The increased density of the habenular neurons, high impulsivity, aggression and resistant fear memory in Disc1-Q31L genetic mouse model of depression.

Mood disorders affect nearly 300 million humans worldwide, and it is a leading cause of death from suicide. In the last decade, the habenula has gained increased attention due to its major role to modulate emotional behavior and related psychopathologies, including depression and bipolar disorder, through the modulation of monoamines' neurotransmission. However, it is still unclear which genetic factors may directly affect the function of the habenula and hence, could contribute to the psychopathological mechanisms of mood disorders. Disrupted-In-Schizophrenia-1 (DISC1) gene is among robust gene-candidates predisposing to major depression, bipolar disorder and schizophrenia in humans. DISC1-Q31L, a well-established genetic mouse model of depression, offers a unique opportunity for translational studies. The current study aimed to probe morphological features of the habenula in the DISC1-Q31L mouse line and detect novel behavioral endophenotypes, including the increased emotionality in mutant females, high aggression in mutant males and deficient extinction of fear memory in DISC1 mutant mice of both sexes. The histological analysis found the increased neural density in the lateral and medial habenula in DISC1-Q31L mice regardless of sex, hence, excluding direct association between the habenular neurons and emotionality in mutant females. Altogether, our findings demonstrated, for the first time, the direct impact of the DISC1 gene on the habenular neurons and affective behavior in the DISC1-Q31L genetic mouse line. These new findings suggest that the combination of the DISC1 genetic analysis together with habenular neuroimaging may improve diagnostics of mood disorder in clinical studies.