Hypoactivity of the lateral habenula contributes to negative symptoms and cognitive dysfunction of schizophrenia in rats.

Dopaminergic (DAergic) hypofunction in the medial prefrontal cortex (mPFC) has been implicated in the negative and cognitive symptoms of schizophrenia and is regulated by serotonergic (5-HTergic) neurons in the dorsal raphe nucleus (DRN). The lateral habenula (LHb) is a key element in controlling DRN 5-HT neurons. We investigated how the LHb impacts the activity of mPFC neurons and whether it mediates the involvement of DRN on development of symptoms in a pharmacological animal model of schizophrenia. We used immunohisochemistry to assess cytochrome-c oxidase (COX) activity of the LHb in MK-801 model rats and extracellular firing recording to compare firing rates in LHb neurons of acute MK-801-treated rats. The sucrose preference, social interaction, and radial arm maze tests were used to access schizophrenia-like behavior in rats with electrolytically lesioned LHb. Finally, we examined levels of the dopamine D1 receptor (D1R) and tyrosine hydroxylase (TH) in the mPFC, and tryptophan hydroxylase 2 (TPH2) in the DRN of rats with LHb lesions to determine the possible mechanism underlying the schizophrenia-like behavior associated with lesioned LHb. We found that COX levels and LHb neuron firing rates decreased significantly in MK-801-treated animals. The LHb lesions induced negative and cognitive, but not positive symptoms of schizophrenia. The D1R and TH levels decreased in the mPFC while TPH2 expression elevated in the DRN and mPFC of LHb-lesioned rats. These results suggest that LHb hypoactivity may contribute to the negative and cognitive symptoms of schizophrenia by downregulating D1R expression in the mPFC, which might be mediated by DRN 5-HT neurons.