Profiling the Nucleus Accumbens Proteome in an Experimental Model of Inflammatory Bowel Disease

Ayanabha Chakraborti, Department of Surgery, University of Alabama at Birmingham

A strong connection between the status of the intestinal environment and the function of the central nervous system (CNS) is increasingly being recognized. The bidirectional feedback loop commonly referred to as ‘gut-brain’ axis facilitates two-way communication between the central and the enteric nervous system, linking brain emotional and cognitive centers with peripheral intestinal functions (1). It has recently been reported that alterations in gut microbiota can affect behavioral responses to drugs of abuse (2). Major alterations in gastrointestinal (GI) physiology such as those resulting from bariatric surgery can affect reward/addiction behaviors (3). However, much remains to be discovered regarding the dialogue between the CNS and the GI system (4) and how it can contribute to drug addiction. Given that addictive drugs usurp brain reward circuitry including that which is committed to feeding behavior, it is rationale to hypothesize that altered gut-brain communication may impact formation, maintenance or relapse of the addicted state.

Inflammatory bowel diseases (IBD) represent a major health concern with continuously rising incidence and prevalence (5). Reports have suggested that persons with IBD may be at an increased risk for substance abuse and dependence (6-8). Furthermore, the risk of IBD is higher in persons with alcohol addiction (9). In addition, anxiety and depression related symptoms are frequently comorbid in patients with IBD (10). Such comorbidity may also substantially increase the risk of addiction as both mood disorders and drug addiction are associated with major disruptions in brain reward circuitry (11) and it is well established that mood disorders may motivate individuals to resort to drugs of abuse to cope with their negative affective states (12). However, the mechanistic link between gastrointestinal inflammation and addictive behavior remains poorly understood.

The nucleus accumbens (NAc) serves as a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Exposure to drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to give rise to a pathologic motivation for drug seeking (13). Very little is known as to how GI inflammation may impact this brain region that plays a central role in the reward circuitry of the brain. Our preliminary data suggest that intestinal inflammation is associated with alterations in NAc dependent behavior as well as changes in synaptic function and phosphorylation patterns of some key neuronal signaling proteins in this brain region. Here, we propose to use a well-characterized mouse model of IBD to comprehensively investigate the effects of intestinal inflammation on the NAc proteome using state of the art proteomics approaches. Since, protein phosphorylation serves as a major posttranslational modification involved in a broad array of physiological functions we will also examine the possible role of these regulatory mechanisms in altering reward circuitry following intestinal inflammation. Furthermore, we will investigate the effect of bowel inflammation on behavioral responses to morphine and corresponding proteomic changes in the NAc. The study will generate novel insights on how gut-brain cross talk may potentially play a role in addiction.

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