Subcortical Estrogen Effect on The Hippocampus

Summary

Principal Investigator: C Leranth
Abstract: DESCRIPTION (Provided by applicant): The purpose of this proposal is to determine which subcortical structures are involved in gonadal hormonal actions on the hippocampus, in female rats. Animal studies, as well as human observations demonstrated that estrogen has a beneficial effect on hippocampus-associated cognitive functions and symptoms of Alzheimer's patients. The cellular targets of gonadal hormones in these processes are ill-defined. Experiments demonstrated that systemic hormonal manipulations result in dramatic changes in the density of CA1 hippocampal area pyramidal cell dendritic spines. However, there are no convincing data that hippocampal CA1 area pyramidal cells are the direct targets of estrogen. On the other hand, subcortical areas that regulate the activity of the hippocampus, including the medial septum diagonal band of Broca (MSDB) and supramammillary area (SUM) contain nuclear estrogen receptors. Therefore, we hypothesize that gonadal hormones, in addition to acting directly in the hippocampus, regulate hippocampal synaptic plasticity by affecting these estrogen receptor-containing subcortical structures that regulate hippocampal electric activity. This view is supported by recent observations that systemic estrogen administration to fimbria/fornix-transected ovariectomized (OVX) rats does not restore, but local estrogen administration into the supramammillary area dramatically increases CA1 area pyramidal cell spine synapse density. To further elaborate these observations, the following questions will be addressed: (a) is there a difference between the effect of unilateral versus bilateral estrogen implants into the SUM? (b) What is the transmitter content of SUM neurons involved in this process? (c) Are both the MSDB cholinergic and GABAergic septo-hippocampal neurons involved in mediating estrogenic effect to the hippocampus? and (d) Do SUM neurons mediate estrogenic effect to the hippocampus directly or indirectly, via the MSDB?
Funding Period: 2002-07-01 - 2007-06-30
more information: NIH RePORT

Top Publications

  1. ncbi The 17alpha and 17beta isomers of estradiol both induce rapid spine synapse formation in the CA1 hippocampal subfield of ovariectomized female rats
    Neil J MacLusky
    Center for Neural Recovery and Rehabilitation Research, Helen Hayes Hospital, West Haverstraw, New York, New York 10993, USA
    Endocrinology 146:287-93. 2005
  2. ncbi Calretinin expression in hilar mossy cells of the hippocampal dentate gyrus of nonhuman primates and humans
    László Seress
    Central Electron Microscopic Laboratory, Faculty of Medicine, University of Pecs, Pecs, Hungary
    Hippocampus 18:425-34. 2008
  3. pmc Bisphenol A prevents the synaptogenic response to testosterone in the brain of adult male rats
    Csaba Leranth
    Department of Ob Gyn, Yale University School of Medicine, 333 Cedar Street, FMB 312, New Haven, Connecticut 06520, USA
    Endocrinology 149:988-94. 2008
  4. pmc Sex steroids and the dentate gyrus
    Tibor Hajszan
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA
    Prog Brain Res 163:399-415. 2007
  5. pmc Extrinsic afferent systems to the dentate gyrus
    Csaba Leranth
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, FMB 312, New Haven, CT 06520, USA
    Prog Brain Res 163:63-84. 2007
  6. pmc Effects of androgens and estradiol on spine synapse formation in the prefrontal cortex of normal and testicular feminization mutant male rats
    Tibor Hajszan
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Endocrinology 148:1963-7. 2007
  7. ncbi Nucleus reuniens of the midline thalamus: link between the medial prefrontal cortex and the hippocampus
    Robert P Vertes
    Center for Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, FL 33431, United States
    Brain Res Bull 71:601-9. 2007
  8. ncbi Androgen modulation of hippocampal synaptic plasticity
    N J MacLusky
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA
    Neuroscience 138:957-65. 2006
  9. ncbi Androgen effects on hippocampal CA1 spine synapse numbers are retained in Tfm male rats with defective androgen receptors
    Neil J MacLusky
    Departments of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Endocrinology 147:2392-8. 2006
  10. pmc The environmental estrogen bisphenol a inhibits estradiol-induced hippocampal synaptogenesis
    Neil J MacLusky
    Center for Neural Recovery and Rehabilitation Research, Helen Hayes Hospital, New York, New York 10993 1195, USA
    Environ Health Perspect 113:675-9. 2005

