O papel do Interferão-gamma na compreensão dos mecanismos de regulação neuro-imune associados ao use de substâncias psicoactivas e à dependência

The number of people with substance use disorders (SUDs) has raised by 45% over the last decade reaching 40M people in need for effective treatment. INTERFERINg aims at applying fundamental knowledge, to promote new therapeutic approaches and improve patient outcomes in substance abuse. This requires finding new targets and biomarkers that allow monitoring how addiction progresses and the success of ongoing treatments. Because addiction is characterized by marked individual susceptibility, INTERFERINg aims also at identifying biomarkers that allow more personalized interventions, to facilitate the assessment of the neurobiological underpinnings of substance use and, ultimately, demonstrate the efficacy of treatment approaches. For too many years, research in this field was led by a neurocentric perspective, neglecting glial cell and peripheral signaling. Over the last years the Addiction Biology Lab at i3S has been focused in shifting this neurocentric view of addiction and SUDs, into a paradigm where glia cells are equally relevant. We have moved forward by showing that: i) microglia activation by astrocyte-derived TNF is critical for Meth-induced behavior[6], ii) neuronal cells exposed to Meth, resort to contact-dependent mechanisms to reduce microglia activation and self-protect[8], and iii) microglia activation by alcohol intake leads to frontal synaptic loss and anxiety[7]. More recently, we have collected data demonstrating that peripheral immune signaling is relevant to Meth neurotoxic, and that INTERFERINg with the expression of peripheral cytokines such as IL10 is sufficient to prevent Meth acute neurotoxic effects (Fig1-3). Importantly, our preliminary data indicates that, in prolonged exposure to Meth, modulating the availability of IFNg holds protecting power (Fig.4-6). In this context, the INTERFERINg project responds to a critical need of effective treatments for People Who Use Drugs (PWUD), and builds on the central hypothesis that circulating cytokines can be used to reduce relapse likelihood, while also monitoring the success of treatment in SUDs. To address this hypothesis, INTERFERINg will rely on the multidisciplinary expertise of Summavielle’s team to fulfill the following complementary goals: 1) Clarify the role of both in central and circulating IFNg levels using a mouse model of chronic Meth exposure (ACTIVITY1). 2) Resort to a IFNgKO mouse model to unravel the molecular signalling involved in IFNg both centrally and at the peripheral level, and identify promising therapeutic targets/signalling pathways to modulate action of IFNg (or associated targets) (ACTIVITY2). 3) Validate the targets selected in ACTIVITY 2, achieving protection against the effects of psychoactive substances by INTERFERING with the IFNg or IFNg-related molecular targets (ACTIVITY3). 4) Simultaneously, clarify if the circulating levels of IFNg hold predictive value in monitoring treatment success in people who use drugs (PWUD) by evaluating their levels and their correlation mental-health psychologic features relevant to relapse. For this, we will optimize and validate a miniaturized biosensor (already available at i3S) to facilitate monitoring the circulating levels of IFNg in PWUD undergoing dishabituation treatments (ACTIVITY4). Globally, we aim at demonstrating that peripheral neuro-immune regulation can be targeted to reduce relapse rates and provide means for timely and personalized monitoring at the point-of-care.