Andrea C. Wilson

Bounded Memory and Biases in Information Processing

Before choosing among two actions with state‐dependent payoffs, a Bayesian decision‐maker with a finite memory sees a sequence of informative signals, ending each period with fixed chance. He summarizes information observed with a finite‐state automaton. I characterize the optimal protocol as an equilibrium of a dynamic game of imperfect recall; a new player runs each memory state each period. Players act as if maximizing expected payoffs in a common finite action decision problem. I characterize equilibrium play with many multinomial signals. The optimal protocol rationalizes many behavioral phenomena, like “stickiness,” salience, confirmation bias, and belief polarization.

Leuprolide acetate: a drug of diverse clinical applications

Leuprolide acetate is a synthetic nonapeptide that is a potent gonadotropin-releasing hormone receptor (GnRHR) agonist used for diverse clinical applications, including the treatment of prostate cancer, endometriosis, uterine fibroids, central precocious puberty and in vitro fertilization techniques. As its basic mechanism of action, leuprolide acetate suppresses gonadotrope secretion of luteinizing hormone and follicle-stimulating hormone that subsequently suppresses gonadal sex steroid production. In addition, leuprolide acetate is presently being tested for the treatment of Alzheimers disease, polycystic ovary syndrome, functional bowel disease, short stature, premenstrual syndrome and even as an alternative for contraception. Mounting evidence suggests that GnRH agonist suppression of serum gonadotropins may also be important in many of the clinical applications described above. Moreover, the presence of GnRHR in a multitude of non-reproductive tissues including the recent discovery of GnRHR expression in the hippocampi and cortex of the human brain indicates that GnRH analogs such as leuprolide acetate may also act directly via tissue GnRHRs to modulate (brain) function. Thus, the molecular mechanisms underlying the therapeutic effect of GnRH analogs in the treatment of these diseases may be more complex than originally thought. These observations also suggest that the potential uses of GnRH analogs in the modulation of GnRH signaling and treatment of disease has yet to be fully realized.

Reproductive hormones regulate the selective permeability of the blood-brain barrier ☆

Reproductive hormones have been demonstrated to modulate both gap and tight junction protein expression in the ovary and other reproductive tissues, however the effects of changes in reproductive hormones on the selective permeability of the blood-brain barrier (BBB) remain unclear. Age-related declines in BBB integrity correlate with the loss of serum sex steroids and increase in gonadotropins with menopause/andropause. To examine the effect of reproductive senescence on BBB permeability and gap and tight junction protein expression/localization, female mice at 3 months of age were either sham operated (normal serum E2 and gonadotropins), ovariectomized (low serum E2 and high serum gonadotropins) or ovariectomized and treated with the GnRH agonist leuprolide acetate (low serum E2 and gonadotropins). Ovariectomy induced a 2.2-fold increase in Evans blue dye extravasation into the brain. The expression and localization of the cytoplasmic membrane-associated tight junction protein zona occludens 1 (ZO-1) in microvessels was not altered among groups indicating that the increased paracellular permeability was not due to changes in this tight junction protein. However, ovariectomy induced a redistribution of the gap junction protein connexin-43 (Cx43) such that immunoreactivity relocalized from along the extracellular microvascular endothelium to become associated with endothelial cells. An increase in Cx43 expression in the mouse brain following ovariectomy was suppressed in ovariectomized animals treated with leuprolide acetate, indicating that serum gonadotropins rather than sex steroids were modulating Cx43 expression. These results suggest that elevated serum gonadotropins following reproductive senescence may be one possible cause of the loss of selective permeability of the BBB at this time. Furthermore, these findings implicate Cx43 in mediating changes in BBB permeability, and serum gonadotropins in the cerebropathophysiology of age-related neurodegenerative diseases such as stroke and Alzheimers disease.

Identification of a regulatory loop for the synthesis of neurosteroids: a steroidogenic acute regulatory protein-dependent mechanism involving hypothalamic-pituitary-gonadal axis receptors.

