Sensory information processing impairments following prenatal cannabis exposure: focusing on noradrenaline to move towards early and sex-tailored therapeutic strategies

How we experience the world is fundamental to survival and guides our behavior from completing a simple motor task to forming relationships. Perhaps unsurprisingly, the inability to filter out sensory information, a function termed sensorimotor gating, is an early and transversal endophenotype for diverse neuropsychiatric disorders. Nevertheless, research on the mechanisms linking maladaptive information processing and psychopathology is surprisingly lacking. According to epidemiological data, prenatal cannabis exposure (PCE) is a predictive risk factor for sensorimotor gating deficits. Notably, a rat model of PCE was able to (1) show that only preadolescent males display impaired sensorimotor gating functions upon subsequent “hits” (e.g. acute stress), and (2) associate this at-risk endophenotype with aberrant dopamine (DA) signalling in the mesolimbic pathway, which stretches from the ventral tegmental area (VTA) to the nucleus accumbens shell (NAcS). Remarkably, females do not show any of these alterations. One proposed gate towards these sex-dependent vulnerable and resilient phenotypes is the locus coeruleus (LC), the major source of noradrenaline (NA) in the brain and a key regulator of the stress response. Indeed, the LC, besides being a sexually dimorphic nucleus, is known to innervate the VTA and influence the mesolimbic DA pathway, including transmission in the NAcS. Nevertheless, the implication of LC→VTA NA inputs in the context of sensorimotor gating has never been investigated. The current project proposes to employ state-of-the-art neurobiological techniques to test with unprecedented precision and resolution the overarching hypothesis that the LC NA system exerts a sex-dependent regulatory role onto VTA DA functioning in the context of sensory information processing in health and disease (i.e. PCE, stress). Identifying biased NA mechanisms could be exploited to restore deranged developmental trajectories during sensitive windows of neurodevelopment.