Depression is among the leading causes of disability worldwide, which reflects the current lack of understanding of its underlying mechanisms (Friedrich, 2017; Menke, 2018). Metabolic alterations are emerging as key etiological factors for the development of neuropsychiatric disorders, including depression (Pei and Wallace, 2018; Andreazza and Nierenberg, 2018; Kim et al., 2019). The strong reliance of the brain on high energy consumption would make it particularly vulnerable to metabolic alterations (Pei and Wallace, 2018). In addition, chronic stress has a strong capacity to trigger and exacerbate depression (de Kloet et al., 2005; Richter-Levin and Xu, 2018) and impinges metabolic-costly neuronal adaptations in structure and function (Turner and Lloyd, 2004; de Kloet et al., 2005; McEwen et al., 2015). Accordingly, stress-associated depletion of brain's energy resources could lead to impaired neuronal plasticity underlying depression (Morava and Kozicz, 2013; Picard et al., 2018). Mitochondria, by powering the brain with energy production, play a central role in the adaptation and response to stress (Picard et al., 2015), and mitochondrial supplements could provide an efficient means of protecting brain structures that are particularly vulnerable to stress (Parikh et al., 2009).

However, not all individuals are equally affected by stress (Duclot and Kabbaj, 2013; McEwen et al., 2015; Russo et al., 2012); while some individuals show a high vulnerability to develop depression, others endure resilience following stress exposure (Russo et al., 2012; Weger and Sandi, 2018). It remains unclear which factors provide resilience to stress in certain individuals and what are the underlying mechanisms (Larrieu and Sandi, 2018; Ménard et al., 2017). In addition to the great predictive power of high anxiety trait in defining stress vulnerability (Sandi et al., 2008; Castro et al., 2012; for reviews, see Sandi and Richter-Levin (2009); Russo et al., 2012; Weger and Sandi, 2018), epidemiological, clinical and animal work point to a link between social hierarchies and depression (Larrieu and Sandi, 2018).

Recently, in the C57BL/6J inbred mouse strain, we found that high rank animals were more susceptible to display social avoidance following exposure to chronic social defeat stress (CSDS), while low rank mice were not affected (Larrieu et al., 2017). Data from ¹H-magnetic resonance spectroscopy [¹H-MRS; one of the few non-invasive methods that can provide direct information on brain metabolism in vivo (Duarte et al., 2012)] revealed a relationship between the metabolic profile of the nucleus accumbens [NAc; a hub brain region for the regulation of motivated behaviors (Robbins and Everitt, 1996) implicated in the pathophysiology of depression (Francis and Lobo, 2017)], social rank, and vulnerability to stress. Thus, while under basal conditions low rank showed lower levels of energy-related metabolites than high rank mice, it was only the low rank/resilient group that displayed increased metabolite levels following CSDS (Larrieu et al., 2017). These observations suggested that metabolic targeting may be an optimal treatment intervention and confirmed that NAc is a particularly sensitive structure that might beneficiate from energetic support.

Acetyl-L-carnitine (LAC) has been recently shown to have promising potency to rapidly alleviate depressive-like symptoms in preclinical studies (Bigio et al., 2016; Lau et al., 2017; Wang et al., 2015; Nasca et al., 2013) and in humans, where emerging clinical evidence supports its good tolerability (Wang et al., 2014; Veronese et al., 2018). LAC is an endogenous short-chain acetyl ester of free carnitine involved in the transport of long chain fatty acids into the mitochondria for degradation by beta oxidation thus, contributing to energy metabolism (Ferreira and McKenna, 2017). In addition, LAC can facilitate the removal of oxidative products, provide acetyl groups for protein acetylation, be used as a precursor for acetylcholine, or be incorporated into neurotransmitters such as glutamate, glutamine and GABA (Ferreira and McKenna, 2017). However, it is not known whether LAC treatment can counteract brain metabolic alterations specifically observed in the context of stress-induced depression.

