Short-term caloric restriction exerts neuroprotective effects following mild traumatic brain injury by promoting autophagy and inhibiting astrocyte activation
Introduction
Traumatic brain injury (TBI), with trauma related primary and secondary mechanisms of neuronal damage is a leading cause of mortality and long-term disability [1], [2]. Approximately 75–90% of the 1.7 million TBI-related emergency room visits in the US each year are a result of mild TBI (mTBI) [3]. Patients with mTBI, unlike those with moderate and severe TBI, may show cognitive impairment with a lack of obvious tissue lesions in the brain [4], [5]. Moreover, some patients with mTBI still have measurable cognitive impairment after 1 year [6]. However, the pathology underlying mTBI is poorly understood and treatment modalities are essentially absent [7]. Thus, it is extremely urgent to investigate the mechanisms underlying mTBI-induced cognitive impairment in order to mitigate the sequelae of mTBI.
Autophagy, which is the principal mechanism for bulk degradation of superfluous or aberrant cytoplasmic components, has been implicated both clinically and experimentally in the delayed response to TBI [8]. Induction of autophagy after TBI may serve to eliminate aberrant cellular components, thus maintaining cellular homeostasis. Emerging data suggest that autophagy flux may be either increased or decreased after TBI. Therefore, autophagy may play either a beneficial or detrimental functional role after injury. However, it appears that a relatively mild injury could lead to upstream activation of autophagy flux as a protective mechanism [9]. Previous studies have indicated that several key molecular components participate in the initiation, progression and completion of autophagy, such as the mammalian target of rapamycin (mTOR), which inhibits autophagy, and Beclin1 and light chain (LC) 3, which promote it [10].
The underlying biological mechanisms of caloric restriction (CR), which is a dietary intervention that provides reduced energy intake without compromising nutrient adequacy, has been investigated for decades as the most robust and reliable experimental strategy for extending the longevity of laboratory animals [11]. Recent studies suggest that CR protects the central nervous system from neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease [12]. Numerous hypothetical mechanisms have been proposed to explain the neuroprotective effects of CR, including autophagy. Although the molecular mechanisms are still obscure, it has been proposed that CR protects the brain after TBI in a rat model [13] by suppressing microglial activation [14] and elevating brain derived neurotrophic factor (BDNF) [15], [16]. Therefore, the work described here was designed to test the hypothesis that CR can improve spatial memory in a mouse model of TBI and to begin to identify underlying molecular mechanisms that may lead to improved outcomes.
Section snippets
Animals and diet
Sixty 12-week-old male C57BL/6 mice, from the Beijing Weitong Lihua Experimental Animal Technology Co., Ltd [SCXK(jing)2012-0001] were fed ad libitum for 1 week before the beginning of the experiments. All animal study protocols were approved by the Institutional Animal Care and Ethics Committee of Xuan Wu Hospital, Capital Medical University (No. 2012-5-68-HX) in Beijing, China.
Animals were randomly divided into three groups according to the diet after suffering from mTBI: the normal control
Changes in the body weight and NSS score
To determine the general effects of CR and HC diets after mTBI, we weighed groups of mice before mTBI and on days 7, 14, 21, and 28 post-mTBI. As shown in Fig. 1 A, there were no significant differences in body weights between mice in the mTBI + NC (23.92 ± 1.44 g), mTBI + CR (23.65 ± 1.02 g), and mTBI + HC (23.32 ± 1.54 g) groups at the beginning of the experiment (P > 0.05). From 7 days after mTBI until the end of the study, the body weights of the mTBI + CR group were significantly lower than those of the mTBI +
Discussion
In the present study, we provided evidence that treatment with CR for 30 days inhibits astrocyte activation and ameliorates learning and memory impairment after mTBI in mice. The therapeutic effects were associated with CR-induced LC3b and Beclin1 upregulation, indicative of the promotion of autophagy. Moreover, high-energy diet treatment had the opposite effects on astrocyte activation and hippocampal pathology.
The MWM test is widely used to assess rodent cognition, which is sensitive to
Conclusion
These data demonstrate that high-energy intake and CR have opposite effects after mTBI. High-energy intake presents a risk factor that can contribute to cognitive impairment after mTBI. Conversely, CR has been shown to reduce cognitive dysfunction, indicating that appropriate low caloric intake for a short time may be an effective way to prevent cognitive impairment after mTBI. The results may help us to better understand the mechanism behind mTBI and cognitive impairment.
Competing financial interests
The author(s) declare that there are no competing financial interests.
Conflict of interest
None.
Acknowledgments
This work was supported by the following grants: Beijing Natural Science Foundation (7132033, 7132044, 7174310), and National Natural Science Foundation of China (81600927).
References (58)
Luteolin provides neuroprotection in models of traumatic brain injury via the Nrf2-ARE pathway
Free Radic. Biol. Med.
(2014)- et al.
Moderate and severe traumatic brain injury in adults
Lancet Neurol.
(2008) Long-term consequences: effects on normal development profile after concussion
Phys. Med. Rehabil. Clin. N. Am.
(2011)- et al.
The use of telomere length as a predictive biomarker for injury prognosis in juvenile rats following a concussion/mild traumatic brain injury
Neurobiol. Dis.
(2016) - et al.
Spatial memory following damage to hippocampal CA3 pyramidal cells with kainic acid: impairment and recovery with preoperative training
Brain Res.
(1981) - et al.
