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


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.

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Figure 1: Increased excitatory synaptic transmission onto VTA-projecting LHb neurons in the learned helplessness models of depression.
Figure 2: Enhanced synaptic transmission onto VTA-projecting LHb neurons correlates with helpless behaviour of individual animals.
Figure 3: Presynaptic mechanism underlying the increase in excitatory synaptic transmission onto VTA-projecting LHb neurons in helpless animals.
Figure 4: DBS in the LHb suppresses excitatory synaptic transmission and reverses learned helplessness.


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We thank K. Deisseroth for help and suggestions, A. Gifford and A. Biegon for sharing equipment and laboratory space, and members of the Malinow Lab and Li Lab for discussions. This study was supported by the Dana Foundation (B.L.), the Biobehavioral Research Awards for Innovative New Scientists (BRAINS) from the National Institute of Mental Health, National Institutes of Health (1R01MH091903-01) (B.L.) and the Shiley-Marcos Endowment (R.M.).

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B.L., J.P., M.M. and C.C contributed equally to the study. B.L., J.P., M.M., C.C., C.D.P. and D.S. performed and analysed the experiments. C.C. and B.L. made the figures. B.L., F.H. and R.M. designed the study. B.L. and R.M. wrote the manuscript.

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Correspondence to Bo Li or Roberto Malinow.

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The authors declare no competing financial interests.

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Li, B., Piriz, J., Mirrione, M. et al. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature 470, 535–539 (2011).

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