In this study, we investigated the ability of LAC supplementation to protect vulnerable mice against stress induced depressive-like behaviors. As indicated above, socially dominant C57BL/6J mice, were at higher risk of developing depression-like behavior following exposure to CSDS (Larrieu et al., 2017). Here, in order to exclude that the identified vulnerability is a mere reflect of the social stressor used (Larrieu and Sandi, 2018), a first aim of this study was to assess the link between social rank and vulnerability to develop depressive-like behaviors using chronic exposure to a non-social (e.g., physical) stressor. To this end, and given that lipid peroxidation has been shown to be increased by restrain stress in the striatum (Atif et al., 2008), we exposed mice to the well-established 21 day restrain stress protocol (Lau et al., 2017; Nasca et al., 2015). Subsequently, we studied the impact of LAC treatment coinciding with the last week of stress exposure on the concentration of up to 20 metabolites in the NAc using in vivo ¹H-MRS at 14 Tesla (Larrieu et al., 2017; Duarte et al., 2012; Mlynárik et al., 2008). We also tested mice for depressive-like behaviors, including motivation to explore social conspecifics and coping responses in the forced swim test (FST) (Nestler et al., 2002). Besides the evident translational potential of ¹H-MRS at 14 T in identifying biomarkers, rodent ¹H-MRS studies at ultra-high field bridge a potential pathological indicator and its associated molecular signature to physiological mechanisms.

In this study, using in vivo ¹H-MRS at 14 T, we identified a chronic stress-related metabolic signature in the NAc of high rank mice -identified as a group of high vulnerability to develop depressive-like behaviors- that was partially restored by LAC treatment. High rank animals were defined as those that following cohabitation in groups of 4 males, emerged as ranks 1 and 2 in the social confrontation tube test. Our results provide an in vivo metabolic basis for understanding of antidepressant-like properties of LAC and its protective effects against chronic stress.

When exposed to chronic social defeat (i.e., daily exposure and defeat by an aggressive mouse), high rank C57BL/6J mice living in tetrads are at higher risk of developing social avoidance (i.e., a depressive-like behavior) than low rank mice (Larrieu et al., 2017). Our results reinforce the view that social rank in mice predicts vulnerability to stress. In addition, given the non-social character of the CRS protocol, our results argue against the view that their vulnerability would be solely based upon loss of social status (Larrieu and Sandi, 2018). It is important to note that, under basal conditions (i.e., before stress application), higher rank is related to higher anxiety-like behaviors as indicated by their exploration of an elevated plus maze (but note that these animals did not differ from low rank in the time spent in the center of the open field, only in their latency to enter the zone), as high anxiety trait is a well-established risk factor to develop stress-related depressive behaviors (Sandi et al., 2008; Castro et al., 2012; for reviews, see Sandi and Richter-Levin (2009); Russo et al., 2012; Weger and Sandi, 2018). However, a note of caution should be added as previous work suggests that whereas dominant mice tend to display more novelty-related exploratory behavior than less dominant mice, differences in anxiety-related behaviors seem to be less consistent (see Varholick et al., 2018, and references herein). We would also like to emphasize that we find a high reliability and linearity of social rank assessed under our experimental conditions that involve at least 5 weeks of cohabitation prior to carrying out the social confrontation tube test (see also Larrieu et al., 2017). This characterization may determine a different phenotype than studies in which social hierarchy is established within the first 2–3 weeks of cohabitation. Indeed, a recent study showed that during early cohabitation, dominance ranks of mice changed with repeated measurement, but became more stable between the 2nd and 3rd week of testing (Varholick et al., 2018). An additional issue to consider is that, for our analyses, we have grouped ranks 1 and 2 as high rank mice and ranks 3 and 4 as low rank. Although this grouping allows revealing statistical differences in the evaluated variables, each of the ranks in a tetrad home cage hierarchy may in fact lead to idiosyncratic phenotypes. In the future, it would be important to address vulnerability to stress for each specific rank in the colony.

