Functionally altered neurocircuits in a rat model of treatment-resistant depression show prominent role of the habenula.

Treatment-resistant depression (TRD) remains a pressing clinical problem. Optimizing treatment requires better definition of the function and specificity of the brain circuits involved. To investigate disease-related alterations of brain function we used a genetic animal model of TRD, congenital learned helplessness (cLH), and functional magnetic resonance imaging as a translational tool. High-resolution regional cerebral blood volume (rCBV) and resting-state functional connectivity measurements were acquired at 9.4T to determine regional dysfunction and interactions that could serve as vulnerability markers for TRD. Effects of cLH on rCBV were determined by statistical parametric mapping using 35 atlas-based regions of interest. Effects of cLH on functional connectivity were assessed by seed region analyses. Significant bilateral rCBV reductions were observed in the lateral habenula, dentate gyrus and subiculum of cLH rats. In contrast, focal bilateral increase in rCBV was observed in the bed nucleus of stria terminalis (BNST), a component of the habenular neurocircuitry. Functional connectivity was primarily enhanced in cLH rats, most notably with respect to serotonergic projections from the dorsal raphe nucleus to the forebrain, within the hippocampal-prefrontal network and between the BNST and lateral frontal regions. Dysregulation of neurocircuitry similar to that observed in depressed patients was detected in cLH rats, supporting the validity of the TRD model and suitability of high-field fMRI as a translational technology to detect and monitor vulnerability markers. Our findings also define neurocircuits that can be studied for TRD treatment in patients, and could be employed for translational research in rodent models.