Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia; Discipline of Anatomy, School of Medicine, James Cook University, Townsville, QLD, Australia.
Psychoneuroendocrinology. 2013 Dec;38(12):3102-14. doi: 10.1016/j.psyneuen.2013.09.010. Epub 2013 Sep 20.
Tumour necrosis factor-α (TNF-α) plays an important role not only in immunity but also in the normal functioning of the central nervous system (CNS). At physiological levels, studies have shown TNF-α is essential to maintain synaptic scaling and thus influence learning and memory formation while also playing a role in modulating pathological states of anxiety and depression. TNF-α signals mainly through its two receptors, TNF-R1 and TNF-R2, however the exact role that these receptors play in TNF-α mediated behavioural phenotypes is yet to be determined.
We have assessed TNF(-/-), TNF-R1(-/-) and TNF-R2(-/-) mice against C57BL/6 wild-type (WT) mice from 12 weeks of age in order to evaluate measures of spatial memory and learning in the Barnes maze (BM) and Y-maze, as well as other behaviours such as exploration, social interaction, anxiety and depression-like behaviour in a battery of tests. We have also measured hippocampal and prefrontal cortex levels of the neurotrophins nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) as well as used immunohistochemical analyses to measure number of proliferating cells (Ki67) and immature neurons (DCX) within the dentate gyrus.
We have shown that young adult TNF(-/-) and TNF-R1(-/-) mice displayed impairments in learning and memory in the BM and Y-maze, while TNF-R2(-/-) mice showed good memory but slow learning in these tests. TNF(-/-)and TNF-R2(-/-) mice also demonstrated a decrease in anxiety like behaviour compared to WT mice. ELISA analyses showed TNF(-/-) and TNF-R2(-/-) mice had lower levels of NGF compared to WT mice.
These results indicate that while lack of TNF-α can decrease anxiety-like behaviour in mice, certain basal levels of TNF-α are required for the development of normal cognition. Furthermore our results suggest that both TNF-R1 and TNF-R2 signalling play a role in normal CNS function, with knockout of either receptor impairing cognition on the Barnes maze.
肿瘤坏死因子-α（TNF-α）不仅在免疫中而且在中枢神经系统（CNS）的正常功能中都起着重要作用。在生理水平上，研究表明 TNF-α对于维持突触缩放从而影响学习和记忆形成是必不可少的，同时在调节焦虑和抑郁的病理状态方面也起着作用。TNF-α主要通过其两个受体 TNF-R1 和 TNF-R2 发出信号，然而，这些受体在 TNF-α 介导的行为表型中的确切作用尚未确定。
我们从 12 周龄起对 TNF（-/-）、TNF-R1（-/-）和 TNF-R2（-/-）小鼠与 C57BL/6 野生型（WT）小鼠进行了评估，以评估 Barnes 迷宫（BM）和 Y 迷宫中的空间记忆和学习测量，以及其他行为，如探索、社交互动、焦虑和抑郁样行为在一系列测试中。我们还测量了海马体和前额叶皮层的神经营养因子神经生长因子（NGF）和脑源性神经营养因子（BDNF）水平，并使用免疫组织化学分析来测量齿状回中的增殖细胞（Ki67）和未成熟神经元（DCX）的数量。
我们表明，年轻成年 TNF（-/-）和 TNF-R1（-/-）小鼠在 BM 和 Y 迷宫中表现出学习和记忆障碍，而 TNF-R2（-/-）小鼠在这些测试中表现出良好的记忆但学习速度较慢。TNF（-/-）和 TNF-R2（-/-）小鼠也表现出与 WT 小鼠相比焦虑样行为减少。ELISA 分析表明，TNF（-/-）和 TNF-R2（-/-）小鼠的 NGF 水平低于 WT 小鼠。
这些结果表明，虽然缺乏 TNF-α可以降低小鼠的焦虑样行为，但某些基础水平的 TNF-α对于正常认知的发展是必需的。此外，我们的结果表明，TNF-R1 和 TNF-R2 信号都在正常 CNS 功能中发挥作用，敲除任一受体都会损害 Barnes 迷宫上的认知。
