Evidence of functional brain reorganization on the basis of blood flow changes in the CAG140 knock-in mouse model of Huntington’s disease

Abstract

Neuroimaging, especially functional brain mapping, may provide insights into the distributed involvement of multiple brain regions and loops in disorders classically associated with pathology of a localized region. One example is Huntington's disease (HD), typically classified as a basal ganglia disorder. Here, we report genotypic differences in cerebral perfusion mapping in an HD mouse model characterized by a gene knock-in (KI) of a human exon 1 CAG140 expansion repeat (CAG140 KI mice). Animals were examined at 6 months and compared with wild-type littermates. Regional cerebral blood flow (rCBF) was mapped in the awake, nonrestrained, male mouse at rest using [C]-iodoantipyrine autoradiography and analyzed in three-dimensionally reconstructed brains by statistical parametric mapping. Our results showed significant changes in rCBF between CAG140 KI and WT mice, such that CAG140 KI animals showed hypoperfusion of the basal ganglia motor circuit and hyperperfusion of cerebellar-thalamic and somatosensory regions. Significant hypoperfusion was also noted in CAG140 KI mice in the prelimbic and cingulate cortex (medial prefrontal area) and the hippocampus - areas associated with cognitive processing and mood. Changes in rCBF were apparent in the absence of motor deficits (rotarod test) or atrophy in the striatum (caudate-putamen) or hemispheric volume. Our results suggest a functional reorganization of whole-brain networks at a presymptomatic stage in the life of the CAG140 KI mouse. Functional brain mapping in animals may, in the future, serve as a translational biomarker for identifying sites of early synaptic change in the HD brain and for directing targeted preclinical molecular studies and clinical therapies.

Exogenous l‐lactate promotes astrocyte plasticity but is not sufficient for enhancing striatal synaptogenesis or motor behavior in mice

“…For example, astrocyte‐dependent regulation of glutamate neurotransmission is increased in the presence of astrocyte‐neuron co‐cultures (Hasel et al., 2017; Pellerin & Magistretti, 1994). In addition, changes in these genes were observed in the striatum, a region engaged in motor behavior, but not in the ETC, a region not engaged in motor behavior during treadmill walking (Wang et al., 2013, 2016). However, in walking mice, these l ‐lactate‐induced changes in astrocyte‐specific genes involved in glutamate neurotransmission were not accompanied by changes in synaptogenesis as indicated by the lack of change in synaptic protein markers PSD‐95 and synaptophysin expression nor improved motor performance on the rotarod.…”

Exercise induces region‐specific remodeling of astrocyte morphology and reactive astrocyte gene expression patterns in male mice

“…In the context of normal brain function, exercise can act as a mechanism for brain maintenance, allowing motor and cognitive learning to occur (Davies et al, ). In the context of neurodegenerative diseases, such as Parkinson's or Huntington's disease, where motor and cognitive dysfunction is evident, skilled exercise can be harnessed to restore dysfunctional circuits, including cortico‐striatal circuitry (Petzinger et al, ; Wang et al, ). While much of motor learning and exercise‐induced neuroplasticity has focused on the protection and restoration of neurons, studies from our group are beginning to identify and support an important role for astrocytes.…”

The Mechanism of the Effect of Exercise Training on the Morphology of Neurons in the Caudate Putamen of the Mice

“…Then, in studying the effect of different load exercises on brain tissue morphology, neuron size and dendritic spine density are two very important indicators. Therefore, this experiment selected the size of neurons and dendritic spine density as test indicators to study the effects of different load swimming training on brain tissue morphology in order to expand the understanding of scientific training [3]. In this study, only from the size of neurons and dendritic spine density, to explore the physical changes caused by the morphology of the cerebral cortex sensory area and caudate putamen neurons.…”