Functional connectivity alterations in a murine model of optic neuritis

Abstract

The basis for neuronal dysfunction following inflammatory demyelination of the central nervous system (CNS) remains poorly understood. We characterized the network response to white matter injury in the anterior visual pathway using an experimental model of optic neuritis (ON), as ON is often an early manifestation of immune-mediated CNS demyelination in multiple sclerosis (MS). Optical intrinsic signal imaging was performed before and after the induction of ON in mice to measure changes in cortical network functional connectivity. We observed a greater loss of connectivity between homotopic visual cortices in ON mice compared to controls. Further, decreases in homotopic visual cortex connectivity were associated with visual acuity loss in ON mice. These results demonstrate that network connectivity changes resulting from ON can be modeled in an experimental murine system. Future studies will identify the mechanisms that cause neuronal dysfunction due to white matter injury seen in MS.

Functional connectivity structure of cortical calcium dynamics in anesthetized and awake mice

“…This intermediate frequency band was selected given the maximal correlation recently observed between spontaneous GCaMP6 and HbT at approximately 0.21Hz [ 33 ]. Data from the anesthetized state were selected to directly build upon previously-reported literature on functional connectivity using OIS hemodynamic contrasts [ 2 – 6 , 36 – 38 ]. Further, the delay times derived from spontaneous data could be compared to the delay time from forepaw stimulation.…”

“…Due to the lack of full characterization of the relationship and neurophysiology of neurovascular coupling in evoked versus spontaneous activity conditions, we also carried out this analysis by delay-shifting spontaneous data using delays determined from seed-trace pairs of resting-state data ( Fig 5C and 5D ). For reference, we evaluated the same seed locations previously used for hemodynamic functional connectivity mapping in spontaneous data acquired from mice under anesthesia [ 2 , 3 , 6 ]( S1 Fig ). Within the intermediate frequency band, GCaMP6 produced intact functional connectivity patterns ( Fig 5D , middle) similar to concurrent HbO 2 maps ( Fig 5D , top; S2 Table ), as well as to maps made using deoxyhemoglobin (HbR) ( Fig 5D , bottom; S2 Table ).…”

“…Functional connectivity has been used to show that functionally-related areas can have correlated spontaneous neural and hemodynamic activity, even in the absence of tasks. Similar to human fcMRI, mouse fcOIS provides a sensitive assay for several neurological diseases, including ischemic stroke [ 3 ], Alzheimer’s disease [ 4 , 5 ], and optic neuritis [ 6 ] using functional connectivity. At infraslow (<0.1 Hz) and intermediate (0.08–0.4 Hz) frequencies used for most functional connectivity mapping, the hemodynamic signals are a reasonable report of neural activity [ 7 – 11 ].…”

Effective Connectivity Measured Using Optogenetically Evoked Hemodynamic Signals Exhibits Topography Distinct from Resting State Functional Connectivity in the Mouse

“…Compared to imaging methods directly related to electrophysiology, for example, calcium indicators ( Vanni and Murphy 2014 ; Ma et al 2016 ; Wright et al 2017 ), and voltage sensitive dyes ( Ferezou et al 2007 ; Lim et al 2012 ), the hemodynamic response is ~5–100× slower. However, this slowness does not compromise studies focused on topography as opposed to neural dynamics.…”

“…Compared to viral vector injections, the use of transgenic mice offers the advantage of more global expression and markedly increased flexibility as the site of stimulation can be easily controlled using mirrors ( Ayling et al 2009 ; Lim et al 2012 ). Optical intrinsic signal imaging (OIS) allows for rapid wide-field recording of spontaneous ( White et al 2011 ; Bero et al 2012 ; Bauer et al 2014 ; Bumstead et al 2016 ; Wright et al 2017a ) or induced ( Grinvald et al 1986 ; Frostig et al 1990 ; Bouchard et al 2009 ) hemodynamic fluctuations in the mouse brain. Here, we use optogenetic photostimulation in combination with OIS imaging in awake mice to create an Opto-EC mapping assay.…”