LAC supplementation during the last week of the 3 week CRS protocol was efficient to protect high rank/vulnerable mice from the development of enhanced passive coping responses (i.e., higher floating levels) in the FST. Importantly, LAC levels are markedly reduced in patients with major depressive disorder, particularly in those with treatment-resistant depression and higher reported rates of early life stress in the form of childhood trauma (Nasca et al., 2018). Our results in the FST are in line with previous rodent studies showing the ability of LAC to reduce immobility time in this test (Wang et al., 2015; Bigio et al., 2016; Lau et al., 2017; Pulvirenti et al., 1990) with several small clinical trials in humans reporting effectiveness of LAC treatment in amelioration of depressive symptoms (Martinotti et al., 2011; Pettegrew et al., 2002; Zanardi and Smeraldi, 2006; Wang et al., 2014; Pettegrew et al., 2000). Growing evidence showed the ability of LAC to ameliorate both social interaction and social avoidance at the chronic restraint stress and social defeat stress paradigms in mice with baseline anxiety-like behavior, increased systemic inflammation and decreased hippocampal volume (Lau et al., 2017; Nasca et al., 2019). Thus, the lack of LAC efficiency in reversing stress-induced deficits in social avoidance in mice with different social hierarchy range in the current study pave the way for future research in understading whether the social rank based on the SCTT relate to a mouse' behavior in a light-dark test that probably gets at the same anxiety versus resilient traits. It will be important to study whether social dominance and light dark traits co-occur in the same mice or whether these traits define distinct susceptible phenotypes that may show a differential responssivness to treatments. Moreover, the succesful LAC-induced reversal of increased floating in the FST would fit well with a view that the individual’s NAc metabolic millieu is critically relevant for the animal’s engagement in energetically-costly behaviors (van der Kooij et al., 2018b). Accordingly, depressive-like behaviors which are more fundamentally dependent on resources mobilization would be more likely to be reversed by LAC’s energy support. Restoring normal metabolic function is, thus, more likely to affect behavior in the context set by the FST – that is fighting against an inescapable situation. This view fits well with the particular focus of this study on energy metabolism in the NAc. This postulate is supported by previous studies that showed that pharmacological manipulations leading to either impaired or boosted mitochondrial function in the nucleus accumbens were found to boost energetically-costly high rank behaviors during a social competition test between two male rats (Hollis et al., 2015; van der Kooij et al., 2018a).

Active coping in the FST depends upon dopamine actions in the NAc (Tye et al., 2013; de Kloet and Molendijk, 2016) and LAC has been shown to increase DA release in vivo (Harsing et al., 1992; Tolu et al., 2002) and to prevent a chronic stress-induced decrease in DA output in the NAc shell (Masi et al., 2003). In addition, stress has been shown to induce alterations in the accumbal oxidative stress system (Della et al., 2012; Ignácio et al., 2017), and LAC treatment to exert neuroprotective effects by inhibition of glial activation and oxidative stress in the striatum in an animal model of DAergic neuron damage (Singh et al., 2016). Furthermore, lipid peroxidation has been shown to be increased by immobilization stress in the rat striatum and L-carnitine to reduce associated striatal lipid peroxidation (Méndez-Cuesta et al., 2011). Interestingly, both in rodents (Méndez-Cuesta et al., 2011) and in zebrafish (Marcon et al., 2019), LAC was effective to reverse lipid peroxidation damage in stressed animals while being devoid of effect in controls.

