Diminished activation of excitatory neurons in the prelimbic cortex leads to impaired working memory capacity in mice

Jiang，Li Xin1,2,3; Huang，Geng Di4,5; Tian，Yong Lu6,7; Cong，Ri Xu8; Meng，Xue9; Wang，Hua Li1,2,3; Zhang，Chen10; Yu，Xin1,2,3

2023-12-01

10.1186/s12915-023-01674-3

BMC Biology   Impact Factor & Quartile

1741-7007

Background: Working memory capacity impairment is an early sign of Alzheimer's disease, but the underlying mechanisms remain unclear. Clarifying how working memory capacity is affected will help us better understand the pathological mechanism of Alzheimer's disease. We used the olfactory working memory capacity paradigm to evaluate memory capacity in 3-month-old 5XFAD (an animal model of Alzheimer's disease) mice. Immunofluorescence staining of the prefrontal cortex was performed to detect the number of FOS-positive neurons, calmodulin-dependent protein kinase II-positive neurons, and glutamate decarboxylase-positive neurons in the prelimbic cortex and infralimbic cortex. A chemogenetic method was then used to modulate the inhibition and activation of excitatory neurons in the prelimbic cortex of wild-type and 5XFAD mice and to measure the memory capacity of mice. Results: Working memory capacity was significantly diminished in 5XFAD mice compared to littermate wild-type mice. Neuronal activation of the prelimbic cortex, but not the infralimbic cortex, was attenuated in 5XFAD mice performing the olfactory working memory capacity task. Subsequently, the FOS-positive neurons were co-localized with both calmodulin-dependent protein kinase II-positive neurons and glutamate decarboxylase-positive neurons. The results showed that the activation of excitatory neurons in the prelimbic cortex was correlated with working memory capacity in mice. Our results further demonstrate that the chemogenetic inhibition of prelimbic cortex excitatory neurons resulted in reduced working memory capacity in wild-type mice, while the chemogenetic activation of prelimbic cortex excitatory neurons improved the working memory capacity of 5XFAD mice. Conclusion: The diminished activation of prelimbic cortex excitatory neurons in 5XFAD mice during task performance is associated with reduced working memory capacity, and activation modulation of excitatory neurons by chemogenetic methods can improve memory capacity impairment in 5XFAD mice. These findings may provide a new direction for exploring Alzheimer's disease therapeutic approaches.

5XFAD mice Alzheimer's disease Excitatory neuron FOS Working memory capacity

SCI

English

Others

Young Scientists Fund[82101492];Shenzhen Science and Technology Innovation Program[RCBS20221008093252091];

Life Sciences & Biomedicine - Other Topics

Biology

WOS:001048593600002

BMC

BIOLOGY & BIOCHEMISTRY

2-s2.0-85167765870

Scopus

1.Peking University Institute of Mental Health (Sixth Hospital),Beijing,No.51 Huayuanbei Road, Haidian District,100191,China
2.National Clinical Research Center for Mental Disorders & NHC Key Laboratory of Mental Health (Peking University),Beijing,100191,China
3.Beijing Municipal Key Laboratory for Translational Research On Diagnosis and Treatment of Dementia,Beijing,100191,China
4.Department of Addiction Medicine,Shenzhen Clinical Research Center for Mental Disorders,Shenzhen Mental Health Center,Shenzhen Kangning Hospital,Shenzhen,No.77 Zhenbi Road, Pingshan District,518118,China
5.Affiliated Mental Health Center,Southern University of Science and Technology,Shenzhen,No.1088 Xueyuan Avenue, Fuguang Community, Taoyuan Street, Nanshan District,518118,China
6.School of Psychological and Cognitive Sciences,Peking University,Beijing,No.5 Summer Palace Road, Haidian District,100871,China
7.IDG/McGovern Institute for Brain Research,Peking University,Beijing,100871,China
8.Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education,College of Life Sciences,Peking University,Beijing,100871,China
9.National Center of Gerontology,Beijing Hospital,Beijing,No.1 Dahua Road, Dongdan, Dongcheng District,100005,China
10.Beijing Key Laboratory of Neural Regeneration and Repair,Advanced Innovation Center for Human Brain Protection,School of Basic Medical Sciences,Capital Medical University,Beijing,No.10 Xitoutiao, You’anmenwai, Fengtai District,100069,China

Jiang，Li Xin,Huang，Geng Di,Tian，Yong Lu,et al. Diminished activation of excitatory neurons in the prelimbic cortex leads to impaired working memory capacity in mice[J]. BMC Biology,2023,21(1).

Jiang，Li Xin.,Huang，Geng Di.,Tian，Yong Lu.,Cong，Ri Xu.,Meng，Xue.,...&Yu，Xin.(2023).Diminished activation of excitatory neurons in the prelimbic cortex leads to impaired working memory capacity in mice.BMC Biology,21(1).

Jiang，Li Xin,et al."Diminished activation of excitatory neurons in the prelimbic cortex leads to impaired working memory capacity in mice".BMC Biology 21.1(2023).