Deciphering neural origins of interhemispheric striatal resting-state functional connectivity using simultaneous chemogenetic fMRI and triple-spectral fiber photometry

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

PROJECT SUMMARY The brain is a complex patchwork of interconnected regions, and network approaches have become increasingly useful for understanding its functional architecture. Resting-state fMRI (rs-fMRI) has emerged as the prominent tool for non-invasive investigation of large-scale functional networks at rest. However, little is known about the neuronal mechanisms responsible for the formation of rs-fMRI functional connectivity. This knowledge is critical to interpret rs-fMRI data, causally model brain states, predict behavior, and design network- based treatment regimens for neuropsychiatric and neurological disorders. Among all brain regions, striatum may represent a unique example to study the neural origins of rs-fMRI. Findings in literature have repeatedly shown that rs-fMRI signals in the striatum of both hemispheres are highly synchronized, yet viral tracing studies showed no direct anatomical connections between bilateral striatum. This raises an intriguing question – how is bilateral striatal rs-fMRI connectivity formed without any direct anatomical connection? Addressing this question could have major implications in understanding what rs-fMRI signals in striatum represent. Three possible scenarios may explain the existence of interhemispheric striatal rs-fMRI connectivity: (1) synchronous firing of striatal GABAergic MSNs, (2) synchronous release of glutamate from cortico-striatal or thalamo-striatal projections, and (3) synchronous release of dopamine from nigro-striatal projections. Here, we hypothesize that (2) and (3) are the origins, with (3) being the most prominent source. We formed such a hypothesis because (1) rigorous prior study from our team members suggested that MSN firing between two hemispheres is asynchronous, and (2) dopamine neurons are well known pacemaker cells. Our team recently pioneered a multi- channel, spectrally resolved, MR-compatible fiber photometry technique that is ideal to decipher the neural origins of rs-fMRI. Rigorous prior research has demonstrated our unique ability to simultaneously measure multiple fluorescent sensor activities across multiple brain regions during fMRI. In Aim 1, we will measure three major neuronal components with simultaneous fiber-photometry and fMRI in bilateral striatum. Those components are: (1) presynaptic glutamatergic releases; (2) presynaptic dopaminergic releases; and (3) postsynaptic calcium-weighted neuronal activities. We hypothesized that interhemispheric striatal fMRI connectivity might be related to presynaptic dopamine releases in the striatum. In Aim 2, we will interrogate the causal influence of glutaminergic and dopaminergic projections on interhemispheric striatal rs-fMRI connectivity using chemogenetics. We hypothesized that silencing unilateral dopamine activity in the SNc may interrupt interhemispheric striatal rs-fMRI connectivity. We will unilaterally express inhibitory DREADD in striatum- projecting cortical neurons, in MSNs, and in nigral dopamine neurons, and repeat the same experiments as in Aim 1 before and after the administration of DREADD agonist deschloroclozapine (DCZ). In summary, this project aims to address significant missing knowledge about the neural correlates of interhemispheric striatal fMRI connectivity. The investigators have a strong track record in this line of research and will bring Innovation to the field by bridging local cellular imaging and analytical methods to address novel hypotheses well supported by rigorous prior research.