CREB-regulated transcription coactivator 1 (CRTC1) plays a pivotal role in regulating the expression of genes involved in neuronal survival, synaptic plasticity, and long-term potentiation by interacting with cAMP response element-binding protein (CREB). Our research utilizes a Crtc1 knockout (KO) mouse model, which exhibits increased aggressiveness, depressive-like behavior, and obesity in males. The bidirectional relationship between obesity and major depressive disorder (MDD) is well-established, with both conditions linked to elevated neuroinflammatory markers in various brain regions. CRTC1 overexpression has been associated with a protective effect against neuroinflammation in the hippocampus. Given the phenotype of our KO mice, we hypothesize that Crtc1 KO males may experience increased neuroinflammation, potentially serving as a triggering factor for depression symptoms and obesity in adulthood. Preliminary experiments revealed subtle differences in microglia morphology of naïve wild-type (WT) and KO male mice. After immune system stimulation via lipopolysaccharide (LPS) injection, Crtc1 KO mice displayed prolonged sickness behavior, with continued weight loss up to 48 hours after injection, whereas WT mice ceased losing weight after 24 hours. Additionally, WT mice resumed voluntary running-wheel activity 36 hours post-injection, while KO mice refrained for 72 hours. Furthermore, KO mice exhibited higher hippocampal CCL2 (MCP-1) levels at 24 hours suggesting a heightened immune response to LPS in the absence of CRTC1. Future studies will explore LPS-induced depressive-like behavior in WT and KO mice including the serotonin/kynurenine pathway imbalance and also astrocytic and microglial factors. These projects aim to enhance our understanding of CRTC1's role in emotional regulation, neuroinflammation, and metabolic disturbances.