Our in vivo ¹H-MRS at 14 T identified key metabolites implicated in the response to chronic restrain stress and LAC treatment in the NAc. Among the nine metabolites loading highly in FA Factor one, five (i.e., taurine, phosphocreatine, glutamate, aspartate and NAA) were reduced by stress in high rank/vulnerable mice and two of them (i.e., taurine and phosphocreatine) reversed by LAC treatment. Taurine is a sulfur containing amino acid, with no involvement in protein synthesis, but with several functions ranging from antioxidant, signaling molecule and osmolyte (Hansen et al., 2006; Yang et al., 2013; Wang et al., 2016; Jamshidzadeh et al., 2017). Brain taurine concentrations have been shown to be reduced by chronic stress (Barbosa Neto et al., 2012) and hyperglycemic conditions (Malone et al., 2008). Although in our study we did not find stress-related changes in animals’ glycemic state following CRS, the repeated stress schedule implemented in our CRS protocol is known to lead to increased blood glucose levels with every daily stress manipulation (e.g., van der Kooij et al., 2018b). It will be important to address whether this is the mechanism that leads to the reduction in accumbal taurine levels observed in our study, as well as exploring how metabolite changes induced by stress and LAC relate to mitochondrial function. Strikingly, in an early study, Sershen et al. (1991) specifically observed a reversal by LAC of ageing-induced reductions in taurine in the striatum, not of any other amino acid in the striatum or of taurine or other amino acids in any other brain region. Importantly, in our study, we also found that NAc taurine levels were the only ones from the measured metabolites that negatively correlated with passive coping responses in the FST, reinforcing the link between levels of this amino acid and energetically-costly coping responses to adversity. In a recent 7T ¹H-MRS in humans, we have recently found a negative correlation between trait anxiety and NAc taurine content (Strasser et al., 2019). Given the high link between trait anxiety and vulnerability to depression (Sandi and Richter-Levin, 2009; Weger and Sandi, 2018), our results support the interest in investigating the causal link between NAc taurine and its potential antidepressant actions.

Our finding that LAC increased phosphocreatine levels in high rank/vulnerable stressed mice is consistent with former reports indicating that LAC treatment increases phosphocreatine in the brain (Castro et al., 2012; Smeland et al., 2012; Aureli et al., 1994; Aureli et al., 1990; Hansen et al., 2006). Accordingly, LAC treatment likely improves the capacity of the brain to produce high-energy phosphates, which may be highly beneficial under conditions of disturbed energy metabolism. Several mechanisms have been implicated in the energy-boosting effects of LAC, many of them relating to an increased oxidative capacity of mitochondria through the direct release of oxidable fuel from LAC itself, or indirectly, in avoiding substrate inhibition of pyruvate dehydrogenase (PDH) by excess of AcCoA (Smeland et al., 2012; Broderick et al., 1992; Panchal et al., 2015; Virmani et al., 1995). Our results are in line with the idea of a restored mitochondrial function and support by LAC, visible through the increase in PCr, as well as taurine.

In addition, we observed that LAC restored levels of PCho and the ratio of GPC/PCho, which are disrupted by stress as well in high rank mice. PCho serves as a precursor of phosphatidylcholine (PtdCho), one of the main brain phospholipids, while GPC is its degradation product (Morash et al., 1988). The GPC/PCho ratio is thus considered to reflect the membrane turnover, typically increased in the case of neurodegeneration or excitotoxicity (Nitsch et al., 1992; Kristián and Siesjö, 1998). Increase in GPC can only arise from increased phospholipase activity, which is frequent during excitotoxic events and has been proposed to be a consequence of astrocyte activation (Klein, 2000; Ha et al., 2014). LAC and its deacetylated form L-carnitine (LC) are endogenous metabolites involved mainly in the transport and beta-oxidation of lipids. Exchange of LC with LAC and other acylcarnitines trough carnitine-acylcarnitine translocase (CACT) allows a bidirectional flow from cytoplasm into the inner mitochondrial matrix membrane for lipid oxidation. LAC supplementation could thus have a positive effect on phospholipid metabolism, by restoring normal balance between lipid degradation and synthesis.

