OLFACTORY BEHAVIORS AND RESPONSES IN FOREBRAIN-SPECIFIC <EM>CCN2</EM> KNOCKOUT MICE

Cellular communication network factor 2 (CCN2) is a matricellular protein with well-established roles in connective tissues. CCN2 is also expressed in the nervous system, particularly in olfaction-related brain regions, but its neural function remains unclear. To investigate the role of CCN2 in the brain, we generated forebrain-specific Ccn2 knockout (FbCcn2 KO) mice. Olfactory behaviors were assessed using a habituation/dishabituation paradigm with different odor stimuli. Neuronal activation was evaluated by c-fos expression in the olfactory bulb and multiple olfaction-related brain regions. In parallel, transcriptomic profiling of the olfactory bulb was performed using RNA sequencing.FbCcn2 KO mice exhibited normal olfactory discrimination. However, homozygous FbCcn2 KO mice spent significantly more time investigating bedding from unfamiliar mice of the opposite sex (OS) compared with bedding from the same sex (SS) and with control mice. In FbCcn2 KO mice, OS olfactory cues induced stronger activation in specific regions associated with both the main and accessory olfactory systems. Notably, male and female mice showed distinct patterns of olfactory-evoked neural activation. Transcriptomic analysis revealed significant downregulation of approximately 29 genes related to cell migration, proliferation, and differentiation, following Ccn2 deletion.These findings suggest that CCN2-expressing neurons contribute to olfactory-mediated social behaviors and the activation of associated neural circuits. Moreover, CCN2 may influence olfactory bulb development. This study identifies a previously unrecognized role for CCN2 in the olfactory system and establishes the FbCcn2 KO mouse as a valuable model for investigating olfactory processing.