Synaptic potentiation onto habenula neurons in the learned helplessness model of depression

Abstract

It has recently been shown that neurons in the lateral habenula (LHb), a nucleus that projects to midbrain reward areas, can signal negative reward or 'disappointment' by modulating a dopaminergic centre, and may be disrupted in depressive disorders. Experiments in rats exhibiting learned helplessness (a model of major depression) now show that excitatory synapses onto LHb neurons are potentiated, and that this correlates with helplessness behaviour. Depleting transmitter release by repeated electrical stimulation of the LHb using a protocol similar to deep brain stimulation rescues both synaptic changes and learned helplessness behaviour. These results point to a mechanism by which deep brain stimulation in LHb could be effective in treating depression. It has recently been shown that neurons in the lateral habenula (LHb), a nucleus that projects to midbrain reward areas, can signal aversive outcomes and may be disrupted in depressive disorders. This study now shows that in rats exhibiting learned helplessness (a model of major depression) excitatory synapses onto LHb neurons are potentiated, and that this correlates with helplessness behaviour. Furthermore, depleting transmitter release by repeated electrical stimulation of LHb using a protocol similar to deep brain stimulation rescues both synaptic changes and learned helplessness behaviour. The cellular basis of depressive disorders is poorly understood1. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome)2,3,4. LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA)2,5, that control reward-seeking behaviour6 and participate in depressive disorders7. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal’s helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed8,9, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.