A role for astrocytes in the LAC mechanism of action is also suggested by the normalization of stress-induced decreases in Gln content observed in the LAC-treated high rank group. Gln is mostly abundant in astrocytes (typically 80% of total concentration) due to their specific expression of glutamine synthetase (GS), which plays a key role in glutamate recycling at the synapse (Norenberg and Martinez-Hernandez, 1979; Bak et al., 2006). Astrocytic function is fundamental in the resilience to stress and regulation of extrasynaptic glutamate homeostasis (Pellerin and Magistretti, 1994; Nasca et al., 2017). For instance, LAC has shown effective control of astroglial cystine-glutamate exchanger (xCT), which is thought to improve mGlu2 function in hippocampus as a response to stress. A similar transcriptional response could be expected for glial GS, given its established responsiveness to glucocorticoids in stress (Rozovsky et al., 1995; Carter et al., 2013), an effect that could underlie the observed Gln changes. Even though the acetyl moiety of LAC has been shown to be utilized for the build-up of metabolic neurotransmitters synthesized from the TCA cycle (Kuratsune et al., 2002), LAC treatment in our study did not restore the stress-induced decrease of Glu, NAA and Asp observed in the nucleus accumbens of the high rank mice. This would suggest that LAC effects on these metabolites within the NAc may be secondary and part of an indirect and slower process. Nevertheless, as NAA, Glu and Asp measured with MRS reflect mainly neuronal metabolism (Van den Berg et al., 1969; Bhakoo, 2012), we can hypothesize that astrocytes are the first beneficiary of LAC supplementation. Astrocytes are indeed specifically shaped to uptake blood fatty acids, ketone bodies and acetate, and presumably LAC (Blázquez et al., 1998; Valdebenito et al., 2016; Rae et al., 2012).

Altogether, our findings highlight an accumbal metabolic signature for vulnerability to stress and response treatment. By implying an accumbal energy- and membrane metabolism process underlying the behavioral outcome, our study identifies molecular candidates responding in opposite direction to chronic stress and LAC treatment, opening possible mechanistic pathways underlying the anti-depressant-like effect of LAC. In particular, we underscore a strong association between NAc taurine and coping behaviors in an energetically-costly adversity task as well as antidepressant LAC actions. However, it is important to note that our study of LAC effectiveness circumscribed to high rank mice. In the future, it will be important to establish whether LAC treatment would be effective to overcome emotional changes induced by a chronic stress regime capable of affecting low rank individuals and whether LAC treatment could be more effective in the high rank mice because of differential endogenous levels of LAC based on social hierarchy.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Antoine Cherix

   Laboratory for Functional and Metabolic Imaging (LIFMET), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

   Contribution

   Conceptualization, Formal analysis, Investigation, Visualization

   For correspondence

   antoine.cherix@epfl.ch

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4168-8273

2. Thomas Larrieu

   Laboratory of Behavioral Genetics, Brain and Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

   Present address

   Center for Psychiatric Neurosciences, Lausanne University Hospital (CHUV), Site de Cery, Lausanne, Switzerland

   Contribution

   Conceptualization, Formal analysis, Supervision, Investigation

   Competing interests

   No competing interests declared

3. Jocelyn Grosse

   Laboratory of Behavioral Genetics, Brain and Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

   Contribution

   Conceptualization, Formal analysis, Investigation

   Competing interests

   No competing interests declared

4. João Rodrigues

   Laboratory of Behavioral Genetics, Brain and Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

   Contribution

   Conceptualization, Formal analysis, Investigation

   Competing interests

   No competing interests declared

5. Bruce McEwen

   Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, United States

   Contribution

   Conceptualization, Supervision

   Competing interests

   No competing interests declared

6. Carla Nasca

   Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, United States

   Contribution

   Conceptualization, Supervision

   Competing interests

   No competing interests declared

7. Rolf Gruetter

   Laboratory for Functional and Metabolic Imaging (LIFMET), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

   Contribution

   Conceptualization, Supervision, Funding acquisition

   Competing interests

   No competing interests declared

8. Carmen Sandi

   Laboratory of Behavioral Genetics, Brain and Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

   Contribution

   Conceptualization, Supervision, Funding acquisition, Project administration

   For correspondence

   carmen.sandi@epfl.ch

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7713-8321

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