The role of the CA3 hippocampal subregion in spatial memory: a process oriented behavioral assessment
Progr. Neuro-Psychopharmacol. Biol. Psychiatry
(2009) Selective cognitive impairment following traumatic brain injury in rats
Behav. Brain Res.
(1993)- et al.
Virtual environment navigation tasks and the assessment of cognitive deficits in individuals with brain injury
Behav. Brain Res.
(2007) A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning
Neuroscience
(2002)High fat feeding promotes simultaneous decline in insulin sensitivity and cognitive performance in a delayed matching and non-matching to position task
Behav. Brain Res.
(2011)
Dietary restriction started after spinal cord injury improves functional recovery
Exp. Neurol.
A murine model of mild traumatic brain injury exhibiting cognitive and motor deficits
J. Surg. Res.
Minocycline plus N-acetylcysteine synergize to modulate inflammation and prevent cognitive and memory deficits in a rat model of mild traumatic brain injury
Exp. Neurol.
Rapamycin is a neuroprotective treatment for traumatic brain injury
Neurobiol. Dis.
Mild traumatic brain injury results in extensive neuronal degeneration in the cerebral cortex
J Neuropathol. Exp. Neurol.
Chronic impairment of prospective memory after mild traumatic brain injury
J. Neurotrauma
Cognitive deficits and mild traumatic brain injury
BMJ
Cerebrolysin improves cognitive performance in rats after mild traumatic brain injury
J. Neurosurg.
Function and mechanisms of autophagy in brain and spinal cord trauma
Antioxid. Redox Signal.
Stimulation of autophagy by rapamycin protects neurons from remote degeneration after acute focal brain damage
Autophagy
Neuroprotective effects of Co-UltraPEALut on secondary inflammatory process and autophagy involved in traumatic brain injury
J. Neurotrauma
Genetic links between diet and lifespan: shared mechanisms from yeast to humans
Nat. Rev. Genet.
Energy intake, meal frequency, and health: a neurobiological perspective
Annu. Rev. Nutr.
Dietary intake alters behavioral recovery and gene expression profiles in the brain of juvenile rats that have experienced a concussion
Front. Behav. Neurosci.
Caloric restriction suppresses microglial activation and prevents neuroapoptosis following cortical injury in rats
PLoS One
Chronic caloric restriction reduces tissue damage and improves spatial memory in a rat model of traumatic brain injury
J. Neurosci. Res.
Caloric restriction can improve learning ability in C57/BL mice via regulation of the insulin-PI3K/Akt signaling pathway
Neurol. Sci.
Influence of age-related learning and memory capacity of mice: different effects of a high and low caloric diet
Aging Clin. Exp. Res.
Mouse closed head injury model induced by a weight-drop device
Nat. Protoc.
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2020, IBRO ReportsCitation Excerpt :The Morris water maze test demonstrated that the animals under CR had less latency to find the platform than the control groups, and the HFD group a higher number of platform crossings than the other groups. It has also been shown that CR decreased GFAP, mTOR levels, and increased LC3B levels, demonstrating that CR can improve cognitive deficits due to mTBI (Liu et al., 2017). Rich et al. conducted a study testing the hypothesis that CR could improve spatial memory in a model of traumatic brain injury in two-month-old male mice.
Western diet aggravates neuronal insult in post-traumatic brain injury: Proposed pathways for interplay
2020, EBioMedicineCitation Excerpt :Interestingly, WD-fed mice exhibit increased phosphorylation of mTOR in the brain coinciding with increased microglial activation and cognitive dysfunction [104]. Moreover, the increased signs of neuroinflammation post TBI, observed in high-caloric intake mice compared to normal caloric-intake mice, were accompanied by increased levels of mTOR, which demonstrates that WD contributes to the secondary brain injury in part through activation of mTOR [105]. Alternatively, mTOR acts as a potent inhibitor of autophagy.
Periodic dietary restriction ameliorates amyloid pathology and cognitive impairment in PDAPP-J20 mice: Potential implication of glial autophagy
2019, Neurobiology of DiseaseCitation Excerpt :In recent years, attention has been put into dietary restriction (DR) as a potential neuroprotective strategy. Evidence suggests that DR of food intake could lead to the prevention of chronic diseases and to increase longevity in different animal models (Mattson, 2005; McCay et al., 1935), modulating energy metabolism, antioxidant defenses, inflammation and autophagy, among other pathways (Liu et al., 2017). Moreover, DR can prevent age-related alterations in motor and cognitive function, dendritic plasticity and glial function in rats and mice (Ma et al., 2018; Mladenovic Djordjevic et al., 2010; Moroi-Fetters et al., 1989), potentially reducing the impact of age-associated diseases.
Aging, lifestyle and dementia
2019, Neurobiology of DiseaseThe role of autophagy in acute brain injury: A state of flux?
2019, Neurobiology of DiseaseCitation Excerpt :In children after severe TBI, p62/sequestosome 1 (SQSTM1) and Beclin 1 are increased in cerebrospinal fluid (CSF) compared with CSF from control patients, with p62 concentration associated with unfavorable outcome, consistent with increased, overwhelmed, and/or impaired autophagic flux (Au et al., 2017). Using a weight-drop model which produces diffuse brain injury, Y. Liu et al. (2017) recently showed that caloric restriction after mild TBI results in increased autophagy markers in the CA3 region of the hippocampus, with a twofold increase in Beclin 1, a threefold increase in LC3, as well as decreased mammalian target of rapamycin (mTOR) compared to injured animals with normal diets. Calorie-restricted mice also demonstrated better cognitive performance, measured by escape latency on Morris-water maze testing.