Insulin resistance is a major contributor to the neuroplasticity deficits observed in patients with metabolic disorders. However, the relative contribution of peripheral versus central insulin resistance in the development of neuroplasticity deficits remains equivocal. To distinguish between peripheral and central insulin resistance, we developed a lentiviral vector containing an antisense sequence selective for the insulin receptor (LV-IRAS). We previously demonstrated that intra-hippocampal injection of this vector impairs synaptic transmission and hippocampal-dependent learning and memory in the absence of peripheral insulin resistance. In view of the increased risk for the development of neuropsychiatric disorders in patients with insulin resistance, the current study examined depressive and anxiety-like behaviors, as well as hippocampal structural plasticity in rats with hippocampal-specific insulin resistance. Following hippocampal administration of either the LV-control virus or the LV-IRAS, anhedonia was evaluated by the sucrose preference test, despair behavior was assessed in the forced swim test, and anxiety-like behaviors were determined in the elevated plus maze. Hippocampal neuron morphology was studied by Golgi-Cox staining. Rats with hippocampal insulin resistance exhibited anxiety-like behaviors and behavioral despair without differences in anhedonia, suggesting that some but not all components of depressive-like behaviors were affected. Morphologically, hippocampal-specific insulin resistance elicited atrophy of the basal dendrites of CA3 pyramidal neurons and dentate gyrus granule neurons, and also reduced the expression of immature dentate gyrus granule neurons. In conclusion, hippocampal-specific insulin resistance elicits structural deficits that are accompanied by behavioral despair and anxiety-like behaviors, identifying hippocampal insulin resistance as a key factor in depressive illness.

胰岛素抵抗是在代谢紊乱患者中观察到的神经可塑性缺陷的主要原因。然而，外周与中枢胰岛素抵抗在神经可塑性缺陷的发展中的相对贡献仍然模棱两可。为了区分外周和中枢胰岛素抵抗，我们开发了一种慢病毒载体，其中包含对胰岛素受体 (LV-IRAS) 具有选择性的反义序列。我们之前已经证明，在没有外周胰岛素抵抗的情况下，海马内注射这种载体会损害突触传递和海马依赖性学习和记忆。鉴于胰岛素抵抗患者发生神经精神疾病的风险增加，目前的研究检查了抑郁和焦虑样行为，以及海马特异性胰岛素抵抗大鼠的海马结构可塑性。在 LV 控制病毒或 LV-IRAS 海马给药后，通过蔗糖偏好测试评估快感缺乏，在强迫游泳测试中评估绝望行为，并在高架十字迷宫中确定焦虑样行为。通过高尔基-考克斯染色研究海马神经元形态。具有海马胰岛素抵抗的大鼠表现出焦虑样行为和行为绝望，而快感缺乏没有差异，这表明抑郁样行为的部分而非全部成分受到影响。在形态学上，海马特异性胰岛素抵抗引起 CA3 锥体神经元和齿状回颗粒神经元的基底树突萎缩，并且还降低了未成熟齿状回颗粒神经元的表达。总之，海马特异性胰岛素抵抗引起结构性缺陷，伴随着行为绝望和焦虑样行为，将海马胰岛素抵抗确定为抑郁症的关键因素。