Biology subjects

Sandi, C.

Publications and source records attributed to Sandi, C..

23 records · Page 2Linked to original sources

bioRxiv2019

Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine: An in vivo 1H-magnetic resonance spectroscopy study at 14 T

BackgroundEmerging evidence suggests that hierarchical status may provide vulnerability to develop stress-induced depression. Energy metabolism in the nucleus accumbens (NAc) was recently related to hierarchical status and vulnerability to develop depression-like behavior. Acetyl-L-carnitine (LAC), a mitochondria-boosting supplement, has shown promising antidepressant-like effects opening promising therapeutic strategies for restoring energy balance in depressed patients. Here, we investigated the metabolic impact in the NAc of antidepressant LAC treatment in chronically stressed mice.\n\nMethodMice were characterized for emotional behaviors and social rank. They were then exposed to chronic restraint stress (CRS) for 21 days and subsequently tested in a social behavior (SB) test. A group of mice was also given LAC supplementation during the 7 last CRS days. Mice were then tested in the SB and forced swim tests (FST) and scanned in vivo using 1H-magnetic resonance spectroscopy (1H-MRS) to quantitatively assess the NAc neurochemical profile.\n\nResultsDominant, but not subordinate, mice showed behavioral vulnerability to CRS. In the NAc, dominant mice showed reduced levels of several energy-related metabolites. LAC treatment counteracted stress-induced behavioral changes in dominant mice, and normalized levels of taurine, phosphocreatine, glutamine and phosphocholine in the NAc. No major accumbal metabolic changes were observed in subordinate mice.\n\nConclusionHigh social rank is confirmed as a vulnerability factor to develop chronic stress-induced depressive-like behaviors. We reveal a metabolic signature in the NAc for the antidepressant-like effects of LAC in vulnerable mice, characterized by restoration of stress-induced alterations in neuroenergetics and lipid function.

neuroscience↗

bioRxiv2019

The glucocorticoid receptor in the nucleus accumbens plays a crucial role in social rank attainment in rodents

Social hierarchy in social species is usually established through competitive encounters with conspecifics. It determines the access to limited resources and, thus, leads to reduced fights among individuals within a group. Despite the known importance of social rank for health and well-being, the knowledge about the processes underlying rank attainment remains limited. Previous studies have highlighted the nucleus accumbens (NAc) as a key brain region in the attainment of social hierarchies in rodents. In addition, glucocorticoids and the glucocorticoid receptor (GR) have been implicated in the establishment of social hierarchies and social aversion. However, whether GR in the NAc is involved in social dominance is not yet known. To address this question, we first established that expression levels of GR in the NAc of high anxious, submissive-prone rats are lower than that of their low anxious, dominant-prone counterparts. Furthermore, virally-induced downregulation of GR expression in the NAc in rats led to an improvement of social dominance rank. We found a similar result in a cell-specific mouse model lacking GR in dopaminoceptive neurons (i.e., neurons containing dopamine receptors). Indeed, when cohabitating in dyads of mixed genotypes, mice deficient for GR in dopaminoceptive neurons had a higher probability to become dominant than wild-type mice. Overall, our results highlight GR in the NAc and in dopaminoceptive neurons as an important regulator of social rank attainment.

neuroscience↗

bioRxiv2019

Constitutive differences in glucocorticoid responsiveness are related to divergent spatial information processing abilities

The stress response facilitates survival through adaptation and is intimately related to cognitive processes. The Morris water maze task probes spatial learning and memory in rodents and glucocorticoids (i.e. corticosterone in rats) have been suggested to elicit a facilitating action on memory formation. Moreover, the early aging period (around 16-18 months of age) is susceptible to stress- and glucocorticoid-mediated acceleration of cognitive decline. In this study, we tested three lines of rats selectively bred according to their individual differences in corticosterone responsiveness to repeated stress exposure during juvenility. We investigated whether endogenous differences in glucocorticoid responses influenced spatial learning, long-term memory and reversal learning abilities in a Morris water maze task at early aging. Additionally, we assessed the quality of the different swimming strategies of the rats. Our results indicate that rats with differential corticosterone responsiveness exhibit similar spatial learning abilities but different long-term memory retention and reversal learning. Specifically, the high corticosterone responding line had a better long-term spatial memory, while the low corticosterone responding line was impaired for both long-term retention and reversal learning. Our modeling analysis of performance strategies revealed further important line-related differences. Therefore, our findings support the view that individuals with high corticosterone responsiveness would form stronger long-term memories to navigate in stressful environments. Conversely, individuals with low corticosterone responsiveness would be impaired at different phases of spatial learning and memory.

animal behavior and cognition↗

bioRxiv2018

Nucleus accumbens neurochemistry in human anxiety: A 7T 1H-MRS study

Individual differences in anxiety provide a differential predisposition to develop neuropsychiatric disorders. The neurochemical underpinnings of anxiety remain elusive, particularly in deep structures, such as the nucleus accumbens (NAc) whose involvement in anxiety is being increasingly recognized. We examined the associations between the neurochemical profile of human NAc metabolites involved in neural excitation and inhibition and inter-individual variation in temperamental and situational anxiety. Twenty-seven healthy 20-30 years-old human males were phenotyped with questionnaires for state and trait anxiety (State-Trait Anxiety Inventory, STAI), social anxiety (Liebowitz Social Anxiety Scale), depression (Beck Depression Inventory, BDI) and fatigue (Mental and Physical State Energy and Fatigue Scales, SEF). Using proton magnetic resonance spectroscopy (1H-MRS) at 7 Tesla (7T), we measured metabolite levels for glutamate, glutamine, GABA and taurine in the NAc with. Salivary cortisol was also measured. Strikingly, trait anxiety was negatively associated with NAc taurine content. Perceived situational stress was negatively associated with NAc GABA, while positively with the Glu/GABA ratio. These findings were specific, as no correlation was observed between NAc taurine or GABA and other phenotypic variables examined (i.e., state anxiety, social anxiety, depression, or cortisol), except for a negative correlation between taurine and state physical fatigue. This first 7T study of NAc neurochemistry shows relevant metabolite associations with individual variation in anxiety traits and situational stress and state anxiety measurements. The novel identified association between NAc taurine levels and trait anxiety may pave the way for clinical studies aimed at identifying new treatments for anxiety and related disorders.

neuroscience↗

bioRxiv2018

Chronic corticosterone enhancement aggravates alpha-synuclein brain spreading pathology and substantia nigra neurodegeneration in mice

Chronic stress and associated heightened glucocorticoid levels are risk factors for depression, a common non-motor symptom in Parkinsons disease (PD). However, how heightened glucocorticoids influence PD neuropathology [alpha-synuclein (-Syn) containing Lewy pathology and neurodegeneration] and disease progression is unclear. To address this knowledge gap, we investigated the impact of chronic corticosterone administration on -Syn pathology, neurodegeneration, behavior and mitochondrial function in a mouse model of -Syn pathology spreading after intracerebral injection of -Syn preformed fibrils (PFFs). Our results demonstrate that heightened corticosterone aggravates neurodegeneration and -Syn pathology spreading, intriguingly to specific brain regions, such as the entorhinal cortex. Corticosterone-treatment abolished distinct physiological adaptations after PFF-injection and induced differential physiological and behavioral consequences. Taken together, our work points to elevated glucocorticoids as a risk factor for the development of the neuropathological hallmarks of PD. Strategies aimed at reducing glucocorticoid levels might slow down pathology spreading and disease progression in synucleinopathy.

neuroscience↗