Probing brain function with pharmacological MRI

The development of functional Magnetic Resonance Imaging (fMRI) has heralded a revolution in neuroscience, providing clinicians with a method to non-invasively investigate the spatio-temporal patterns of neuro-functional activity. Although primarily developed for human investigations, there exists significant scope for the application of fMRI in pre-clinical species as a translational and investigational platform across different areas of neuroscience and psychiatry research. However, the realization of this potential is hampered by a number of experimental constraints which make the application of fMRI methods to animal models less than straightforward. As a result, most fMRI research in laboratory species has been reduced to the employment of basic somato-sensory stimulation paradigms, thus greatly limiting the translational potential of the technique. An interesting approach to overcome some of these limitations has been dubbed “pharmacological MRI” (phMRI) and relies on the use of fMRI to map patterns of brain activity induced by psychoactive drugs. The approach has demonstrated the ability to elicit reliable fMRI signals even under anaesthesia, and to enable selective stimulation of different neurotransmitter systems. Building upon the homology between brain circuits in humans and laboratory animals, phMRI techniques thus offer the opportunity of significantly expanding the stimulation repertoire available to preclinical fMRI research, by allowing to selectively probe specific aspects of brain function under different preconditioning states. Within this framework, the research presented herein was aimed to broaden the scope of application of preclinical phMRI both as a translational technique, when applied to clinically-relevant disease models, and more generally as a versatile platform for the pre-clinical investigation of brain activity and its functional topology as a function of behavioural, pharmacological or genetic preconditioning. In a first group of studies, we developed a phMRI assay to map the circuitry activated by NMDAR antagonists in the rat brain. These psychotogenic compounds are widely exploited to model schizophrenia symptoms and to provide experimental models that may prove useful in the development of novel treatments for the disorder. The results of this research highlighted a conserved cortico-limbo-thalamic circuit that is activated by NMDAR antagonists both in humans and preclinical species, which can be modulated by existing and novel antipsychotic drugs (Section 4.1). The translational potential of phMRI measurements was further corroborated by a second group of studies, where a multi-parametric phMRI-based approach was applied to investigate multiple facets of brain function in a rodent cocaine selfSummary X administration model, a behavioural paradigm of established construct-validity for research of drug addiction. This line of investigation revealed specific basal and reactive functional alterations in the brain of cocaine-exposed rodents closely related to those observed in analogous neuroimaging studies in humans (Section 4.2). In a third line of investigation, the combined use of advanced neuro-genetic targeting strategies (i.e. pharmacogenetic silencing) and phMRI has proven successful in establishing direct correlations between cells, circuit and complex behaviours in genetically engineered mouse lines. These studies (Section 4.3) have led to the identification of a novel cell population in the amygdala that controls the behavioural response to fear through the recruitment of cholinergic circuits. Finally, the phMRI approach has proven a powerful tool to explore functional connectivity in rodents, and to map a variety of different neurotransmitter pathways by performing measures of correlated responses in spatially remote brain areas. This has provided a useful playground to explore novel statistical methods of analysis of functional connectivity represented in terms of complex networks (Section 4.4). Collectively, the results of this work strongly corroborate the translational use of phMRI approaches, and pave the way to the integrated implementation of phMRI and advance genetic manipulation as a novel powerful platform for basic neurobiological research.