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?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042644-02
Application #
6640050
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Mitler, Merrill
Project Start
2002-07-01
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$271,819
Indirect Cost
Name
Yale University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
MacLusky, Neil J; Thomas, Gladis; Leranth, Csaba (2017) Low dietary soy isoflavonoids increase hippocampal spine synapse density in ovariectomized rats. Brain Res 1657:361-367
Leranth, Csaba; Szigeti-Buck, Klara; Maclusky, Neil J et al. (2008) Bisphenol A prevents the synaptogenic response to testosterone in the brain of adult male rats. Endocrinology 149:988-94
Seress, Laszlo; Abraham, Hajnalka; Czeh, Boldizsar et al. (2008) Calretinin expression in hilar mossy cells of the hippocampal dentate gyrus of nonhuman primates and humans. Hippocampus 18:425-34
Hajszan, Tibor; MacLusky, Neil J; Leranth, Csaba (2008) Role of androgens and the androgen receptor in remodeling of spine synapses in limbic brain areas. Horm Behav 53:638-46
Hajszan, Tibor; Milner, Teresa A; Leranth, Csaba (2007) Sex steroids and the dentate gyrus. Prog Brain Res 163:399-415
Leranth, Csaba; Hajszan, Tibor (2007) Extrinsic afferent systems to the dentate gyrus. Prog Brain Res 163:63-84
Hajszan, Tibor; MacLusky, Neil J; Johansen, Jamie A et al. (2007) Effects of androgens and estradiol on spine synapse formation in the prefrontal cortex of normal and testicular feminization mutant male rats. Endocrinology 148:1963-7
Vertes, Robert P; Hoover, Walter B; Szigeti-Buck, Klara et al. (2007) Nucleus reuniens of the midline thalamus: link between the medial prefrontal cortex and the hippocampus. Brain Res Bull 71:601-9
MacLusky, Neil J; Hajszan, Tibor; Johansen, Jamie A et al. (2006) Androgen effects on hippocampal CA1 spine synapse numbers are retained in Tfm male rats with defective androgen receptors. Endocrinology 147:2392-8
MacLusky, N J; Hajszan, T; Prange-Kiel, J et al. (2006) Androgen modulation of hippocampal synaptic plasticity. Neuroscience 138:957-65

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