Protective actions of ovarian hormones in the serotonin system of macaques

Cynthia Bethea, Arubala Reddy, Yukari Tokuyama, Jessica A. Henderson, Fernanda B. Lima

    Research output: Contribution to journalArticle

    57 Citations (Scopus)

    Abstract

    The serotonin neurons of the dorsal and medial raphe nuclei project to all areas of the forebrain and play a key role in mood disorders. Hence, any loss or degeneration of serotonin neurons could have profound ramifications. In a monkey model of surgical menopause with hormone replacement and no neural injury, E and P decreased gene expression in the dorsal raphe nucleus of c-jun n-terminal kinase (JNK1) and kynurenine mono-oxygenase (KMO) that promote cell death. In concert, E and P increased gene expression of superoxide dismutase (SOD1), VEGF, and caspase inhibitory proteins that promote cellular resilience in the dorsal raphe nucleus. Subsequently, we showed that ovarian steroids inhibit pivotal genes in the caspase-dependent and caspase-independent pathways in laser-captured serotonin neurons including apoptosis activating factor (Apaf1), apoptosis-inducing factor (AIF) and second mitochondria-derived activator of caspases (Smac/Diablo). SOD1 was also increased specifically in laser-captured serotonin neurons. Examination of protein expression in the dorsal raphe block revealed that JNK1, phosphoJNK1, AIF and the translocation of AIF from the mitochondria to the nucleus decreased with hormone therapy, whereas pivotal execution proteins in the caspase pathway were unchanged. In addition, cyclins A, B, D1 and E were inhibited, which would prevent re-entry into the cell cycle and catastrophic death. These data indicated that in the absence of gross injury to the midbrain, ovarian steroids inhibit the caspase-independent pathway and cell cycle initiation in serotonin neurons. To determine if these molecular actions prevented cellular vulnerability or death, we examined DNA fragmentation in the dorsal raphe nucleus with the TUNEL assay (terminal deoxynucleotidyl transferase nick end labeling). Ovarian steroids significantly decreased the number of TUNEL-positive cells in the dorsal raphe. Moreover, TUNEL staining prominently colocalized with TPH immunostaining, a marker for serotonin neurons. In summary, ovarian steroids increase the cellular resilience of serotonin neurons and may prevent serotonin neuron death in women facing decades of life after menopause. The survival of serotonin neurons would support cognition and mental health.

    Original languageEnglish (US)
    Pages (from-to)212-238
    Number of pages27
    JournalFrontiers in Neuroendocrinology
    Volume30
    Issue number2
    DOIs
    StatePublished - Jul 2009

    Fingerprint

    Macaca
    Serotonin
    Hormones
    Caspases
    Neurons
    Apoptosis Inducing Factor
    In Situ Nick-End Labeling
    Steroids
    Menopause
    Cell Cycle
    Mitochondria
    Lasers
    Mitogen-Activated Protein Kinase 8
    Cyclin B
    Kynurenine
    Mediodorsal Thalamic Nucleus
    Anatomic Models
    Gene Expression
    Cyclin A
    Cyclin E

    Keywords

    • Apoptosis
    • Apoptosis-inducing factor
    • Estrogen
    • JNK1
    • Laser capture
    • Mitochondria
    • Neuroprotection
    • Progesterone
    • Serotonin
    • TUNEL

    ASJC Scopus subject areas

    • Endocrine and Autonomic Systems

    Cite this

    Protective actions of ovarian hormones in the serotonin system of macaques. / Bethea, Cynthia; Reddy, Arubala; Tokuyama, Yukari; Henderson, Jessica A.; Lima, Fernanda B.

    In: Frontiers in Neuroendocrinology, Vol. 30, No. 2, 07.2009, p. 212-238.

    Research output: Contribution to journalArticle

    Bethea, Cynthia ; Reddy, Arubala ; Tokuyama, Yukari ; Henderson, Jessica A. ; Lima, Fernanda B. / Protective actions of ovarian hormones in the serotonin system of macaques. In: Frontiers in Neuroendocrinology. 2009 ; Vol. 30, No. 2. pp. 212-238.
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