and better recovery at both 3 and 12 months after stroke compared with the other cohorts. However, on detailed examination, it was found that these patients also had significantly higher prestroke function. Pre-existing depression was significantly higher in women, and depressed patients had poorer outcomes 3 months after stroke. Information regarding isolation is notably absent from most large stroke databases. A more comprehensive evaluation of social interaction should be obtained to more accurately measure social isolation. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.
    Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 12/2014; 24(2). DOI:10.1016/j.jstrokecerebrovasdis.2014.09.024 · 1.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Epidemiologic studies have shown sex differences in ischemic stroke. The four core genotype (FCG) mouse model, in which the testes determining gene, Sry, has been moved from Y chromosome to an autosome, was used to dissociate the effects of sex hormones from sex chromosome in ischemic stroke outcome. Middle cerebral artery occlusion (MCAO) in gonad intact FCG mice revealed that gonadal males (XXM and XYM) had significantly higher infarct volumes as compared with gonadal females (XXF and XYF). Serum testosterone levels were equivalent in adult XXM and XYM, as was serum estrogen in XXF and XYF mice. To remove the effects of gonadal hormones, gonadectomized FCG mice were subjected to MCAO. Gonadectomy significantly increased infarct volumes in females, while no change was seen in gonadectomized males, indicating that estrogen loss increases ischemic sensitivity. Estradiol supplementation in gonadectomized FCG mice rescued this phenotype. Interestingly, FCG male mice were less sensitive to effects of hormones. This may be due to enhanced expression of the transgene Sry in brains of FCG male mice. Sex differences in ischemic stroke sensitivity appear to be shaped by organizational and activational effects of sex hormones, rather than sex chromosomal complement.Journal of Cerebral Blood Flow & Metabolism advance online publication, 12 November 2014; doi:10.1038/jcbfm.2014.186.
    Journal of Cerebral Blood Flow & Metabolism 11/2014; 35(2). DOI:10.1038/jcbfm.2014.186 · 5.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neurogenic stress cardiomyopathy (NCM) has been associated with poor outcomes in the setting of aneurysmal subarachnoid hemorrhage (aSAH). Much less is known regarding recovery of cardiac function. The aim of this prospective cohort study was to study the rate of early cardiac recovery after NCM and the potential effect of NCM on short term functional recovery. A secondary aim sought to determine whether certain biomarkers may be associated with the development of NCM.Methods Patients with confirmed aSAH between November 2012 and October 2013 were prospectively enrolled and received echocardiograms within 48 h of admission. Ejection fraction (%) and regional wall motion abnormality score index (RWMI) were noted. All patients with confirmed aSAH had a troponin and BNP level drawn on admission. Patients with confirmed NCM received a follow up echocardiogram 7–21 days after the initial echocardiogram. Clinical follow up at 3 months evaluated mortality, mRS and mBI scores.Results63 patients with confirmed aSAH were enrolled. In this cohort 11 (17%) patients were confirmed to have NCM. The NCM group had higher in-hospital mortality [n = 4(36.4%)] compared to the non-NCM group [n = 5(9.6%)] (p = .021). At 3 months the development of NCM was associated with an unfavorable mRS (p = 0.042) and mBI (p = 0.005). Both an elevated BNP (>100 pg/mL) and elevated troponin (>0.3 mg/dL) were associated with the development of NCM. Follow-up echocardiograms were performed within 21 days of admission on 8 patients with NCM. An abnormal RWMI of 1.5 or higher was present in 5(71%) patients.ConclusionNCM is a frequent complication associated with aSAH. The onset of the disease occurs early in the course of aSAH and an elevated BNP and troponin may be associated with the onset of NCM. Cardiac function often remains impaired during the acute recovery phase potentially impeding resuscitation during this period. The routine use of short term follow-up echocardiography may be recommended.
    Clinical Neurology and Neurosurgery 11/2014; 128. DOI:10.1016/j.clineuro.2014.10.017 · 1.25 Impact Factor
  • Source
    Lin Liu, Louise McCullough, Jun Li
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Stroke is the primary cause of long-term disability in the United States. Interestingly, mounting evidence has suggested potential sex differences in the response to stroke treatment in patients as, at least in part, distinct cell death programs may be triggered in females and males following stroke. The NIH has recognized that females are strikingly under-represented in pre-clinical trials. Calcium/calmodulin-dependent protein kinase kinase (CaMKK) is a major kinase that is activated by elevated intracellular calcium. It has recently been suggested that CaMKK and CaMK IV, a downstream target molecule, are neuroprotective in stroke in males. In this study, we examined stroke outcomes in ovariectomized CaMKK ß and CaMK IV deficient females. Cell death/survival signaling and inflammatory responses were assessed.ResultsOur results demonstrated that CaMKK ß or CaMK IV KO exacerbated both ischemic injury and behavioral deficits in female mice. Genetic deletion of CaMKK ß or CaMK IV increased hemorrhagic transformation after stroke, and this was associated with both increased MMP9 activity and loss of the blood