Altered functional connectivity networks in acallosal and socially impaired BTBR mice

Abstract

Agenesis of the corpus callosum (AgCC) is a congenital condition associated with wide-ranging emotional and social impairments often overlapping with the diagnostic criteria for autism. Mapping functional connectivity in the acallosal brain can help identify neural correlates of the deficits associated with this condition, and elucidate how congenital white matter alterations shape the topology of large-scale functional networks. By using resting-state BOLD functional magnetic resonance imaging (rsfMRI), here we show that acallosal BTBR T+tpr3tf/J (BTBR) mice, an idiopathic model of autism, exhibit impaired intra-hemispheric connectivity in fronto-cortical, but not in posterior sensory cortical areas. We also document profoundly altered subcortical and intra-hemispheric connectivity networks, with evidence of marked fronto-thalamic and striatal disconnectivity, along with aberrant spatial extension and strength of ipsilateral and local connectivity. Importantly, inter-hemispheric tracing of monosynaptic connections in the primary visual cortex using recombinant rabies virus confirmed the absence of direct homotopic pathways between posterior cortical areas of BTBR mice, suggesting a polysynaptic origin for the synchronous rsfMRI signal observed in these regions. Collectively, the observed long-range connectivity impairments recapitulate hallmark neuroimaging findings in autism, and are consistent with the behavioral phenotype of BTBR mice. In contrast to recent rsfMRI studies in high functioning AgCC individuals, the profound fronto-cortical and subcortical disconnectivity mapped suggest that compensatory mechanism may not necessarily restore the full connectional topology of the brain, resulting in residual connectivity alterations that serve as plausible substrates for the cognitive and emotional deficits often associated with AgCC.

Can Mouse Imaging Studies Bring Order to Autism Connectivity Chaos?

“…This notion is empirically corroborated by the recent observation that cytoarchitecturally homologous regions such as anterior cingulate and retrosplenial cortices (Vogt and Paxinos, 2014) similarly serve as connectivity hubs in humans and mice (Cole et al, 2010; Tomasi and Volkow, 2011; Liska et al, 2015). Moreover, the application of rsfMRI to the mouse brain comes with several important advantages, including the possibility to use quantitative imaging modalities for an objective endo-phenotypic characterization of ASD-related pathology complementary to behavioral assays, and to validate its readouts with invasive techniques that are off limits for human research, including local field potentials (LFPs) coherence mappings (Zhan et al, 2014), local injection of neuronal tracers (Sforazzini et al, 2016), as well as an ever-increasing array of histopathological, stereological, or immunohistochemical post-mortem analyses.…”

Autism-Like Behavior in BTBR Mice Is Improved by Electroconvulsive Therapy

“…However, it should be noted that the lack of corpus callosum alone cannot explain the presence of autism-like behavior; indeed, postnatal mechanical lesion to the corpus callosum in LP/J mice (which are genetically close to BTBR mice but show no autism-like behavioral abnormalities) failed to produce autism-like impairments [46]. Concurrently with the compromised long-range connectivity, BTBR mice exhibit aberrant intrahemispheric connectivity as identified by diffusion tensor imaging [20], which is another widely acknowledged attribute of the autistic brain [47]. With this regard, ECT was shown to reduce local connectivity in prefrontal cortex [29], an effect which, if experimentally confirmed, could explain, at least in part, its therapeutic effect in BTBR mice.…”

“…For this, we chose BTBR T + tf/J mice, which present with a spectrum of behavioral perturbations (e.g., impaired sociability and repetitive behavior), as well as neuropathological abnormalities (e.g., absence of corpus callosum, i.e., deficient long-range connectivity) consistent with autism [19,20], and are commonly used in autism research. We report that ECT transiently reverses autism-like behavioral abnormalities in BTBR mice, and that therapeutic effects of ECT may be partly regulated by central oxytocin signaling.…”

Functional network study on the wild type and DISC1 transgenic mice

“…Disease models being studied include mouse models of amyloidosis and Alzheimer's disease (Shah et al, 2013;Grandjean et al, 2014c;Zerbi et al, 2014;Grandjean et al, 2016;Shah et al, 2016b), and models of autism (Zhan et al, 2014;Haberl et al, 2015;Sforazzini et al, 2016 Major mental illnesses include Schizophrenia (SZ), major depression and bipolar disorders. These illnesses are complex brain disorders driven by a combination of genetic and environmental factors (Tsuang et al, 2004;Dean and Murray, 2005;Brandon and Sawa, 2011).…”

“…The reasons are mainly due to technical and physiological issues, including low SNR because of the high magnetic field of small animal scanners, application of anaesthesia and tight control of physiological states of the mouse during scanning (Benveniste and Blackband, 2006;Guilfoyle et al, 2013;Nasrallah et al, 2014a). Recent progress in mouse rs-fMRI includes studies on the detectable RSNs in healthy mice under anaesthesia (Jonckers et al, 2011;Guilfoyle et al, 2013;Grandjean et al, 2014b;Mechling et al, 2014;Nasrallah et al, 2014a;Sforazzini et al, 2014;Stafford et al, 2014;Zerbi et al, 2015), some network topological properties observed in mice (Mechling et al, 2014;Liska et al, 2015), comparative studies on different anaesthetic protocols (Grandjean et al, 2014b;Jonckers et al, 2014), and studies on mouse models of some brain disorders (Shah et al, 2013;Grandjean et al, 2014c;Zerbi et al, 2014;Haberl et al, 2015;Grandjean et al, 2016;Sforazzini et al, 2016).…”