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Aims/hypothesis <p>Diabetes is characterised by dysfunctional insulin release and action, and it is a risk factor for Alzheimer’s disease, the most common form of dementia. Alterations in brain insulin signalling and metabolism have been linked with Alzheimer’s disease. We hypothesised that loss of brain insulin might alter learning and memory performance.</p> Methods <p>We used qPCR, immunofluorescence and western blot analysis to confirm that the ancestral insulin gene, <i>Ins2</i>, is transcribed within the brain, including in the hippocampus. To determine how locally produced insulin influences hippocampal function, we used mice with germline <i>Ins2</i> knockout (<i>Ins2</i><sup>−/−</sup>) and the normal complement of wild-type <i>Ins1</i> alleles. Compensation from the <i>Ins1</i> gene ensured normal glucose tolerance, normal insulin sensitivity, normal fasting insulin and normal body weight under these diet and housing&#xa0;conditions. We analysed visuo-spatial learning and memory performance using the Morris water maze. We used RNA sequencing to provide unbiased analysis of gene expression in isolated hippocampi.</p> Results <p>Hippocampal <i>Ins2</i> mRNA was higher in female mice than in males, and was modulated by diet. Learning and memory were significantly impaired in female <i>Ins2</i><sup>−/−</sup> mice relative to wild-type mice, while the performance of male <i>Ins2</i><sup>−/−</sup> and wild-type mice did not differ. RNA sequencing showed that cyclin D1 (<i>Ccnd1</i>) was significantly reduced in <i>Ins2</i><sup>−/−</sup> mice.</p> Conclusions/interpretation <p>Our data point to female-specific roles for brain-derived <i>Ins2</i> in learning and memory function in mice.</p> Graphical Abstract <p></p>

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Loss of brain insulin production impairs learning and memory in female mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月12日

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  • Stella K. Baehring,
  • Timothy P. O’Leary,
  • Haoning Howard Cen,
  • Danae Holenka,
  • Kyungchan Kim,
  • Sunday Ajayi,
  • Daniel Semenov,
  • Manuel Belmadani,
  • Hong Li,
  • Arya E. Mehran,
  • Honey Modi,
  • Melissa M. Page,
  • Søs Skovsø,
  • Paul Pavlidis,
  • Shernaz X. Bamji,
  • Eun-Kyoung Kim,
  • James D. Johnson

摘要

Aims/hypothesis

Diabetes is characterised by dysfunctional insulin release and action, and it is a risk factor for Alzheimer’s disease, the most common form of dementia. Alterations in brain insulin signalling and metabolism have been linked with Alzheimer’s disease. We hypothesised that loss of brain insulin might alter learning and memory performance.

Methods

We used qPCR, immunofluorescence and western blot analysis to confirm that the ancestral insulin gene, Ins2, is transcribed within the brain, including in the hippocampus. To determine how locally produced insulin influences hippocampal function, we used mice with germline Ins2 knockout (Ins2−/−) and the normal complement of wild-type Ins1 alleles. Compensation from the Ins1 gene ensured normal glucose tolerance, normal insulin sensitivity, normal fasting insulin and normal body weight under these diet and housing conditions. We analysed visuo-spatial learning and memory performance using the Morris water maze. We used RNA sequencing to provide unbiased analysis of gene expression in isolated hippocampi.

Results

Hippocampal Ins2 mRNA was higher in female mice than in males, and was modulated by diet. Learning and memory were significantly impaired in female Ins2−/− mice relative to wild-type mice, while the performance of male Ins2−/− and wild-type mice did not differ. RNA sequencing showed that cyclin D1 (Ccnd1) was significantly reduced in Ins2−/− mice.

Conclusions/interpretation

Our data point to female-specific roles for brain-derived Ins2 in learning and memory function in mice.

Graphical Abstract