Obesity/hyperleptinemic phenotype adversely affects hippocampal plasticity: effects of dietary restriction.
Obesity/hyperleptinemic phenotype adversely affects hippocampal plasticity: effects of dietary restriction.
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DOI：
10.1016/j.physbeh.2010.10.020
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发表时间：
2011-08-03
影响因子：
2.9
通讯作者：
Reagan, Lawrence P.
中科院分区：
文献类型：
--
作者：
Grillo, Claudia A.;Piroli, Gerardo G.;Evans, Ashlie N.;Macht, Victoria A.;Wilson, Steven P.;Scott, Karen A.;Sakai, Randall R.;Mott, David D.;Reagan, Lawrence P.
流行病学研究估计，超过 60% 的美国成年人可能属于超重或肥胖，并且人们越来越认识到肥胖会影响中枢神经系统 (CNS) 的功能完整性。我们最近开发了一种慢病毒 (LV) 载体，它产生胰岛素受体 (IR) 反义 RNA 序列 (IRAS)，当注射到下丘脑时，会选择性地降低下丘脑的 IR 信号传导，导致体重、外周脂肪和血浆瘦素水平增加。为了检验这种肥胖/高瘦素血症表型会损害海马突触传递的假设，我们检查了下丘脑接受 LV-IRAS 构建体或 LV-Control 构建体（分别为 Hypo-IRAS 和 Hypo-Con）的大鼠海马的短期增强（STP）和长期增强（LTP）。刺激 Schaffer 络脉会引发 STP，并在 hyper-Con 大鼠的 CA1 区域发展为 LTP；相反，hypo-IRAS 大鼠表现出 STP，但未能发展为 LTP。为了更仔细地研究高瘦素血症在这些电生理缺陷中的潜在作用，低 IRAS 受到温和的食物限制范例的影响，这些范例可以：1）防止肥胖表型的发展；或 2) 逆转低 IRAS 大鼠中已确定的肥胖表型。这两种模式都恢复了 CA1 区的 LTP，并逆转了在低 IRAS 大鼠海马中观察到的 GluA1 Ser845 AMPA 受体亚基表达磷酸化/总比率的下降。总的来说，这些数据支持肥胖损害海马突触传递的假设，并支持这些缺陷是通过海马瘦素活性受损介导的假设。
Epidemiological studies estimate that greater than 60% of the adult US population may be categorized as either overweight or obese and there is a growing appreciation that obesity affects the functional integrity of the central nervous system (CNS). We recently developed a lentivirus (LV) vector that produces an insulin receptor (IR) antisense RNA sequence (IRAS) that when injected into the hypothalamus selectively decreases IR signaling in hypothalamus, resulting in increased body weight, peripheral adiposity and plasma leptin levels. To test the hypothesis that this obesity/hyperleptinemic phenotype would impair hippocampal synaptic transmission, we examined short term potentiation (STP) and long term potentiation (LTP) in the hippocampus of rats that received the LV-IRAS construct or the LV-Control construct in the hypothalamus (hypo-IRAS and hypo-Con, respectively). Stimulation of the Schaffer collaterals elicits STP that develops into LTP in the CA1 region of hypo-Con rats; conversely, hypo-IRAS rats exhibit STP that fails to develop into LTP. To more closely examine the potential role of hyperleptinemia in these electrophysiological deficits, hypo-IRAS were subjected to mild food restriction paradigms that would either: 1) prevent the development of the obesity phenotype; or 2) reverse an established obesity phenotype in hypo-IRAS rats. Both of these paradigms restored LTP in the CA1 region and reversed the decreases in the phosphorylated/total ratio of GluA1 Ser845 AMPA receptor subunit expression observed in the hippocampus of hypo-IRAS rats. Collectively, these data support the hypothesis that obesity impairs hippocampal synaptic transmission and support the hypothesis that these deficits are mediated through impairment of hippocampal leptin activity.
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影响因子：
2.9
作者：
Bruehl H;Wolf OT;Sweat V;Tirsi A;Richardson S;Convit A
通讯作者：
Convit A
影响因子：
2.9
作者：
Grillo, C. A.;Tamashiro, K. L.;Reagan, L. P.
通讯作者：
Reagan, L. P.
影响因子：
2.9
作者：
Jurdak, Nicole;Kanarek, Robin B.
通讯作者：
Kanarek, Robin B.
影响因子：
3
作者：
Banks, WA;DiPalma, CR;Farrell, CL
通讯作者：
Farrell, CL
影响因子：
1.9
作者：
Greenwood, CE;Winocur, G
通讯作者：
Winocur, G