Brain sex steroids are derived from both peripheral (primarily gonadal) and local (neurosteroids) sources and are crucial for neurogenesis, neural differentiation and neural function. The mechanism(s) regulating the production of neurosteroids is not understood. To determine whether hypothalamic‐pituitary‐gonadal axis components previously detected in the extra‐hypothalamic brain comprise a feedback loop to regulate neuro‐sex steroid (NSS) production, we assessed dynamic changes in expression patterns of steroidogenic acute regulatory (StAR) protein, a key regulator of steroidogenesis, and key hypothalamic‐pituitary‐gonadal endocrine receptors, by modulating peripheral sex hormone levels in female mice. Ovariectomy (OVX; high serum gonadotropins, low serum sex steroids) had a differential effect on StAR protein levels in the extrahypothalamic brain; increasing the 30‐ and 32‐kDa variants but decreasing the 37‐kDa variant and is indicative of cholesterol transport into mitochondria for steroidogenesis. Treatment of OVX animals with E2, P4, or E2 + P4 for 3 days, which decreases OVX‐induced increases in GnRH/gonadotropin production, reversed this pattern. Suppression of gonadotropin levels in OVX mice using the GnRH agonist leuprolide acetate inhibited the processing of the 37‐kDa StAR protein into the 30‐kDa StAR protein, confirming that the differential processing of brain StAR protein is regulated by gonadotropins. OVX dramatically suppressed extra‐hypothalamic brain gonadotropin‐releasing hormone 1 receptor expression, and was further suppressed in E2‐ or P4‐treated OVX mice. Together, these data indicate the existence of endocrine and autocrine/paracrine feedback loops that regulate NSS synthesis. Further delineation of these feedback loops that regulate NSS production will aid in developing therapies to maintain brain sex steroid levels and cognition.

Antibodies to Potato Virus Y Bind the Amyloid β Peptide: IMMUNOHISTOCHEMICAL AND NMR STUDIES*

Studies in transgenic mice bearing mutated human Alzheimer disease (AD) genes show that active vaccination with the amyloid β (Aβ) protein or passive immunization with anti-Aβ antibodies has beneficial effects on the development of disease. Although a trial of Aβ vaccination in humans was halted because of autoimmune meningoencephalitis, favorable effects on Aβ deposition in the brain and on behavior were seen. Conflicting results have been observed concerning the relationship of circulating anti-Aβ antibodies and AD. Although these autoantibodies are thought to arise from exposure to Aβ, it is also possible that homologous proteins may induce antibody synthesis. We propose that the long-standing presence of anti-Aβ antibodies or antibodies to immunogens homologous to the Aβ protein may produce protective effects. The amino acid sequence of the potato virus Y (PVY) nuclear inclusion b protein is highly homologous to the immunogenic N-terminal region of Aβ. PVY infects potatoes and related crops worldwide. Here, we show through immunocytochemistry, enzyme-linked immunosorbent assay, and NMR studies that mice inoculated with PVY develop antibodies that bind to Aβ in both neuritic plaques and neurofibrillary tangles, whereas antibodies to material from uninfected potato leaf show only modest levels of background immunoreactivity. NMR data show that the anti-PVY antibody binds to Aβ within the Phe4–Ser8 and His13–Leu17 regions. Immune responses generated from dietary exposure to proteins homologous to Aβ may induce antibodies that could influence the normal physiological processing of the protein and the development or progression of AD.Studies in transgenic mice bearing mutated human Alzheimer disease (AD) genes show that active vaccination with the amyloid beta (Abeta) protein or passive immunization with anti-Abeta antibodies has beneficial effects on the development of disease. Although a trial of Abeta vaccination in humans was halted because of autoimmune meningoencephalitis, favorable effects on Abeta deposition in the brain and on behavior were seen. Conflicting results have been observed concerning the relationship of circulating anti-Abeta antibodies and AD. Although these autoantibodies are thought to arise from exposure to Abeta, it is also possible that homologous proteins may induce antibody synthesis. We propose that the long-standing presence of anti-Abeta antibodies or antibodies to immunogens homologous to the Abeta protein may produce protective effects. The amino acid sequence of the potato virus Y (PVY) nuclear inclusion b protein is highly homologous to the immunogenic N-terminal region of Abeta. PVY infects potatoes and related crops worldwide. Here, we show through immunocytochemistry, enzyme-linked immunosorbent assay, and NMR studies that mice inoculated with PVY develop antibodies that bind to Abeta in both neuritic plaques and neurofibrillary tangles, whereas antibodies to material from uninfected potato leaf show only modest levels of background immunoreactivity. NMR data show that the anti-PVY antibody binds to Abeta within the Phe4-Ser8 and His13-Leu17 regions. Immune responses generated from dietary exposure to proteins homologous to Abeta may induce antibodies that could influence the normal physiological processing of the protein and the development or progression of AD.

