RESUMO
Both unipolar and bipolar depression have been linked with impairments in executive functioning (EF). In particular, mood symptom severity is associated with differences in common EF, a latent measure of general EF abilities. The relationship between mood disorders and EF is particularly salient in adolescence and young adulthood when the ongoing development of EF intersects with a higher risk of mood disorder onset. However, it remains unclear if common EF impairments have associations with specific symptom dimensions of mood pathology such as blunted positive affect, mood instability, or physiological arousal, or if differences in common EF more broadly relate to what is shared across various symptom domains, such as general negative affect or distress. To address this question, bifactor models can be applied to simultaneously examine the shared and unique contributions of particular mood symptom dimensions. However, no studies to our knowledge have examined bifactor models of mood symptoms in relation to measures of common EF. This study examined associations between common EF and general vs. specific symptom dimensions (anhedonia, physiological arousal, and mania) using structural equation modeling in adolescents and young adults with varying severity of mood symptoms (n = 495, ages = 13-25 years, 68.69% female). A General Depression factor capturing shared variance across symptoms statistically predicted lower Common EF. Additionally, a factor specific to physiological arousal was associated with lower Common EF. Anhedonia-specific and Mania-specific factors were not significantly related to Common EF. Altogether, these results indicate that deficits in common EF are driven by, or reflect, general features of mood pathology that are shared across symptom dimensions but are also specifically associated with physiological arousal.
RESUMO
Blood-brain barrier (BBB) breakdown is a hallmark of many diseases of the central nervous system (CNS). Loss of BBB integrity in CNS diseases such as viral encephalitis results in the loss of nutrient/oxygen delivery, rapid infiltration of immune cells, and brain swelling that can exacerbate neuronal injury. Despite this, the cellular and molecular mechanisms that underlie BBB breakdown in viral encephalitis are incompletely understood. We undertook a comprehensive analysis of the cellular and molecular signaling events that induce BBB breakdown in an experimental model of virus-induced encephalitis in which neonatal mice are infected with reovirus (serotype 3 strain Abney). We show that BBB leakage during reovirus infection correlates with morphological changes in the vasculature, reductions in pericytes (BBB supporting cells), and disorganization of vascular junctions. Pathway analysis on RNA sequencing from brain endothelial cells identified the activation of interferon (IFN) signaling within the brain vasculature following reovirus infection. Our in vitro and in vivo studies show that type II IFN mediated by IFN-γ, a well known antiviral signal, is a major contributor to BBB leakage during reovirus infection. We show that IFN-γ reduces barrier properties in cultured brain endothelial cells through Rho kinase (ROCK)-mediated cytoskeletal contractions, resulting in junctional disorganization and cell-cell separations. In vivo neutralization of IFN-γ during reovirus infection significantly improved BBB integrity, pericyte coverage, attenuated vascular ROCK activity, and junctional disorganization. Our work supports a model in which IFN-γ acts directly on the brain endothelium to induce BBB breakdown through a mechanism involving ROCK-induced junctional disorganization.IMPORTANCE In an experimental viral encephalitis mouse model in which mice are infected with reovirus, we show that IFN-γ induces blood-brain barrier leakage. We show that IFN-γ promotes Rho kinase activity, resulting in actin cytoskeletal contractions in the brain endothelium that lead to vascular junctional disorganization and cell-cell separations. These studies now provide insight into a previously unknown mechanism for how blood-brain barrier breakdown occurs in viral encephalitis and implicates IFN-γ-Rho kinase activity as major contributor to this phenomenon. By identifying this mechanism of blood-brain barrier breakdown, we now provide potential therapeutic targets in treating patients with viral causes of encephalitis with the hope of limiting damage to the central nervous system.