Alzheimer's disease (AD) is a serious neurodegenerative disease with cognitive and emotional impairment as its main behavior. Regulating adult hippocampal neurogenesis (AHN) to improve the cognitive and emotional impairment of AD has been a scientific problem for neuroscientists, but the effectiveness is still controversial. Recently, Yadong Li (now a researcher at the Songjiang Research Institute of Shanghai Jiao Tong University School of Medicine) and Yanjia Luo (co-first author, now a researcher at the Ninth People's Hospital of Shanghai Jiao Tong University School of Medicine), postdoctoral fellows of Song Juan's research group at the University of North Carolina at Chapel Hill (UNC), have made important research progress in the regulation of adult hippocampal newborn neurons to improve cognitive and emotional disorders of AD. Related results were published on April 6 in the "Activation of hypothalamic-enhanced adult-born neurons restores cognitive and affective function in. Alzheimer's disease is featured as an Article in Cell Stem Cell.

In recent years, improving the cognitive and emotional impairment of AD by regulating hippocampal neurogenesis has been a hot research topic. In 2018, the Tanzi group of Harvard Medical School successfully saved the damaged AHN in AD mice by manipulating the P7C3 and Wnt3 genes, but unfortunately, improving AHN alone is not enough to improve the memory impairment of AD mice. Only a combination of BDNF and AHN enhancement strategies can improve memory (Choi, Science 2018). Interestingly, Salta's group reported that rescuing miR-132 improved neurogenesis and memory in AD mice (Walgrave, Cell Stem Cell 2021). Similarly, subsequent reports showed that the deletion of Bax gene also increased the number of new neurons in the hippocampus of AD mice and also improved memory (Mishra, J Exp Med 2022). These results suggest that different intervention strategies for AHN may have significant differences in the effect of saving newborn neurons in hippocampus to improve memory. The above methods of gene manipulation do not control the dynamic process of neurodevelopment and the mechanism is unclear.

Different from genetic manipulation, targeting neural circuits can achieve precise regulation of different stages of AHN and increase the number of new neurons in the hippocampus. Dr. Yadong Li et al. previously reported that the awakening nucleus hypothalamic supramillary nucleus (SuM) promotes spatial memory retrieval by releasing glutamate and GABA transmitters into the dentate gyrus of the hippocampus (Yadong Li, eLife 2020). Interestingly, stimulation of the SuM circuit significantly promoted hippocampal neurogenesis and increased the number and maturity of new hippocampal neurons. Further activation of new hippocampal neurons regulated by the SuM circuit by chemical genetic methods significantly improved the memory ability of mice and opposed anxietic-like behaviors (Yadong Li, Yanjia Luo et al., Nat Neurosci 2022). Accordingly, Yadong Li et al proposed a new strategy to improve memory by multilevel regulation of hippocampal neurogenesis (number, development degree and activity of newborn neurons) (Yadong Li, Yanjia Luo & Juan Song, Curr Opin Neurobiol 2023).

So can manipulating the SuM circuit improve neurogenesis in AD mice? Based on the above strategy, the researchers first increased the number and maturity of newborn neurons in the hippocampus by stimulating SuM. Unfortunately, despite the increase in the number of new neurons in the hippocampus, the spatial memory and emotional function of AD mice were not significantly changed, suggesting that increasing the number of new neurons in the hippocampus of AD mice through a strategy of loop manipulation is not enough to improve impaired frontal memory and emotional behavior.

Activating new neurons in the hippocampus of healthy mice improves memory ability, so the researchers tried activating new neurons in the hippocampus of mice with AD. However, chemogenetic methods to excite new neurons in the hippocampus were also insufficient to improve memory and emotional function in AD mice. This may be related to the impaired hippocampal neurogenesis in AD mice.

