Dorsal Hippocampus Drives Context-Induced Cocaine Seeking via Inputs to Lateral Septum

Lateral septum (LS) has re-emerged as an important structure in reward and addiction; however, LS afferents that drive addiction behaviors are unknown. Here, we used a modified self-administration/reinstatement procedure combined with anatomical, pharmacological, and chemogenetic techniques to characterize LS, and hippocampal inputs to LS, in two established triggers of drug relapse-context- and cue-induced reinstatement of cocaine seeking. We found that inactivation of LS neurons attenuated both context- and cue-induced reinstatement of cocaine seeking. However, dorsal hippocampus inputs to LS showed enhanced neuronal activation (as measured by Fos expression) during context-induced, but not cue-induced reinstatement. Additionally, chemogenetic inhibition of dorsal, but not ventral, hippocampal inputs to LS specifically attenuated context-induced reinstatement. Together these findings elucidate the importance of LS in reinstatement of cocaine seeking, and indicate that dorsal hippocampal inputs to LS mediate context-, but not cue-induced, reinstatement of cocaine seeking.