Gobinath Aarthi R, Workman Joanna L, Chow Carmen, Lieblich Stephanie E, Galea Liisa A M
Program in Neuroscience, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z3 Canada.
Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, BC V6T 1Z4 Canada.
Biol Sex Differ. 2017 Jun 2;8:20. doi: 10.1186/s13293-017-0142-x. eCollection 2017.
Postpartum depression affects approximately 15% of mothers and represents a form of early life adversity for developing offspring. Postpartum depression can be treated with prescription antidepressants like fluoxetine (FLX). However, FLX can remain active in breast milk, raising concerns about the consequences of neonatal FLX exposure. The hippocampus is highly sensitive to developmental stress, and males and females respond differently to stress at many endpoints, including hippocampal plasticity. However, it is unclear how developmental exposure to FLX alters the trajectory of hippocampal development. The goal of this study was to examine the long-term effects of maternal postpartum corticosterone (CORT, a model of postpartum depression) and concurrent FLX on hippocampal neurogenesis in male and female offspring.
Female Sprague-Dawley rat dams were treated daily with either CORT or oil and FLX or saline from postpartum days 2-23. Offspring were perfused on postnatal day 31 (pre-adolescent), postnatal day 42 (adolescent), and postnatal day 69 (adult). Tissue was processed for doublecortin (DCX), an endogenous marker of immature neurons, in the dorsal and ventral hippocampus.
Maternal postpartum CORT reduced density of DCX-expressing cells in the dorsal hippocampus of pre-adolescent males and increased it in adolescent males, suggesting that postpartum CORT exposure disrupted the typical progression of the density of DCX-expressing cells. Further, among offspring of oil-treated dams, pre-adolescent males had greater density of DCX-expressing cells than pre-adolescent females, and maternal postpartum CORT prevented this sex difference. In pre-adolescent females, maternal postpartum FLX decreased the density of DCX-expressing cells in the dorsal hippocampus compared to saline. As expected, maternal CORT reduced the density of DCX-expressing cells in adult female, but not male, offspring. The combination of maternal postpartum CORT/FLX diminished density of DCX-expressing cells in dorsal hippocampus regardless of sex or age.
These findings reveal how modeling treatment of postpartum depression with FLX alters hippocampal neurogenesis in developing offspring differently depending on sex, predominantly in the dorsal dentate gyrus and earlier in life.
产后抑郁症影响约15%的母亲，是发育中后代早期生活逆境的一种形式。产后抑郁症可用氟西汀（FLX）等处方抗抑郁药治疗。然而，FLX可在母乳中保持活性，引发对新生儿接触FLX后果的担忧。海马体对发育应激高度敏感，雄性和雌性在包括海马体可塑性在内的许多指标上对压力的反应不同。然而，尚不清楚发育过程中接触FLX如何改变海马体发育轨迹。本研究的目的是研究母体产后皮质酮（CORT，产后抑郁症模型）和同时使用的FLX对雄性和雌性后代海马体神经发生的长期影响。
从产后第2天至第23天，对雌性斯普拉-道利大鼠母鼠每日给予CORT或油以及FLX或生理盐水。在出生后第31天（青春期前）、第42天（青春期）和第69天（成年期）对后代进行灌注。对背侧和腹侧海马体中的双皮质素（DCX，未成熟神经元的内源性标志物）进行组织处理。
母体产后CORT降低了青春期前雄性大鼠背侧海马体中表达DCX的细胞密度，而在青春期雄性大鼠中则增加了该密度，这表明产后接触CORT扰乱了表达DCX的细胞密度的典型变化进程。此外，在接受油处理的母鼠的后代中，青春期前雄性大鼠表达DCX的细胞密度高于青春期前雌性大鼠，而母体产后CORT消除了这种性别差异。在青春期前雌性大鼠中，与生理盐水相比，母体产后FLX降低了背侧海马体中表达DCX的细胞密度。正如预期的那样，母体CORT降低了成年雌性后代而非成年雄性后代中表达DCX的细胞密度。母体产后CORT/FLX联合使用降低了背侧海马体中表达DCX的细胞密度，无论性别或年龄如何。
这些发现揭示了用FLX模拟产后抑郁症治疗如何根据性别不同地改变发育中后代的海马体神经发生，主要发生在背侧齿状回且在生命早期。
