Dissecting the lateral hypothalamic input to the dorsal raphe nucleus and its role in major depression

Abstract

Disturbance of the central serotonin system has long been thought of playing a leading role in major depressive disorder. The main serotonergic nucleus of the brain, the dorsal raphe nucleus (DRN), integrates inputs from multiple brain regions, a large fraction of which is coming from the lateral hypothalamic area (LHA). In this study, we have examined whether plasticity at the LHA-DRN pathway contributes to the development of depressive or resilient phenotypes in mice undergoing chronic social stress. To activate LHA terminals in DRN, an AAV-ChR2-YFP was injected in the LHA of 6 weeks old C57BL/6J male mice. Two weeks later, these mice were subjected to chronic social defeat stress (CSDS) protocol. 24-h after CSDS, mice were classified as either susceptible or resilient when evaluated in a social interaction test, and acute brain slices encompassing the DRN were prepared. During whole-cell patch-clamp recordings of DRN neurons, 5 ms blue light pulses were delivered to activate LHA axons terminals, and postsynaptic currents were measured to investigate pre- and postsynaptic plasticity. In resilient mice, we found a significant increase in paired-pulse ratio at GABAergic synapses, indicating the decreased GABA release probability. In susceptible mice, we measured an important trend toward a decrease in the AMPAr/NMDAr ratio, indicating synaptic depression at the LHA-DRN pathway caused by CSDS. These results suggest that synaptic dysfunction may play an important role in the behavioral phenotype found in depression.