The present study directly tested the role of hippocampus and hippocampal subfields volume in the interplay between poor sleep quality and depressive symptoms in healthy populations. Our findings improved our current understanding of the relationship between sleep disturbance, depressive symptomatology, and hippocampal subfields in the healthy populations. In coincide with recent studies investigating the association between self-reported sleep quality and hippocampal subfield volumes in healthy elderly group 32,33, the present study also revealed sleep quality did not correlate with total hippocampal volume in healthy populations. However, self-reported sleep quality was found to be negatively correlated with the volume of hippocampal subfields, including DG, CA-3 and CA-4. Notably, the CA-4 is frequently considered as a part of the DG (Duvernoy et al., 2013; Liu et al., 2021). Also, self-reported depressive symptoms were found to be negatively correlated with several hippocampal subfields including DG, CA-1, CA-3, CA-4, HATA as well as the total hippocampal volume. In addition, the present study revealed that the volume of hippocampal subfields DG (including CA-4) significantly mediated the influence of poor sleep quality on self-reported depressive symptoms. Because DG is considered to play a crucial role in the hippocampal neurogenesis 48, poor sleep quality may contribute to depression through a reduction of DG volume leading to impaired neurogenesis, which is crucial for the regulation of mood 23,26.
With a large sample size (n = 1603), this study is the first to indicate an association between poor sleep quality and volume loss of the CA-3/CA-4/DG hippocampal subfields in healthy young adults. This finding is consistent with previous research by Neylan et al. (2010), which showed that subjective insomnia severity is associated with volume loss of the CA-3/dentate subfields 31 in PTSD patients. The association of self-reported sleep quality with the CA-3/CA-4/DG subfield volume is also consistent with animal models that have shown that chronic sleep disruption is associated with decreased neurogenesis and dendritic branching in these structures 13,14. Moreover, this association between sleep quality and hippocampal subfield volume is in alignment with both previous studies that have investigated the association between sleep disorders and hippocampal subfield volumes18,31 and previous studies that have indicated that reduced hippocampal subfield volume was associated with short sleep and sleep disturbance in the elderly group 33,34,49. Animal studies involving sleep and sleep-dependent manipulations demonstrated that the CA-3/CA-4/DG hippocampal subfields are crucial in neural plasticity, reduction of hippocampal cell proliferation and neurogenesis50. Our findings further indicated that certain biological factors, such as experimental sleep restriction or disrupted sleep can have significant effects on neurogenesis in the dentate gyrus, causing changes in the volume of the CA-3/CA-4/dentate region and possibly affecting other subfields, potentially impacting the hippocampal subfield volume.
It is important to note that the present study revealed that poor sleep quality was not associated with the total hippocampal volume. In the literature, the evidence of a relationship between poor sleep and total hippocampal volume is divergent. On one side, a negative association between hippocampal volume and sleep deprivation severity or duration has been reported in disorders characterized by sleep disruption 18,20,22, in healthy older adults 51,52 and in animal studies 14,53. Cumulative evidence, therefore, suggests that sleep may be an important risk factor for hippocampal atrophy54–56. On the other side, other human studies report no association between poor sleep and overall hippocampal volume 32,49,57. One reason for these inconsistent findings may be due to the low sensitivity of a global hippocampal volumetric approach, which may obscure hippocampal subfield distinct vulnerability to poor sleep quality. Indeed, our study revealed that poor sleep quality was associated with volume loss of the CA-3/CA-4/DG subfields. This rationale is in consistent with a recent study which also did not find associations between sleep and total hippocampal volume, but found associations between sleep duration and specific hippocampal subfield volumes33.
Moreover, the present study has revealed that the volume of hippocampal subfields DG (including CA-4) plays a significant role in mediating the impact of poor sleep quality on self-reported depressive symptoms. The DG, a crucial component of the hippocampal trisynaptic circuit, serves as a gate that controls the information flow from cortical regions into the hippocampus 58,59, and plays a critical role in the hippocampal neurogenesis 48. Additionally, the DG has been implicated in mood regulation 26, in addition to its critical role in learning and memory (Hainmueller & Bartos, 2020). To this end, poor sleep quality may contribute to depressive symptoms through a reduction of DG volume leading to impaired neurogenesis which is crucial for the regulation of mood. Moreover, the observed mediating effects of DG in the interplay between sleep quality and depressive symptoms are supported by several lines of evidence in humans with psychiatric disorders and in animal models of depression. For example, patients with MDD have decreased hippocampal volume, including DG 60,61, and manipulation of DG circuits or neurogenesis in mice can induce depression-like behaviors 62,63. This alteration in hippocampal subfield volume in depression indicated that the depression may, in part, result from a suppression of hippocampal neurogenesis 16. Considering the observed negative correlation between poor sleep quality and volume size of the CA-3/CA-4/DG hippocampal subfields mentioned above, sleep deficiency can have a significant role in the reduction of hippocampal neurogenesis, which further contributes to the development of depression. Taken together, these observations suggest that interventions aimed at altering the size of DG 9,64 could be a promising therapeutic strategy for depressive symptoms.
Leveraging a large sample size, the present study investigated hippocampal subfield volumes in association with self-reported sleep quality and its mediating role in the determination of how poor sleep quality influences depressive symptoms in healthy young adults. Few studies have examined these associations, however separately, using global hippocampal volumetric measurements only, relatively small sample sizes, and/or based on patient populations (e.g., chronic insomnia, depression and PTSD) and healthy elderly groups. Nonetheless, the present study has several limitations. First, a subjective measure of sleep, the PSQI, was used. Subjective sleep measures are readily available and can be used conveniently to screen and track sleep quality including sleep duration and sleep disorders. Future studies examine the influence of sleep quality on depressive symptoms can incorporate more objective sleep measures such as the duration, efficiency and regularity of sleep obtained by actigraphy and polysomnography. Secondly, causality between sleep quality and depressive symptoms cannot be established in this cross-sectional study. Future studies can use a longitudinal design to test whether poor sleep leads to depressive symptoms via accelerating hippocampal subfield volume loss. Thirdly, our investigation centered on examining the hippocampal structure; nonetheless, it is worth considering that there may be connections with additional regions, including the amygdala, thalamus, and prefrontal cortex. These associations hold potential and should be explored in future research to better understand the impact of poor sleep quality on depressive symptoms. Finally, the study participants were all college students with a limited age range, limiting generalizability of our results to other age groups.