Biology subjects

Munoz-Sanjuan, I.

Publications and source records attributed to Munoz-Sanjuan, I..

4 recordsLinked to original sources

bioRxiv2022

Resting-State fMRI reveals Longitudinal Alterations in Brain Network Connectivity in a Mouse Model of Huntington's Disease

Huntingtons disease is an autosomal, dominantly inherited neurodegenerative disease caused by an expansion of the CAG repeats in exon 1 of the huntingtin gene. Neuronal degeneration and dysfunction that precedes regional atrophy result in the impairment of striatal and cortical circuits that affect the brains large-scale network functionality. However, the evolution of these disease-driven, large-scale connectivity alterations is still poorly understood. Here we used resting-state fMRI to investigate functional connectivity changes in a mouse model of Huntingtons disease in several relevant brain networks and how they are affected at different ages that follow a disease-like phenotypic progression. Towards this, we used the heterozygous (HET) form of the zQ175DN Huntingtons disease mouse model that recapitulates aspects of human disease pathology. Seed- and Region-based analyses were performed at different ages, on 3-, 6-, 10-, and 12-month-old HET and age-matched wild-type mice. Our results demonstrate decreased connectivity starting at 6 months of age, most prominently in regions such as the retrosplenial and cingulate cortices, pertaining to the default mode-like network and auditory and visual cortices, part of the associative cortical network. At 12 months, we observe a shift towards decreased connectivity in regions such as the somatosensory cortices, pertaining to the lateral cortical network, and the caudate putamen, a constituent of the subcortical network. Moreover, we assessed the impact of distinct Huntingtons Disease-like pathology of the zQ175DN HET mice on age-dependent connectivity between different brain regions and networks where we demonstrate that connectivity strength follows a nonlinear, inverted U-shape pattern, a well-known phenomenon of development and normal aging. Conversely, the neuropathologically driven alteration of connectivity, especially in the default mode and associative cortical networks, showed diminished age-dependent evolution of functional connectivity. These findings reveal that in this Huntingtons disease model, altered connectivity starts with cortical network aberrations which precede striatal connectivity changes, which appear only at a later age. Taken together, these results suggest that the age-dependent cortical network dysfunction seen in rodents could represent a relevant pathological process in Huntingtons disease progression.

neuroscience↗

bioRxiv2022

Longitudinal investigation of changes in resting-state co-activation patterns and their predictive ability in the zQ175 DN mouse model of Huntington's disease

Huntingtons disease (HD) is a neurodegenerative disorder caused by expanded ([≥]40) glutamine-encoding CAG repeats in the huntingtin gene, which leads to dysfunction and death of predominantly striatal and cortical neurons. While the genetic profile and behavioural signs of the disease are better known, changes in the functional architecture of the brain, especially before the behavioural symptoms become apparent, are not fully and consistently characterized. In this study, we sought markers at pre, early and late manifest states of phenotypic progression in the heterozygous (HET) zQ175 delta-neo (DN) mouse model, using resting-state functional magnetic resonance imaging (RS-fMRI). This mouse model shows molecular, cellular and circuitry alterations that resemble those seen in HD in humans. Specifically, we investigated, longitudinally, changes in co-activation patterns (CAPs) that are the transient states of brain activity constituting the resting-state networks (RSNs). Most robust changes in the temporal properties of CAPs occurred at the late manifest state; the durations of two anti-correlated CAPs, characterized by simultaneous co-activation of default-mode like network (DMLN) and co-deactivation of lateral-cortical network (LCN) and vice-versa, were reduced in the zQ175 DN HET animals compared to the wild-type mice. Changes in the spatial properties, measured in terms of activation levels of different brain regions, during CAPs were found at all three states and became progressively more pronounced at the manifest states. We then assessed the cross-validated predictive power of CAP metrics to distinguish HET animals from controls. Spatial properties of CAPs performed significantly better than the chance level at all three states with 80% classification accuracy at the early and late manifest states.

neuroscience↗

bioRxiv2022

Benefits of global mutant huntingtin lowering diminish over time in a Huntington's disease mouse model

We have developed a novel inducible Huntingtons disease (HD) mouse model that allows temporal control of whole-body allele-specific mutant Huntingtin (mHtt) expression. We asked whether moderate global lowering of mHtt ([~]50%) was sufficient for long-term amelioration of HD-related deficits and, if so, whether early mHtt lowering (before measurable deficits) was required. Both early and late mHtt lowering delayed behavioral dysfunction and mHTT protein aggregation, as measured biochemically. However, long-term follow up revealed that the benefits, in all mHtt lowering groups, attenuated by 12 months of age. While early mHtt lowering attenuated cortical and striatal transcriptional dysregulation evaluated at 6 months of age, the benefits diminished by 12- months of age and late mHtt lowering was unable to ameliorate striatal transcriptional dysregulation at 12 months of age. Only early mHtt lowering delayed the elevation in cerebrospinal fluid neurofilament light chain that we observed in our model starting at 9 months of age. As small-molecule HTT-lowering therapeutics progress to the clinic, our findings suggest that moderate mHtt lowering allows disease progression to continue, albeit at a slower rate, and could be relevant to the degree of mHTT lowering required to sustain long-term benefit in humans.

neuroscience↗

bioRxiv2021

A novel imaging ligand as a biomarker for mutant huntingtin-lowering in Huntington's disease

Huntingtons disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (PolyQ) tract. While several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, no method is currently available to visualize mHTT levels in the living brain. Here we demonstrate the development of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates. This small molecule radiolabeled with 11C ([11C]CHDI-180R) enables non-invasive monitoring of mHTT pathology in the brain and can track region-and time-dependent suppression of mHTT in response to therapeutic interventions targeting mHTT expression. We further show that therapeutic agents that lower mHTT in the striatum have a functional restorative effect that can be measured by preservation of striatal imaging markers, enabling a translational path to assess the functional effect of mHTT lowering.

neuroscience↗