Scientific Experts

Detail Information

Publications12

  1. ncbi The 17alpha and 17beta isomers of estradiol both induce rapid spine synapse formation in the CA1 hippocampal subfield of ovariectomized female rats
    Neil J MacLusky
    Center for Neural Recovery and Rehabilitation Research, Helen Hayes Hospital, West Haverstraw, New York, New York 10993, USA
    Endocrinology 146:287-93. 2005
    ....
  2. ncbi Calretinin expression in hilar mossy cells of the hippocampal dentate gyrus of nonhuman primates and humans
    László Seress
    Central Electron Microscopic Laboratory, Faculty of Medicine, University of Pecs, Pecs, Hungary
    Hippocampus 18:425-34. 2008
    ..Taken together, mossy cells of nonhuman primates and humans exhibit different expression pattern for calretinin whereas they show similarities in neurochemical content, such as the cocaine and amphetamine-related transcript peptide...
  3. pmc Bisphenol A prevents the synaptogenic response to testosterone in the brain of adult male rats
    Csaba Leranth
    Department of Ob Gyn, Yale University School of Medicine, 333 Cedar Street, FMB 312, New Haven, Connecticut 06520, USA
    Endocrinology 149:988-94. 2008
    ....
  4. pmc Sex steroids and the dentate gyrus
    Tibor Hajszan
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA
    Prog Brain Res 163:399-415. 2007
    ....
  5. pmc Extrinsic afferent systems to the dentate gyrus
    Csaba Leranth
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, FMB 312, New Haven, CT 06520, USA
    Prog Brain Res 163:63-84. 2007
    ..This strong influence is due to the fact that the majority of the extrinsic afferents terminate on a relatively small, but specific, populations of neurons that are able to control large areas of the hippocampal formation...
  6. pmc Effects of androgens and estradiol on spine synapse formation in the prefrontal cortex of normal and testicular feminization mutant male rats
    Tibor Hajszan
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Endocrinology 148:1963-7. 2007
    ..However, because this effect of 5alpha-dihydrotestosterone is not completely lost in Tfm rats, additional mechanisms may also be involved...
  7. ncbi Nucleus reuniens of the midline thalamus: link between the medial prefrontal cortex and the hippocampus
    Robert P Vertes
    Center for Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, FL 33431, United States
    Brain Res Bull 71:601-9. 2007
    ..We discuss the possibility that nucleus reuniens gates the flow of information between the medial prefrontal cortex and hippocampus dependent upon attentive/arousal states of the organism...
  8. ncbi Androgen modulation of hippocampal synaptic plasticity
    N J MacLusky
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA
    Neuroscience 138:957-65. 2006
    ..The unusual specificity of these responses raises the possibility that effects of androgens on the brain may be mediated via different mechanisms than the masculinizing actions of these steroids in non-neural androgen target organs...
  9. ncbi Androgen effects on hippocampal CA1 spine synapse numbers are retained in Tfm male rats with defective androgen receptors
    Neil J MacLusky
    Departments of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Endocrinology 147:2392-8. 2006
    ..These data are consistent with previous results suggesting that androgen effects on hippocampal spine synapses may involve novel androgen response mechanisms...
  10. pmc The environmental estrogen bisphenol a inhibits estradiol-induced hippocampal synaptogenesis
    Neil J MacLusky
    Center for Neural Recovery and Rehabilitation Research, Helen Hayes Hospital, New York, New York 10993 1195, USA
    Environ Health Perspect 113:675-9. 2005
    ..It may also exacerbate the impairment of hippocampal function observed during normal aging, as endogenous estrogen production declines...
  11. ncbi Short-term treatment with the antidepressant fluoxetine triggers pyramidal dendritic spine synapse formation in rat hippocampus
    Tibor Hajszan
    Department of Obstetrics, Gynaecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, FMB 312, New Haven, CT 06520 8063, USA
    Eur J Neurosci 21:1299-303. 2005
    ....
  12. pmc Role of androgens and the androgen receptor in remodeling of spine synapses in limbic brain areas
    Tibor Hajszan
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA
    Horm Behav 53:638-46. 2008
    ....