The l. habenula, a key to understanding depression

We have used an animal model of depression, learned helplessness; to attempt to define the circuit mediating helplessness, determine the cellular basis underlying these circuit changes and the pathology leading to these changes. Using the learned helpless model two rat lines were created by selectively breeding rats either sensitive or resistant to helplessness training selectively with one another. The helpless line has the characteristics of a treatment resistant depression not responding to normal antidepressants or ECT, whereas the non helpless line is resistant to the effects of uncontrollable stress. Using micro PET we determined differences in baseline metabolic rates between the strains. This pointed to the habenula as overactive and suggested the VTA was underactive. Electrophysiological studies showed the l.habenula was 15 fold more active in the helpless line and these cells project in part to the VTA inhibiting DA release. We will show preliminary evidence that the l. habenula appears to receive increased glutaminergic input driving the over activity, and that this may be on the basis of astrocytic dysfunction. Using the helpless line we investigated the effects of bilateral deep brain stimulation. We showed that DBS resulted in depressed activity and an improvement in the helplessness. To determine if the changes seen in the animal model applied to human depression we looked at brain changes in patients subjected to tryptophan depletion. This revealed activation of the habenula, confirming an earlier PET study by Morris et al. Finally we have utilized DBS in a patient with a long history of treatment resistant depression. This resulted in a full recovery which remits within 24 h when the stimulator is off. These data suggest that the l. habenula, which receives cortical and limbic input and alters the activity in the midbrain nuclei, the VTA, DRN and LC may be a critical point in the circuit mediating major depression