Profiling trait anxiety: transcriptome analysis reveals cathepsin B (Ctsb) as a novel candidate gene for emotionality in mice.

Behavioral endophenotypes are determined by a multitude of
counteracting but precisely balanced molecular and physiological
mechanisms. In this study, we aim to identify potential novel
molecular targets that contribute to the multigenic trait
"anxiety". We used microarrays to investigate the gene expression
profiles of different brain regions within the limbic system of
mice which were selectively bred for either high (HAB) or low (LAB)
anxiety-related behavior, and also show signs of comorbid
depression-like behavior. We identified and confirmed
sex-independent differences in the basal expression of 13 candidate
genes, using tissue from the entire brain, including coronin 7
(Coro7), cathepsin B (Ctsb), muscleblind-like 1 (Mbnl1),
metallothionein 1 (Mt1), solute carrier family 25 member 17
(Slc25a17), tribbles homolog 2 (Trib2), zinc finger protein 672
(Zfp672), syntaxin 3 (Stx3), ATP-binding cassette, sub-family A
member 2 (Abca2), ectonucleotide pyrophosphatase/phosphodiesterase
5 (Enpp5), high mobility group nucleosomal binding domain 3 (Hmgn3)
and pyruvate dehydrogenase beta (Pdhb). Additionally, we confirmed
brain region-specific differences in the expression of
synaptotagmin 4 (Syt4).Our identification of about 90 polymorphisms
in Ctsb suggested that this gene might play a critical role in
shaping our mouse model's behavioral endophenotypes. Indeed, the
assessment of anxiety-related and depression-like behaviors of Ctsb
knock-out mice revealed an increase in depression-like behavior in
females. Altogether, our results suggest that Ctsb has significant
effects on emotionality, irrespective of the tested mouse strain,
making it a promising target for future pharmacotherapy.