Iron homeostasis is maintained in the brain, but not the liver, following mild hypoxia.

Abstract Alterations in iron metabolism or oxidative damage in response to hypoxic incidents have been examined following re-oxygenation of the hypoxic tissue. To understand the consequences of decreased tissue oxygen on iron load, metal-catalyzed redox activity and oxidative modifications in isolation from re-oxygenation, the present study exposed mice to either normoxia, or mild hypoxia (380 Torr; ∼10% normobaric oxygen) where the tissue was not allowed to re-oxygenate prior to examination. Brain, liver and skeletal muscle were examined for Fe3+ load, metal-catalyzed redox activity and oxidative modifications to proteins (Nϵ-(carboxymethyl)lysine), lipids (4-hydroxynonenal pyrrole) and nucleic acids (8-hydroxyguanosine). Hypoxia induced a 43% increase in the iron content of the liver (P < 0.001) as determined by ICP-MS and a 3.8-fold increase in Fe3+ load (P < 0.001) as determined by Perls stain. There was a corresponding 2-fold increase in metal-catalyzed redox activity (P < 0.01) in the liver, but no change in the expression of oxidative markers. In contrast, non-significant increases in Fe3+ and metal-catalyzed redox activity were observed in the cerebral cortex, and molecular and granular layers of the hippocampus and cerebellum. Interestingly, hypoxia significantly decreased oxidative modifications to proteins and lipids, but not nucleic acids in most brain regions examined. In addition, hypoxia did not alter the Fe content of skeletal muscle, or the contents of Zn, Cu, Ni or Mn in liver, skeletal muscle, cerebral cortex or hippocampus. Together, these results indicate that there is a tighter regulation of iron metabolism in the brain than the liver, which limits the redistribution of Fe3+ following hypoxia.

P3-199: Multi locus interactions in steroidogenic pathway genes predict Alzheimer's disease

Background: Genetic and biochemical studies have shown that the apolipoprotein E (APOE) 4 allele is a major risk factor for late-onset Alzheimer’s disease (AD), however approximately 50% of AD patients do not carry the allele. Since ApoE transports cholesterol for gonadotropin-regulated steroidogenesis, we examined polymorphisms in a number of the components of the steroidogenic pathway, including LH beta-subunit (LHB), its receptor (LHCGR), GnRH ligand, its receptor (GnRHR), follicle-stimulating hormone (FSH), its receptor (FSHR), steroidogenic acute regulatory protein (STAR) and 2-macroglobulin (A2M), for their association with AD. Methods: DNA samples from 100 AD and 100 control patients were scored for APOE genotype and previously reported polymorphisms (according to the NCBI database) in the aforementioned genes. These data were analyzed using a combination of single-factor tests as well as tests for multi-locus interactions: linkage disequilibrium (LD), logistic regression (LR), and multi-factor dimensionality reduction (MDR). Results: A marginally significant effect was observed for a missense single nucleotide polymorphism (snp) in exon 10 of FSHR: in each of the general (p 0.013), male (p 0.018), and female (p 0.034) populations heterozygosity at this locus was determined to be a risk factor. Other marginal effects were found at loci throughout FSHR in the general population (exon 10, p 0.012 and intron 8, p 0.040), in males (exon 10, p 0.023), and in females (intron 8, p 0.043 and p 0.023). Importantly, two locus pairs showed significant association with AD in all the multi-locus association tests. In the general population a synonymous snp in LH and a missense snp in FSHR demonstrated a protective effect (p 0.006, odds ratio: 0.14). In females, an intronic snp in LHR and a synonymous snp in FSH combined to make a strongly deleterious effect (p 0.001, odds ratio: 44.12). Conclusions: These multi-gene interactions support the importance of considering the role that gene-gene interactions play in the etiology of complex biological diseases and demonstrate the importance of using multiple analytic methods to detect well-supported gene-gene interactions.