Finally, the researchers managed to save the spatial memory and emotional function of AD mice by multi-level regulation of hippocampal newborn neurons, that is, activating the SuM loop to increase the number and development degree of hippocampal newborn neurons, and then stimulating the SuM loop modified hippocampal newborn neurons by chemical genetics (Figure 1).

The researchers further explored the mechanism by which activation of SuM loop-modified hippocampal newborn neurons improves memory. Through the screening of proteomics and the verification of brain chip electrophysiology, fiber optic calcium signal and histochemistry, it was proved that the enhancement of synaptic plasticity of hippocampal neurons, the increase of neuronal activity, and the endocytosis of microglia on amyloid plaques may be the key mechanisms to improve memory (Figure 2).

Based on the previous findings that stimulating the hypothalamic awakening nucleus SuM promotes spatial memory extraction, this study further explored the role and unique mechanism of the awakening circuit in improving memory by regulating hippocampal neurogenesis, and applied it to the intervention of cognitive affective disorder in AD. The highlight of this study is that only a small number (about 300) of hippocampal newborn neurons can be regulated to save the memory and emotional function of AD mice, and a possible molecular mechanism is proposed to improve the cognitive and emotional function of AD mice.

UNC Ling Xie, Professor Xian Chen and Associate Professor Leon Coleman made important contributions to the study.

Expert Comments:

Academician Duan Shumin (Academician of the Chinese Academy of Sciences, Professor and Director of the Department of Medicine of Zhejiang University, Dean of the Institute of Brain Science Transformation of Fudan University, Dean of the Songjiang Research Institute of Shanghai Jiao Tong University)

The mechanism of memory generation and regulation and how to improve the memory impairment in neurodegenerative diseases (such as AD) are the hot and difficult problems in neuroscience research. Song Juan's research group's latest study proposed from a new perspective that the regulation of hippocampal newborn neurons modified by the SuM neural circuit of the hypothalamus may be a new strategy to improve the memory and emotional disorders of AD mice, and explored the mechanism: It was found that activation of SuM modified hippocampal newborn neurons enhanced hippocampal synaptic plasticity, increased the phagocytosis of microglia on amyloid plaques, and expanded the mechanism of regulating hippocampal neurogenesis to improve memory.

Interestingly, the SuM nucleus of the hypothalamus is an important wakefulness promoting brain region. Our previous studies have shown that activation of basal forebrain cholinergic neurons promotes arousal (Yong Han, Current biology 2014), while basal forebrain cholinergic neurons play an important regulatory role in hippocampal dependent memory coding and are damaged in AD. These studies suggest that impaired arousal system may play an important role in the development of memory impairment in AD.

 Professor Huang Li (Professor of School of Basic Medicine, Fudan University, Chairman of the Department of Pharmacology, Chairman of the Chinese Sleep Research Society)

Arousal is the biological basis of memory and emotion, and abnormal arousal can lead to memory and emotion disorders. UNC Juan Song's research group focuses on the role and mechanism of Supramillary nucleus (SuM) in controlling memory. Based on the previous discovery that SuM promotes memory retrieval (eLife 2020), we proposed the role and new mechanism of SuM in promoting learning and memory by regulating hippocampal neurogenesis (Nat Neurosci 2022; Curr Opin Neurobiol2023) and applied this strategy to the intervention of cognitive affective disorder in AD (Cell Stem Cell, 2023).

Wakeful sleep disorders in AD occur earlier than memory impairment, and the findings of this study suggest that intervention in the wakeful system may be a new strategy to improve memory impairment in AD.

