Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood-brain barrier (BBB) permeability and infiltration of peripheral immune signals. We found reduced expression of endothelial cell tight junction protein claudin-5 (cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 down-regulation was sufficient to induce depression-like behaviors following subthreshold social stress while chronic antidepressant treatment rescued cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or AAV-shRNA-cldn5-injected mice caused infiltration of peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors. These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein cldn5, promoting peripheral IL-6 passage across the BBB and depression.

Significance Depression and anxiety have been linked to increased inflammation. However, we do not know if inflammatory status predates onset of disease or whether it contributes to depression symptomatology. We report preexisting individual differences in the peripheral immune system that predict and promote stress susceptibility. Replacing a stress-naive animal’s peripheral immune system with that of a stressed animal increases susceptibility to social stress including repeated social defeat stress (RSDS) and witness defeat (a purely emotional form of social stress). Depleting the cytokine IL-6 from the whole body or just from leukocytes promotes resilience, as does sequestering IL-6 outside of the brain. These studies demonstrate that the emotional response to stress can be generated or blocked in the periphery, and offer a potential new form of treatment for stress disorders.

Mutations of the DJ-1 (PARK7) gene are linked to familial Parkinson's disease. We used gene targeting to generate DJ-1-deficient mice that were viable, fertile, and showed no gross anatomical or neuronal abnormalities. Dopaminergic neuron numbers in the substantia nigra and fiber densities and dopamine levels in the striatum were normal. However, DJ-1؊͞؊ mice showed hypolocomotion when subjected to amphetamine challenge and increased striatal denervation and dopaminergic neuron loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. DJ-1؊͞؊ embryonic cortical neurons showed increased sensitivity to oxidative, but not nonoxidative, insults. Restoration of DJ-1 expression to DJ-1؊͞؊ mice or cells via adenoviral vector delivery mitigated all phenotypes. WT mice that received adenoviral delivery of DJ-1 resisted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine-induced striatal damage, and neurons overexpressing DJ-1 were protected from oxidative stress in vitro. Thus, DJ-1 protects against neuronal oxidative stress, and loss of DJ-1 may lead to Parkinson's disease by conferring hypersensitivity to dopaminergic insults. P arkinson's disease (PD) is a neurodegenerative disorder characterized by tremor, rigidity, akinesia, and postural instability (1). The cause of PD remains unknown, but epidemiological and genetic studies have suggested that the observed loss of dopaminergic neurons in PD is due to defects in common intracellular signaling pathways (2). Genes linked to familial PD include ␣-synuclein (3), Parkin (4), UCH-L1 (5), PINK1 (6), and dardarin (7). Proteins encoded by these genes are thought to be involved in protein aggregation and proteasome function, processes which, when disrupted in model systems, can also result in noninherited forms of PD (8). Recently, loss-of-function mutations in the DJ-1 locus were found in families with autosomal recessive early-onset PD (9). Additional studies have confirmed other DJ-1 mutations in various PD cohorts (10). DJ-1 was initially cloned as a putative oncogene (11) and as part of an RNA-binding complex (12). DJ-1 is highly expressed by normal astrocytes (13) and has been implicated in fertilization (14) and tumorigenesis (15,16). Studies of the crystal structure of DJ-1 (17) suggest that a particular DJ-1 mutation (L166P) reduces DJ-1 protein stability (18)(19)(20), resulting in degradation through the ubiquitin-proteasome system (21, 22). However, the physiological function of DJ-1 remains largely unknown.Motor impairments in PD patients result from inhibition of the nigrostriatal motor pathway. This inhibition is due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) (8). The cause of the dopaminergic neuron loss remains unknown, but oxidative stress leading to apoptotic neuronal death has been implicated (23). Various neurotoxic paradigms have been studied in an effort to reproduce oxidative stress leading to neuronal loss in the SNc. Of these, administration of the well characterized meperidine analogue 1-methyl-4-phenyl-1,2,3,6-te...