CNSC-28. BRAINSTEM NEUROMODULATORY NEURONS PROMOTE GLIOMA GROWTH LOCALLY AND VIA LONG-RANGE PROJECTIONS TO MIDLINE AND CORTICAL STRUCTURES

Abstract

Abstract Neuronal activity robustly drives glioma progression, mediated through paracrine and synaptic neuron-to-glioma interactions. Recent research has focused on glutamatergic and GABAergic neurons, while the impact of neuromodulatory neuron subpopulations and their long-range projections remain unexplored. Here, we explore the glioma-promoting effects of serotonergic and cholinergic brainstem neurons, which project to defined regions throughout the brain. By employing optogenetic stimulation of midbrain serotonergic or cholinergic neurons in mice bearing high-grade glioma allografts or xenografts, we observed robust, circuit-specific effects of each neuromodulatory neuronal subtype on proliferation. Concordant with the anatomy of serotonergic projections, we found that serotonergic neurons of the dorsal raphe nucleus promoted glioma proliferation in the neocortex and pons, while those from the median raphe nucleus increased proliferation in the thalamus. Similarly, stimulation of cholinergic neurons in the laterodorsal tegmentum nucleus enhanced thalamic glioma growth, and stimulation of the pedunculopontine nucleus promoted pontine tumor growth. The long-range neuronal activity-regulated effects on glioma cells were mediated by neurotransmitter secretion at axon terminals, and paracrine signalling protein release locally in the brainstem. The activity-regulated paracrine factor profiles are distinct between serotonergic and cholinergic neurons, illustrating neuron subtype-specific mechanisms affecting glioma cells beyond neurotransmitter differences. Co-culture with hESC/hiPSC-derived cholinergic or serotonergic neurons demonstrated synaptic structures between both neuromodulatory subpopulations and glioma cells, indicating a synaptic component to these neuron-glioma interactions. ScRNA-seq data integration revealed distinct receptor abundances between DMGs and IDH-WT glioblastomas correlating with specific cellular states. Inhibition of these targets – such as M1 or M3 cholinergic receptors in DMG – mitigated the proliferation-inducing effects of the relevant neuron subtype on glioma cells. In summary, these findings introduce brainstem cholinergic and serotonergic neuromodulatory neurons as drivers of high-grade glioma growth in a circuit-specific manner in midline structures and in neocortex, adding to the complexity with which gliomas integrate into brain-wide neural circuitry.