Publications (287) View all
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Article: The influences of reproductive status and acute stress on the levels of phosphorylated delta opioid receptor immunoreactivity in rat hippocampus.
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ABSTRACT: In the hippocampus, ovarian hormones and sex can alter the trafficking of delta opioid receptors (DORs) and the proportion of DORs that colocalize with the stress hormone, corticotropin releasing factor. Here, we assessed the effects of acute immobilization stress (AIS) and sex on the phosphorylation of DORs in the rat hippocampus. We first localized an antibody to phosphorylated DOR (pDOR) at the SER363 carboxy-terminal residue, and demonstrated its response to an opioid agonist. By light microscopy, pDOR-immunoreactivity (ir) was located predominantly in CA2/CA3a pyramidal cell apical dendrites and in interneurons in CA1-3 stratum oriens and the dentate hilus. By electron microscopy, pDOR-ir primarily was located in somata and dendrites, associated with endomembranes, or in dendritic spines. pDOR-ir was less frequently found in mossy fibers terminals. Quantitative light microscopy revealed a significant increase in pDOR-ir in the CA2/CA3a region of male rats 1 h following an injection of the opioid agonist morphine (20mg/kg, I.P). To look at the effects of stress on pDOR, we compared pDOR-ir in males and cycling females after AIS. The level of pDOR-ir in stratum radiatum of CA2/CA3a was increased in control estrus (elevated estrogen and progesterone) females compared to proestrus and diestrus females and males. However, immediately following 30 min of AIS, no significant differences in pDOR levels were seen across estrous cycle phase or sex. These findings suggest that hippocampal levels of phosphorylated DORs vary with estrous cycle phase and that acute stress may dampen the differential effects of hormones on DOR activation in females.Brain research 04/2013; · 2.46 Impact Factor -
Article: Stress and anxiety across the lifespan: structural plasticity and epigenetic regulation.
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ABSTRACT: The brain is the central organ of the body's response to and perception of stress. Both the juvenile and the adult brain show a significant capacity for lasting physiological, structural and behavioral plasticity as a consequence of stress exposure. The hypothesis that epigenetic mechanisms might lie behind the lasting effects of stress upon the brain has proven a fruitful one. In this review, we examine the growing literature showing that stress has a direct impact on epigenetic marks at all life history stages thus far examined and how, in turn, epigenetic mechanisms play a role in altering stress responsiveness, anxiety and brain plasticity across the lifespan and beyond to succeeding generations. In addition, we will examine our own recent findings that stress interacts with the epigenome to regulate the expression of transposable elements in a regionally specific fashion, a finding with significant implications for a portion of the genome which is tenfold larger than that occupied by the genes themselves.Epigenomics 04/2013; 5(2):177-94. -
Article: Innate immunity receptor CD36 promotes cerebral amyloid angiopathy.
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ABSTRACT: Deposition of amyloid-β (Aβ) in cerebral arteries, known as cerebral amyloid angiopathy (CAA), occurs both in the setting of Alzheimer's disease and independent of it, and can cause cerebrovascular insufficiency and cognitive deficits. The mechanisms leading to CAA have not been established, and no therapeutic targets have been identified. We investigated the role of CD36, an innate immunity receptor involved in Aβ trafficking, in the neurovascular dysfunction, cognitive deficits, and amyloid accumulation that occurs in mice expressing the Swedish mutation of the amyloid precursor protein (Tg2576). We found that Tg2576 mice lacking CD36 have a selective reduction in Aβ1-40 and CAA. This reduced vascular amyloid deposition was associated with preservation of the Aβ vascular clearance receptor LRP-1, and protection from the deleterious effects of Aβ on cerebral arterioles. These beneficial vascular effects were reflected by marked improvements in neurovascular regulation and cognitive performance. Our data suggest that CD36 promotes vascular amyloid deposition and the resulting cerebrovascular damage, leading to neurovascular dysfunction and cognitive deficits. These findings identify a previously unrecognized role of CD36 in the mechanisms of vascular amyloid deposition, and suggest that this scavenger receptor is a putative therapeutic target for CAA and related conditions.Proceedings of the National Academy of Sciences 02/2013; · 9.68 Impact Factor -
Article: Post-synaptic density (PSD)-95 binding capacity of G-protein coupled receptor 30 (GPR30), an estrogen receptor that can be identified in hippocampal dendritic spines.
