Browsing by Author "Schäfer, Annika"

ABSTRACT The insular cortex (insula) was recently identified as key neuroanatomical substrate underlying the neurocircuitry of addiction, and a rapidly growing body of evidence ascribe it numerous functional roles in addiction-related behaviours. Yet, neural system interactions through which the insula establishes its roles remain largely unknown. Identifying these critical circuits lays the foundation for the successful advancement of addiction research and therapeutics targeting this brain area. To this end, the current set of experiments aimed to characterize the efferent connections of the anterior insula (AI) to the nucleus accumbens (NAc; AI --> NAc) and the basolateral amygdala (BLA; AI --> BLA); two subcortical regions, which are heavily implicated in reward, motivational and emotional processing. By chemogenetically manipulating the activity of these circuits, their functional roles in modulating alcohol self-administration in alcohol-preferring AA (Alko, Alcohol) rats were examined. While AI --> NAc projections were recently verified anatomically, we first confirmed connectivity of AI --> BLA by injecting a viral retrograde tracer encoding enhanced green fluorescent protein (eGFP) unilaterally into the BLA of AA rats. The functional role of the AI --> BLA and AI --> NAc pathways in mediating alcohol drinking was examined by using the intermittent two-bottle choice paradigm in combination with a Cre-dependent DREADD (Designer Receptor Exclusively Activated by Designer Drug) approach. Projection-specific DREADD expression was achieved by injecting a Cre-dependent viral DREADD vector into the AI while a retrograde virus carrying Cre-recombinase was injected either into the BLA or NAc. CNO-induced activation of the AI --> NAc circuit resulted in a significant increase in alcohol consumption. Curiously, silencing these projections had no effect, either reflecting the intrinsic nature of the NAc circuitry or limitations inherent in the technical approach. Neither chemogenetic silencing nor activation of the AI --> BLA circuit altered alcohol consumption. Furthermore, no changes were observed in the control groups upon systemic CNO administration, indicating no unspecific CNO effects. The current body of work provides new insights into the insula-related circuitry showing that the activity of the AI --> NAc circuit drives alcohol self-administration, whereas AI --> BLA projections are not recruited during this behaviour. This indicates that the insular-striatal circuit belongs to the forebrain neurocircuitry underlying alcohol drinking. The study should be pursued by characterizing the neuronal populations and specific neuronal receptor populations that are involved in the AI --> NAc circuit. Future research should examine other insular-centred circuits that may govern alcohol drinking.