Anhedonic behaviour in a TLR7-driven neuroinflammation mouse model is associated with impaired thalamostriatal signalling and immune cell ingress into the brain

Major depressive disorder (MDD) affects 3.8% of the world population, representing a significant contribution to the global burden of disease (WHO). Around a quarter of people living with MDD demonstrate low-grade inflammation and substantial evidence links peripheral inflammation to anhedonia via disrupted cortico-thalamo-striatal circuitry. We examined clinical human neuroimaging in individuals with systemic inflammation (psoriatic disease), and employed a preclinical model of neuroinflammation, to study relationships between the neuroinflammatory response, neural circuitry and depression-like behaviours. Our preclinical model used a topical treatment of Aldara®, which contains imiquimod (a TLR7/8 agonist) that also induces a psoriasis-like phenotype. Changes in functional connectivity between thalamus and ventral striatum correlated with depression in humans with psoriatic disease, and with anhedonia-like behaviours in Aldara-treated mice. Mice treated with Aldara exhibited reduced sucrose preference and impairments in intrinsic motivational behaviours relative to untreated controls. Within 4 to 6 hours of Aldara treatment, neurons in midline thalamus were activated substantially more than in control animals. Optogenetic activation of midline thalamic projections onto ventral striatum medium spiny neurons revealed that repeated Aldara treatment substantially reduced the magnitude of the evoked thalamic AMPA receptor-mediated post-synaptic currents. In the preclinical model, contributions from both resident and infiltrating immune cells drove neuroinflammation. Further dissection of these pathways revealed that NLRP3 inflammasome activation, infiltrating monocytes and infiltrating T cells all contributed to the neuroinflammatory effects of Aldara.