About Dr. Li Yadong:

Researcher, independent PI, doctoral supervisor, Songjiang Research Institute, Shanghai Jiao Tong University

Li Yadong's research group studied the role and mechanism of arousal in regulating memory under physiological and pathological conditions (neurodegenerative diseases), using EEG/EMG recording, in vivo/in vitro electrophysiology, high-resolution single/two-photon imaging, in vivo multi-channel calcium signal recording, proteomic and photogenetic manipulation methods. Two important wakefulness nuclei in the ventral basal ganglia circuit, the nucleus accumbens and the ventral pallidum, were discovered, which laid a solid foundation for further research on the neural circuits of wakefulness regulating memory (Molecular Psychiatry, 2021; Nature Communications, 2018); The unique mechanism of hypothalamic awakening circuit promoting adult hippocampal neurogenesis and improving memory was revealed, and a new idea was proposed to improve learning and memory by improving arousal level and promoting hippocampal neurogenesis (eLife, 2020; Nature Neuroscience, 2022, Current Opinion in Neurobiology, 2023), and preliminary application to improve AD cognitive and affective disorders (Cell Stem Cell, 2023, J Transl Med, 2023).

Representative papers (# Co-first author,* Corresponding author) :

1. Li Y^#, Luo Y^#, Xie L, Tart D, Sheehy R, Zhang L, Coleman L, Chen X, Song J* (2023). Activation of hypothalamic-enhanced adult-born neurons restores cognitive and affective function in Alzheimer's disease,Cell Stem Cell, 31:1–18.

2. Li Y^#, Luo Y^#, Chen Z, Quintanilla L, Cherasse Y, Lazarus M, Huang Z, Song J* (2022). Hypothalamic modulation of adult hippocampal neurogenesis in mice confers activity-dependent regulation of memory and anxiety-like behavior.Nat Neurosci，25:630-45.

3. Li Y^#; Luo Y^#, Xu W, Ge J, Cherasse Y, Wang Y, Lazarus M, Qu W* & Huang Z* (2021). Ventral pallidal GABAergic neurons control wakefulness associated with motivation through the ventral tegmental pathway.Mol Psychiatry，26:2912-28.

4. Li Y, Bao H, Luo Y, Sullivan Y, Quintanilla L, Wickersham I, Lazarus M, Shin Y, Song J* (2020). Supramammillary nucleus synchronizes with dentate gyrus to regulate spatial memory retrieval through glutamate release.eLife，9:e53129.

5. Wander C^#,Li Y^#,*, Bao H, Asrican B, Luo Y, Sullivan H, Chao T, W, Samantha L, Tart D, Chen Z, Shih Y, Wickersham I, Cohen T, Song J*. Compensatory remodeling of a septo-hippocampal GABAergic network in the triple transgenic Alzheimer’s mouse model, J Transl Med, 2023, in press

6. Li Y^#, Luo Y^#, Song J* (2023); Optimizing memory performance and emotional states: multi-level enhancement of adult hippocampal neurogenesis,Curr Opin Neurobiol, 79.

7. Li Y^#, Ge J^#, Luo Y^#, Xu W, Wang J, Lazarus M, Hong Z, Qu W*, Huang Z* (2019). High cortical delta power correlates with aggravated allodynia by activating anterior cingulate cortex GABAergic neurons in neuropathic pain mice,PAIN, 161:288-299

8. Luo Y^#,Li Y^#, Wang L^#, Yang S, Yuan X, Wang J, Cherasse Y, Lazarus M, Chen J, Qu W*, Huang Z* (2018). Nucleus accumbens controls wakefulness by a subpopulation of neurons expressing dopamine D1 receptors.Nat Commun，9(1):1576.

9. Wu Y^#,Li Y^#, Luo Y, Wang T, Wang H*, Chen S, Qu W, Huang Z*(2015). Gelsemine alleviates both neuropathic pain and sleep disturbance in partial sciatic nerve ligation mice,Acta Pharmacol Sin, 11(36): 1308-1317

10. Asrican B^#, Wooten J^#,Li Y, Quintanilla L, Zhang F, Wander C, Bao H, Yeh C, Luo Y, Olsen R, Lim S, Hu J, Jin P, Song J* (2020). Neuropeptides modulate local astrocytes to regulate adult hippocampal neural stem cells,Neuron, 108(2): 349-366[LY1]