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ABSTRACT: The estrogen 17β-Estradiol (E2) modulates dendritic spine plasticity in the Cornu Ammonis (CA)1 region of the hippocampus, and GPR30 (GPER1) is an estrogen-sensitive G-protein coupled receptor (GPCR) that is expressed in the mammalian brain and in specific sub-regions that are responsive to E2, including the hippocampus. The subcellular localization of hippocampal GPR30 however remains unclear. Here, we demonstrate that GPR30 immunoreactivity (GPR30-IR) is detected in dendritic spines of rat CA1 hippocampal neurons in vivo, and that GPR30 protein can be found in rat brain synaptosomes. GPR30-IR is identified at the post-synaptic density (PSD) and in the adjacent peri-synaptic zone, and GPR30 can associate with the spine scaffolding protein PSD-95 both in vitro and in vivo. This PSD-95 binding capacity of GPR30 is specific and determined by the receptor C-terminal tail which is both necessary and sufficient for PSD-95 interaction. The interaction with PSD-95 functions to increase GPR30 protein levels residing at the plasma membrane surface. GPR30 associates with the N-terminal tandem pair of PDZ domains in PSD-95, suggesting that PSD-95 may be involved in clustering GPR30 with other receptors in the hippocampus. We demonstrate that GPR30 has the potential to associate with additional post-synaptic GPCRs, including the membrane progestin receptor, the corticotropin releasing hormone receptor, and the 5HT1a serotonin receptor. These data demonstrate that GPR30 is well positioned in the dendritic spine compartment to integrate E2 sensitivity directly onto multiple inputs on synaptic activity and might begin to provide a molecular explanation as to how E2 modulates dendritic spine plasticity.Journal of Biological Chemistry 01/2013; · 4.77 Impact Factor -
Article: Depletion of Polysialic Acid from Neural Cell Adhesion Molecule (PSA-NCAM) Increases CA3 Dendritic Arborization and Increases Vulnerability to Excitotoxicity.
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ABSTRACT: Chronic immobilization stress (CIS) shortens apical dendritic trees of CA3 pyramidal neurons in the hippocampus of the male rat, and dendritic length may be a determinant of vulnerability to stress. Expression of the polysialylated form of neural cell adhesion molecule (PSA-NCAM) in the hippocampal formation is increased by stress, while PSA removal by Endoneuraminidase-N (endo-N) is known to cause the mossy fibers to defasciculate and synapse ectopically in their CA3 target area. We show here that enzymatic removal of PSA produced a remarkable expansion of dendritic arbors of CA3 pyramidal neurons, with a lesser effect in CA1. This expansion eclipsed the CIS-induced shortening of CA3 dendrites, with the expanded dendrites of both no-stress-endo-N and CIS-endo-N rats being longer than those in no-stress-control rats and much longer than those in CIS-control rats. As predicted by the hypothesis that ENDO-N-induced dendritic expansion might increase vulnerability to excitotoxic challenge, systemic injection with kainic acid, showed markedly increased neuronal degeneration, as assessed by fluorojade B histochemistry, in rats that had been treated with ENDO-N compared to vehicle treated rats throughout the entire hippocampal formation. PSA removal also exacerbated the CIS-induced reduction in body weight and abolished effects of CIS on NPY and NR2B mRNA levels. These findings support the hypothesis that CA3 arbor plasticity plays a protective role during prolonged stress and clarify the role of PSA-NCAM in stress-induced dendritic plasticity.Experimental Neurology 12/2012; · 4.70 Impact Factor
