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

Depression is a heterogenous condition driven by multiple aetiologies, which make its pathophysiology challenging to map. Stratifying depression by underlying biological causes may allow for more effective, targeted treatments. Immune-mediated inflammation is present in around 20% of individuals with depression and provides a potential mechanistic pathway for some key symptoms such as reward / hedonic impairment. Here we used a non-invasive model of neuroinflammation, topical application of Aldara (a TLR7/8 agonist) for 3 days in mice, to explore relationships between the intracerebral immune response, neural circuitry and behaviours closely linked to depression: motivation, reward and anxiety.

Mice that were treated with Aldara exhibited anhedonia-like behaviour and impairments in intrinsic motivational behaviours (measured through assays such as sucrose preference and nest-building tests) relative to untreated controls, but displayed little anxiety-like behaviour. Aldara-driven neuroinflammation was associated with evidence of immune cell (including lymphoid and myeloid cells) ingression into the brain, and both microglia and astrocytes showed evidence of activation. Within 4 to 6 hours of Aldara treatment, neurons in midline thalamus showed strongly increased Fos immunoreactivity relative to controls. Optogenetic activation of midline thalamic projections onto ventral striatum medium spiny neurons (MSNs) revealed that Aldara treatment substantially reduced the magnitude of the evoked thalamic AMPA receptor-mediated EPSC, but with no change to the AMPA/NMDA ratio nor change in the frequency of amplitude of spontaneous EPSP. Finally, whole brain transcriptome overrepresentation analysis revealed that Aldara treatment led to significant upregulation of genes associated with immune response and downregulation of genes associated with glutamate metabolism and synaptic transmission.

Altogether, our data suggest potential, testable mechanisms through which neuroinflammation can drive anhedonic-like behaviour through activation of resident neural cells, infiltrating activated immune cells and functional changes in thalamostriatal circuitry consistent with increased extrasynaptic glutamate.