Early life stress (ELS) in the form of child abuse/neglect is associated with an increased risk of developing social dysfunction in adulthood. Little is known, however, about the neural substrates or the neuromodulatory signaling that govern ELS-induced social dysfunction. Here, we show that ELS-induced downregulation of dopamine receptor 3 (Drd3) signaling and its corresponding effects on neural activity in the lateral septum (LS) are both necessary and sufficient to cause social abnormalities in adulthood. Using in vivo Ca 2+ imaging, we found that Drd3-expressing-LS (Drd3 LS) neurons in animals exposed to ELS show blunted activity in response to social stimuli. In addition, optogenetic activation of Drd3 LS neurons rescues ELS-induced social impairments. Furthermore, pharmacological treatment with a Drd3 agonist, which increases Drd3 LS neuronal activity, normalizes the social dysfunctions of ELS mice. Thus, we identify Drd3 in the LS as a critical mediator and potential therapeutic target for the social abnormalities caused by ELS.
Early social deprivation (ESD) causes downregulation of Drd3 signaling in the LS
Blunted LS Drd3 neuronal activity mediate ESD-induced social dysfunctions
Drd3 signaling has corresponding effects on neuronal activity in the LS
Activation of Drd3 signaling in the LS normalize social impairments of ESD mice
Exposure to early adverse experiences is associated with an increased risk of developing social dysfunction later in life. Shin et al. show that Drd3 signaling and its corresponding effects on neural activity in the LS are both necessary and sufficient to cause early life stress-induced social abnormalities in adulthood.