LSD1-BDNF activity in lateral hypothalamus-medial forebrain bundle area is essential for reward seeking behavior.

Reward induces activity-dependant gene expression and synaptic plasticity-related changes. Lysine-specific histone demethylase 1 (LSD1), a key enzyme driving histone modifications, regulates transcription in neural circuits of memory and emotional behavior. Herein, we focus on the role of LSD1 in modulating the expression of brain derived neurotrophic factor (BDNF), the master regulator of synaptic plasticity, in the lateral hypothalamus-medial forebrain bundle (LH-MFB) circuit during positive reinforcement. Rats, trained for intracranial self-stimulation (ICSS) via an electrode-cannula assembly in the LH-MFB area, were assayed for lever press activity, epigenetic parameters and dendritic sprouting. LSD1 expression and markers of synaptic plasticity like BDNF and dendritic arborization in the LH, showed distinct increase in conditioned animals. H3K4me2 levels at Bdnf IV and Bdnf IX promoters were increased in ICSS-conditioned rats, but H3K9me2 was decreased. While intra LH-MFB treatment with pan Lsd1 siRNA inhibited lever press activity, analyses of LH tissue showed reduction in BDNF expression and levels of H3K4me2 and H3K9me2. However, co-administration of BDNF peptide restored lever press activity mitigated by Lsd1 siRNA. BDNF expression in LH, driven by LSD1 via histone demethylation, may play an important role in reshaping the reward pathway and hold the key to decode the molecular basis of addiction.