Takahashi L K
Department of Psychiatry, University of Wisconsin Medical School, Madison 53792-2475, USA.
J Neurosci. 1995 Sep;15(9):6023-34. doi: 10.1523/JNEUROSCI.15-09-06023.1995.
Endogenous corticosteroids influence brain development and behavioral expression. In rat pups, a corticosteroid-dependent developmental response is behavioral inhibition, which occurs in situations involving threat. Behavioral inhibition consists of freezing and a reduction in ongoing behavior. It is presently unknown which brain region(s) that bind corticosterone (CORT) is involved in the development of freezing. The hippocampus (HC), however, is the principal target site of CORT that regulates the postnatal development of HC dentate granule cells. Therefore, this study examined whether the HC, and in particular, the dentate granule cells, plays a major role in the early appearance of behavioral inhibition. On postnatal day 9, rat pups received bilateral HC electrolytic lesions, or bilateral HC infusions of colchicine, a neurotoxin selective for dentate granule cells, or bilateral HC infusions of kainic acid, a neurotoxin selective for pyramidal cells in the CA3 field. Control rats received sham operations. After the operations, all rats were adrenalectomized (ADX) and injected daily with 3.0 mg/kg CORT, except on the day of the behavioral test. On day 14, all pups were tested for behavioral inhibition, which consisted of removing the pup from the nest box and placing it in a temperature-controlled enclosure subdivided into two compartments by a wire-mesh partition. The pup was placed in one compartment and an unfamiliar anesthetized adult male rat was placed in the adjacent compartment. Results indicated that preweanling rats with electrolytic lesions ranging from the dorsal to the ventral HC exhibited significant deficits in freezing. Importantly, similar deficits in freezing were present in pups treated with colchicine but not KA. Hence, administration of exogenous CORT is not effective in facilitating the occurrence of freezing in preweanling pups lacking dentate granule cells. To determine whether the dorsal HC dentate gyrus is an essential target site of CORT in facilitating freezing, 9-d-old rats were implanted bilaterally with 30 gauge cannula filled with either CORT or cholesterol. After the operation, all rats were ADX and tested for behavioral inhibition on day 14. During testing, ADX pups with CORT-filled cannulae showed significantly higher levels of freezing than ADX control pups. Taken together, results suggest that during the early postnatal period, the action of endogenous CORT in the HC influences the development of dentate granule cells that play an essential role in mediating the appearance of behavioral inhibition.
内源性皮质类固醇会影响大脑发育和行为表现。在幼鼠中，一种依赖皮质类固醇的发育反应是行为抑制，它发生在涉及威胁的情境中。行为抑制包括僵住不动和正在进行的行为减少。目前尚不清楚哪个与皮质酮（CORT）结合的脑区参与了僵住不动行为的发育。然而，海马体（HC）是CORT的主要靶位点，它调节海马齿状颗粒细胞的出生后发育。因此，本研究考察了HC，尤其是齿状颗粒细胞，在行为抑制早期出现过程中是否起主要作用。在出生后第9天，幼鼠接受双侧海马电解损伤，或双侧海马注射秋水仙碱（一种对齿状颗粒细胞有选择性的神经毒素），或双侧海马注射海藻酸（一种对CA3区锥体细胞有选择性的神经毒素）。对照大鼠接受假手术。手术后，所有大鼠均接受肾上腺切除术（ADX），除行为测试当天外，每天注射3.0mg/kg的CORT。在第14天，对所有幼鼠进行行为抑制测试，测试方法是将幼鼠从巢箱中取出，放入一个温度控制的饲养箱中，该饲养箱由金属丝网隔板分为两个隔室。将幼鼠放在一个隔室中，在相邻隔室中放置一只陌生的麻醉成年雄性大鼠。结果表明，从背侧到腹侧海马体有电解损伤的断奶前大鼠在僵住不动行为上表现出显著缺陷。重要的是，用秋水仙碱处理的幼鼠也出现了类似的僵住不动缺陷，但用海藻酸处理的幼鼠没有。因此，给予外源性CORT对促进缺乏齿状颗粒细胞的断奶前幼鼠出现僵住不动行为无效。为了确定背侧海马齿状回是否是CORT促进僵住不动行为的关键靶位点，给9日龄大鼠双侧植入装满CORT或胆固醇的30号套管。手术后，所有大鼠均接受ADX，并在第14天进行行为抑制测试。在测试过程中，植入装满CORT套管的ADX幼鼠的僵住不动水平显著高于ADX对照幼鼠。综合来看，结果表明在出生后早期，内源性CORT在海马体中的作用影响了齿状颗粒细胞的发育，而齿状颗粒细胞在介导行为抑制的出现中起关键作用。
