RESEARCH

Investigator: Cheng Ta Lee

Schizophrenia is a chronic psychiatric disorder characterized by disruptions in thought processes, perceptions, emotions, and behaviors. It affects about 0.5% of the population in the world. Sensorimotor gating impairment is a clinical indicator of Schizophrenia. 

Cholinergic neurons (CNs) play essential neuromodulatory roles in a variety of neural behaviors, including attention, cognition, consciousness and maintenance of the integrity of thought. Furthermore, cholinergic deficits in basal forebrain (BF) have been commonly reported in Schizophrenia and AD. Increased neuropsychiatric deficits are also associated with subsets of AD patients. 

Recent studies show that BFCNs play a role in regulating sensorimotor gating functions such as prepulse inhibition (PPI), which is impaired in Schizophrenia patients. However, how BFCNs modulate PPI and the involved downstream circuits remain unclear. Here we combined mouse genetics, anatomical, molecular, electrophysiological and optogenetics approaches and behavioral tests to elucidate molecular and circuit mechanisms underlying cholinergic regulation in PPI. Neuregulin 1 (Nrg1) mutations have been associated with subsets of Schizophrenia and AD. Exogenous Nrg1 has been shown to ameliorate AD in mice. We crossed ChAT knock-in Cre mice with floxed Nrg1 mice to conditionally knock out Nrg1 in CNs. 

The conditional knock-out (CKO) mice showed some Schizophrenia-like phenotypes such as impaired PPI, enhanced vocalization, and tremor. By optogenetic manipulation of cholinergic activity during PPI, we found that activity of BFCNs and their projections in prefrontal cortex (PFC) are critical for PPI at low prepulse intensity. By using in vivo single unit recordings, fiber photometry, and optogenetics, we revealed the role of PFC neuronal activity and cholinergic modulation in PFC during PPI. We also performed retrograde labeling to identify the downstream targets of BFCNs in PFC. Taking together, we found that BFCNs can regulate PPI by precise temporal control of PFC activity. This study not only revealed the role of CNs in fast neuromodulation but also provided a new therapeutic strategy in Schizophrenia.