Protective effect of cannabinoid CB1 receptor signalling on noradrenergic neurons of the locus coeruleus

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Our proposed studies in Hypothesis 1 aim to answer the question in which cell population cannabinoid CB1 receptor signalling protects noradrenergic neurons in the locus coeruleus. To clarify whether the protective effect is cell autonomous or systemic, we will compare the onset and severity of mitochondrial deficits and neuronal loss in the LC, as well as the reduction of noradrenergic terminals in the forebrain between wild-type and noradrenergic neuron or astrocyte specific CB1 receptor knockout mice. Additionally, we will compare control and conditional CB1 knockout animals in models of attention, working- and fear-memory – cognitive functions known to be influenced by ageing and also by noradrenergic system. As a readout for glial activity, the density and morphology of microglia and astrocytes, expression of the pro-inflammatory cytokine TNFa in LC will be assessed. To validate our results, we will do the same comparison between CB1STOP constitutive knockouts and mice with restoration of CB1 receptor expression on noradrenergic neurons and astrocytes. In Hypothesis 2 we ask if it is possible to protect LC noradrenergic neurons from age-related changes through an elevation of CB1 receptor signalling. For that, we will treat mice chronically with a low dose D9-tetrahydrocannabinol (THC) before (preventive treatment) and a separate groups of animals after (curative treatment) the onset of significant neuronal loss. Efficacy of treatment will be analysed as a change in attention, memory and gene expression of LC noradrenergic neurons in old animals to a level typical to young ones.