CXCL13 Neutralization Attenuates Neuropsychiatric Manifestations in Lupus-Prone Mice

Neuropsychiatric lupus (NPSLE), the nervous system presentation of systemic lupus erythematosus (SLE), remains challenging to treat due to its unclear pathogenesis and lack of available targeted therapies. A potential contributor to disease progression is brain tertiary lymphoid structures (TLS); these ectopic lymphoid follicles that can develop tissue-targeted antibodies have recently been described in the MRL/lpr lupus mouse strain, a classic model for studying NPSLE. The brains of MRL/lpr mice show a significant increase of CXCL13, an important chemokine in lymphoid follicle formation and retention that may also play a role in the disease progression of NPSLE. The aim of the present study was to inhibit CXCL13 and examine the effect of this intervention on lymphoid formation and the development of neurobehavioral manifestations in lupus mice. Female MRL/lpr mice were injected with an anti-CXCL13 antibody, an IgG1 isotype-matched antibody, or PBS either three times a week for 12 weeks intraperitoneally (IP) starting at 6-8 weeks of age, or continuously intracerebroventricularly (ICV) with an osmotic pump over a two-week period starting at 15 weeks of age. Cognitive dysfunction and depression-like behavior were assessed at the end of treatment. When treatment was delivered IP, anti-CXCL13 treated mice showed significant improvement in cognitive function when compared to control treated mice. Depression-like behavior was attenuated as well. Furthermore, mice that received anti-CXCL13 by the ICV route showed similar beneficial effects. However, the extent of lymphocyte infiltration into the brain and the general composition of the aggregates were not substantively changed by anti-CXCL13 irrespective of the mode of administration. Nevertheless, analysis of brain gene expression in anti-CXCL13 treated mice showed significant differences in key immunological and neuro-inflammatory pathways that most likely explained the improvement in the behavioral phenotype. Our results indicate that CXCL13 affects the behavioral manifestations in the MRL/lpr strain and is important to the pathogenesis of murine NPSLE, suggesting it as a potential therapeutic target.

The Brainstem-Informed Autism Framework: Early Life Neurobehavioral Markers

Autism spectrum disorders (ASD) have long-term implications on functioning at multiple levels. In this perspective, we offer a brainstem-informed autism framework (BIAF) that traces the protracted neurobehavioral manifestations of ASD to early life brainstem dysfunctions. Early life brainstem-mediated markers involving functions of autonomic/arousal regulation, sleep-wake homeostasis, and sensorimotor integration are delineated. Their possible contributions to the early identification of susceptible infants are discussed. We suggest that the BIAF expands our multidimensional understanding of ASD by focusing on the early involvement of brainstem systems. Importantly, we propose an integrated BIAF screener that brings about the prospect of a sensitive and reliable early life diagnostic scheme for weighing the risk for ASD. The BIAF screener could provide clinicians substantial gains in the future and may carve customized interventions long before the current DSM ASD phenotype is manifested using dyadic co-regulation of brainstem-informed autism markers.

Klüver–Bucy syndrome secondary to a nondominant middle cerebral artery ischemic stroke: a case report and review of the literature

Background Klüver–Bucy syndrome is a rare and complex neurobehavioral cluster that occurs in humans and results from a temporal lobe lesion. It can be associated with a variety of causes. Stroke is a rarely reported cause of this syndrome. Case presentation In this report, we present the case of a 68-year-old Saudi male who developed Klüver–Bucy syndrome subsequent to a nondominant middle cerebral artery ischemic stroke involving right temporal lobe. The patient manifested most of the Klüver–Bucy syndrome clinical features, including hypersexuality, hyperphagia, hyperorality, and visual hypermetamorphosis (excessive tendency to react to every visual stimulation with a tendency to touch every such stimulus). These neurobehavioral manifestations improved after he was started on treatment. Conclusions The clinical course, anatomical association relying on pathophysiology, and potential treatment have all been deliberated in regard to the rare occurrence of Klüver–Bucy syndrome resulting from temporal lobe pathology.

Endocannabinoid and dopaminergic system: the pas de deux underlying human motivation and behaviors

Endocannabinoid system (ECS) has been identified ever since cannabinoid, an active substance of Cannabis, was known to interact with endogenous cannabinoid (endocannabinoid/eCB) receptors. It later turned out that eCB was more intricate than previously thought. It has a pervasive role and exerts a multitude of cellular signaling mechanisms, regulating various physiological neurotransmission pathways in the human brain, including the dopaminergic (DA) system. eCB roles toward DA system were robust, clearly delineated, and reproducible with respect to physiological as well as pathological neurochemical and neurobehavioral manifestations of DA system, particularly those involving the nigrostriatal and mesocorticolimbic pathways. The eCB–DA system regulates the basics in the Maslow’s pyramid of hierarchy of needs required for individual survival such as food and sexual activity for reproductive purpose to those of higher needs in the pyramid, including self-actualization behaviors leading to achievement and reward (e.g., academic- and/or work-related performance and achievements). It is, thus, interesting to specifically discuss the eCB–DA system, not only on the molecular level, but also its tremendous potential to be developed as a future therapeutic strategy for various neuropsychiatric problems, including obesity, drug addiction and withdrawal, pathological hypersexuality, or low motivation behaviors.