Although it has become clear that genetic factors substantially influence susceptibility to human psychiatric disorders, only a few families have been proved with mendelian inheritance and specific gene mutations. Assuming that psychiatric disorders are non-mendelian, heterogeneous and polygenic, we and many researchers in the world have conducted a lot of association studies to detect minor effect of candidate genes, however, only a few positive findings endure repetitive replication. In order to gain an insight into the genetic basis of behavior and therefore behavioral disorders, maneuverable model organisms are required and reliable methods of behavioral measurement should be established.

In the past few years we have designed a protocol to induce chronic helplessness (a key symptom of depression) and a paradigm to assess social withdrawal (a key symptom of schizophrenia and social anxiety) in the mice. We also tried to develop devices by digitalizing and automating well established behavioral methods and some of them have been patented in Taiwan and/or USA. Those devices are especially useful in mass behavioral measurements in two complementary approaches, quantitative trait locus (QTL) analysis and chemical (ENU) mutagenesis strategies, which search broadly for genes that influence behavioral traits.

We used a self-made escape box to identify a quantitative trait of vulnerability to helplessness, which is significantly different between C57BL/6 and BALB/c mice. We are initiating a project to phenotype and genotype the F2 mice from an intercross between the two strains. Composite interval mapping and genome-wide interaction analysis will be performed to localize the QTLs, within which the ortholog genes in patients with depression will be analyzed. With the invented devices and a deliberately designed scheme we are going to screen 3000 G3 ENU-mutagenized mice at the Mouse Mutagenesis Program Core Facility (MMP) at the Academia Sinica. The scheme includes a battery of hierarchical behavioral tests and subsequent inheritability testings. Mutated genes responsible for the identified behaviors will be mapped and cloned. Two to four strains of mice mimicking psychiatric disorders are expected in this project. As inheritable animal models of psychiatric disorders, brains of the mutant strains will be studied in imaging, pathophysiology, immunohistochemistry and gene expression profiles, while the living animals can be used to screen novel psychotropic chemicals and therefore help the development of new regimens to improve psychiatric treatments.