Premarin has opposing effects on spatial learning, neural activation and serum cytokine levels in middle age dependent on reproductive history

Abstract

Menopause is associated with cognitive decline, and hormone therapies (HT) can improve cognition dependent on time since menopause. Previous parity also influences cognition in later life. The present study investigated how primiparity and long-term ovariectomy influence cognition, hippocampal neurogenesis, and neuronal activation in middle-aged rats in response to the HT, Premarin. Nulliparous and primiparous rats were sham-ovariectomized or ovariectomized, administered vehicle or Premarin six months later, and trained in the Morris water maze. Premarin improved spatial learning and memory in nulliparous rats, but impaired spatial and reversal learning in primiparous rats. Primiparity increased hippocampal neurogenesis, whereas Premarin treatment decreased immature neurons in both primiparous and nulliparous middle-aged rats in a region-specific manner. Moreover, Premarin increased serum TNF and KC/GRO in nulliparous, but not primiparous, rats, whereas Premarin increased zif268 expression in the CA3 region of the hippocampus in primiparous rats. Thus, primiparity alters how Premarin affects spatial learning, neuronal activation, serum cytokines, and adrenal mass. These findings have implications for the tailored treatment of age-associated cognitive decline in women.