Emerging evidence suggests that hierarchical status provides vulnerability to develop stress-induced depression. Energy metabolic changes in the nucleus accumbens (NAc) were 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 therapeutic opportunities for restoring energy balance in depressed patients. We investigated the metabolic impact in the NAc of antidepressant LAC treatment in chronically-stressed mice using ¹H-magnetic resonance spectroscopy (¹H-MRS). High rank, but not low rank, mice, as assessed with the tube test, showed behavioral vulnerability to stress, supporting a higher susceptibility of high social rank mice to develop depressive-like behaviors. High rank mice also showed reduced levels of several energy-related metabolites in the NAc that were counteracted by LAC treatment. Therefore, we reveal a metabolic signature in the NAc for antidepressant-like effects of LAC in vulnerable mice characterized by restoration of stress-induced neuroenergetics alterations and lipid function.

Debilitating, yet underinvestigated nonmotor symptoms related to mood/emotion, such as depression, are common in Parkinson's disease. Here, we explore the role of depression and of the amygdala, a brain region robustly linked to mood/emotion, in synucleinopathy. We hypothesized that mood/emotional deficits might accelerate Parkinson's disease-linked symptomatology, including the formation of α-synuclein pathology. We combined elevated corticosterone treatment, modeling chronic stress and depression, with a model of seeded α-synuclein pathology in mouse striatum and assessed behavioral parameters with a focus on mood/emotion, and neuropathology. We report behavioral resilience against α-synuclein proteinopathy in the absence of additional insults, potentially based on hormesis/conditioning mechanisms. Elevated corticosterone, however, reversed α-synuclein pathology-induced behavioral adaptations and was associated with increased dopaminergic cell loss as well as aggravated α-synuclein pathology in specific brain regions, such as the entorhinal cortex. These findings point to elevated glucocorticoids as a risk factor for Parkinson's disease progression and highlight the potential of glucocorticoid level reducing strategies to slow down disease progression in synucleinopathy.

Obesity is frequently associated with impairments in the social domain, and stress at puberty can lead to long-lasting changes in visceral fat deposition and in social behaviors. However, whether stress-induced changes in adipose tissue can affect fat-to-brain signaling, thereby orchestrating behavioral changes, remains unknown. We found that peripubertally stressed male—but not female—mice exhibit concomitant increased adiposity and sociability deficits. We show that reduced levels of the adipokine nicotinamide phosphoribosyltransferase (NAMPT) in fat and its extracellular form eNAMPT in blood contribute to lifelong reductions in sociability induced by peripubertal stress. By using a series of adipose tissue and brain region–specific loss- and gain-of-function approaches, we implicate impaired nicotinamide adenine dinucleotide (NAD ⁺ )/SIRT1 pathway in the nucleus accumbens. Impairments in sociability and accumbal neuronal excitability are prevented by normalization of eNAMPT levels or treatment with nicotinamide mononucleotide (NMN), a NAD ⁺ -boosting compound. We propose NAD ⁺ boosters to treat social deficits of early life stress origin.