brain barrier (BBB) protein collagen IV. Transcriptional inactivation was observed in mice lacking either CaMKK ß or CaMK IV, as indicated by reduced levels of phosphorylated cAMP response element-binding protein (p-CREB) and B-cell lymphoma 2 (BCL-2) proteins. Finally, inhibiting this pathway exacerbated the inflammatory response to stroke as CaMKK ß or CaMK IV KO mice had increased levels of the pro-inflammatory serum cytokines tumor necrosis factor alpha (TNF¿) and interleukin 6 (IL-6) after stroke. This suggests that the CaMKK pathway is involved in the immune response to brain injury.Conclusions Inhibition of CaMKK signaling exacerbated stroke outcome and increased BBB impairment, transcriptional inactivation and inflammatory responses in females after stroke. Therefore, CaMKK signaling may be a potential target for stroke treatment in both males and females.
    BMC Neuroscience 10/2014; 15(1):118. DOI:10.1186/s12868-014-0118-2 · 2.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In May of 2014, the NIH Director together with the Director of the Office of Research on Women's Health announced plans to take a multi-dimensional approach to address the over reliance on male cells and animals in preclinical research. The NIH is engaging the scientific community in the development of policies to improve the sex balance in research. The present, past, and future presidents of the Organization for the Study of Sex Differences, in order to encourage thoughtful discussion among scientists, pose a series of questions to generate ideas in three areas: 1. research strategies, 2. educational strategies, and 3. strategies to monitor effectiveness of policies to improve the sex balance in research. By promoting discussion within the scientific community, a consensus will evolve that will move science forward in a productive and effective manner.
    10/2014; 5:15. DOI:10.1186/s13293-014-0015-5
  • Journal of Neuroimmunology 10/2014; 275(1-2):157. DOI:10.1016/j.jneuroim.2014.08.421 · 2.79 Impact Factor
  • Rodney Ritzel, Anita Patel, Josh Crapser, Louise Mccullough
    Journal of Neuroimmunology 10/2014; 275(1-2):207. DOI:10.1016/j.jneuroim.2014.08.557 · 2.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and Purpose-Social isolation (SI) increases stroke incidence and delays poststroke recovery. Women may be at greater risk from the negative consequences of SI, but few studies have examined both sexes in experimental models, and none have evaluated the effects of isolation initiated after stroke. The effects of poststroke SI in men and women were examined, and the role of mitochondrial P53 was evaluated. Methods-C57Bl6 mice were pair-housed (PH; male and ovariectomized female) for 2 weeks, subjected to stroke and then assigned to a housing condition (isolated or PH). The effects of housing on infarct volume and recovery were examined. Changes in Bcl-2 and mitochondrial p53 were assessed by Western blot. A mitochondrial p53 inhibitor (pifithrin-mu) was given to mice of both sexes. Results-Compared with pair-housed mice, poststroke SI significantly increased infarct size in both sexes; SI mice also had worse neurological deficits. The detrimental effects of SI paralleled increases in mitochondrial p53 levels. Pharmacological inhibition of mitochondrial p53 using pifithrin-mu abolished the detrimental effects of SI and reduced cell death. Conclusions-Poststroke SI results in increased ischemic injury in both sexes. The effect of housing on infarct was more pronounced in women. Targeting the mitochondrial P53 pathway could minimize the detrimental effects of isolation after stroke.
    Stroke 09/2014; 45(10). DOI:10.1161/STROKEAHA.114.006553 · 6.02 Impact Factor
  • Meaghan Roy-O’Reilly, Louise D. McCullough
    [Show abstract] [Hide abstract]
    ABSTRACT: Stroke is now the leading cause of adult disability in the United States. Women are disproportionately affected by stroke. Women increasingly outnumber men in the elderly population, the period of highest risk for stroke. However, there is also a growing recognition that fundamental sex differences are present that contribute to differential ischemic sensitivity. In addition, gonadal hormone exposure can impact coagulation and fibrinolysis, key factors in the initiation of thrombosis. In this review we will discuss sex differences in stroke, with a focus on platelets, vascular reactivity and coagulation.
    Experimental Neurology 09/2014; DOI:10.1016/j.expneurol.2014.02.011 · 4.62 Impact Factor
  • Louise D McCullough, Margaret M McCarthy, Geert J de Vries
    Nature 06/2014; 510(7505):340. DOI:10.1038/510340b · 42.35 Impact Factor

Publication Stats

3k Citations
597.85 Total Impact Points

Institutions

  • 2007–2015
    • University of Connecticut
      Сторс, Connecticut, United States
    • Johns Hopkins University
      Baltimore, Maryland, United States
    • Oregon Health and Science University
      Portland, Oregon, United States
  • 2005–2015
    • Hartford Hospital
      • • Department of Neurology
      • • Stroke Center
      Hartford, Connecticut, United States
  • 2011
    • UConn Health Center
      Фармингтон, Connecticut, United States
    • Saint Francis Hospital And Medical Center, Hartford, Ct
      Hartford, Connecticut, United States
  • 2010
    • Wannan Medical College
      Wu-hu-shih, Anhui Sheng, China
    • Yale University
      • Department of Neurology
      New Haven, CT, United States
  • 2001–2005
    • Johns Hopkins Medicine
      • • Department of Neurology
      • • Department of Anesthesiology and Critical Care Medicine
      Baltimore, MD, United States