Estradiol selectively regulates metabolic substrates across memory systems in models of menopause

Abstract

Estrogen loss at menopause is thought to contribute to specific memory problems commonly encountered by women who are transitioning through or who have experienced menopause. Work in preclinical models suggests that estrogens bidirectionally regulate cognition through direct actions on different neural systems called memory systems, enhancing some types of learning and memory while impairing others. The energy load in the brain during cognitive activity is notoriously high, requiring sufficient provisions of metabolic substrates such as glucose, lactate, or ketones for optimal cognition. Thus, it is possible that estrogens bidirectionally regulate energy substrate availability within each system to produce the improvements and impairments in learning and memory. Indeed, estradiol increases extracellular levels of glucose in the hippocampus, a shift that corresponds to the hormone’s beneficial effects on hippocampus-sensitive cognition. In contrast, estradiol decreases levels of lactate and ketones in the striatum, a shift that corresponds to the impairing effects of estradiol on striatum-sensitive cognition. Menopause may thus be associated with both cognitive improvements and impairments depending on estradiol status and on the problem to be solved. We propose that regulation of neural metabolism is one likely mechanism for these bidirectional effects of estradiol on cognition.

摘要

绝经雌激素减少被认为是导致绝经过渡期或绝经后女性通常遇到特定记忆问题的原因。临床前模型表明, 雌激素通过对不同神经系统（称为记忆系统）的直接作用来双向调节认知, 增强某些类型的学习和记忆, 同时损害其他类型。众所周知, 认知活动期间大脑中的能量负荷很高, 需要足够的代谢底物, 如葡萄糖、乳酸或酮类物质, 以实现最佳认知状态。因此, 雌激素有可能在每个系统中双向调节能量底物的可用性, 从而改善或损害学习和记忆能力。事实上, 雌二醇增加了海马体细胞外的葡萄糖水平, 这一变化表明激素对海马体敏感认知的有益影响有关。相比之下, 雌二醇降低纹状体中乳酸和酮的水平, 这种变化表明雌二醇对纹状体感性认知损害作用有关。因此, 绝经可能与认知改善和损害均有关, 这取决于雌二醇水平和待解决的症状。我们认为, 神经代谢的调节是雌二醇对认知产生这些双向影响的一种可能机制。

Keywords:

• Estrogens
• hippocampus
• striatum
• learning strategy
• bioenergetics

Potential conflict of interest

The authors have no competing interests to disclose.

Additional information

Funding

Supported by NIH [AG057947]; Syracuse University Center for Aging and Policy Studies [NIH P30AG034464].