Aims: 

In the central nervous system, the cholinergic nuclei are localized mainly in the basal forebrain and brainstem, and in spinal cord motoneurons. Acetylcholine (ACh) is thus widely distributed throughout the brain and is implicated in a wide range of physiological functions such as learning, memory, attention, motor activity, sleep and wakefulness. Our aim is to analyze, by genetic means, the implication of ACh in the regulation of these integrated functions.

Methods: 

The functional role of cholinergic neurons has been generally addressed by analyzing the effect of either pharmacological treatments or lesions of cholinergic structures. However, the principle classical techniques for lesioning are not cell specific and do not alter just cholinergic neurotransmission. In order to circumvent these limitations, our strategy relies on the selective inhibition of choline acetyltransferase (ChAT) expression in given cholinergic structures and at precise times once embryogenesis and synapse establishment have proceeded normally.

Results: 

We have generated two major tools (i) a conditional knockout of the ChAT gene in mice, (ii) a lentiviral vector producing a sh-RNA which is able to efficiently trigger the inhibition of ChAT expression when delivered by stereotaxic injection. Both animal models are currently being used. They will be discussed together with our initial findings.

Conclusions: 

Our strategy will be instrumental in deciphering the impact of neurotransmitter systems in higher brain functions and their involvement in neuropsychiatric affections.