Our research aims to investigate at multiple levels the molecular mechanisms and neuronal circuits
underlying executive function and nicotine re-inforcement in a simple animal model. The system chosen is the mouse that lends itself to a large variety of approaches, from genetic manipulations and molecular pharmacology to brain imaging and behaviour.
The ultimate goal is to develop a molecular neurobiology of cognitive functions using a novel molecular genetic strategy: the stereotaxic injection in defined brain regions of lentiviral vectors to stably express defined genes. The method has already been successfully used to restore executive functions and nicotine re-inforcement in the mouse (Maskos et al., Nature, 2005) following re-expression of functional nicotinic acetylcholine receptors (nAChRs) in the VTA of nAChR KO mice. It will be further exploited to differentially express genes in defined categories of neurons, e.g. dopaminergic vs. GABAergic, but also to inactivate genes using the expression of siRNAs. The lentiviral strategy will also be extended to the rat brain and to the construction of genetically modified mice and rats (GMMs and GMRs) by infection of early embryos with lentiviral vectors.
Indeed, many advanced behavioural tests cannot be applied to the mouse, but have given a wealth of information on rat behaviour. This approach can even be potentially applied to non-human primates.
nAChRs are known to regulate brain functions such as learning and memory, reward processes and addiction, together with anxiety, central processing of pain, selective attention, sleep and wakefulness. Moreover, nAChRs are implicated in a variety of pathologies, like ADHD, Alzheimer, Tourette, possibly autism, and also ageing. The program will aim at the understanding of the role of defined species of nAChR in the neuronal circuits underlying executive function and nicotine addiction in wild-type and genetically modified organisms. It will include the comparative evaluation of the role of the diverse brain areas and centers engaged in these functions in the mouse, including cortical areas like the prefrontal cortex, primary and secundary sensory areas, the nucleus accumbens, the VTA or the amygdala together with a detailed dissection of the neuromodulatory systems and signal transduction processes under nAChR control.
Combined with the latest developments in functional Magnetic Resonance Imaging (fMRI) and novel fibre-optic deep-brain imaging technology, the cellular and anatomical bases of the underlying brain circuits will be further explored. These data will motivate the development and test of theoretical models (such as the global neuronal wokspace) aimed to define the neural processes that underlie generation of cognitive behaviours and their executive control. In particular, a coherent computational network will be built that defines the pathways and processes by which nicotine modifies executive and motivational processes.