Heterogeneous brain region-specific responses to astrocytic mitochondrial DNA damage in mice.

Astrocytes display context-specific diversity in their functions and respond to noxious stimuli between brain regions. Astrocytic mitochondria have emerged as key players in governing astrocytic functional heterogeneity, given their ability to dynamically adapt their morphology to regional demands on ATP generation and Ca2+ buffering functions. Although there is reciprocal regulation between mitochondrial dynamics and mitochondrial Ca2+ signaling in astrocytes, the extent of this regulation in astrocytes from different brain regions remains unexplored. Brain-wide, experimentally induced mitochondrial DNA (mtDNA) loss in astrocytes showed that mtDNA integrity is critical for astrocyte function, however, possible diverse responses to this noxious stimulus between brain areas were not reported in these experiments. To selectively damage mtDNA in astrocytes in a brain-region-specific manner, we developed a novel adeno-associated virus (AAV)-based tool, Mito-PstI expressing the restriction enzyme PstI, specifically in astrocytic mitochondria. Here, we applied Mito-PstI to two brain regions, the dorsolateral striatum and dentate gyrus, and we show that Mito-PstI induces astrocytic mtDNA loss in vivo, but with remarkable brain-region-dependent differences on mitochondrial dynamics, Ca2+ fluxes, and astrocytic and microglial reactivity. Thus, AAV-Mito-PstI is a novel tool to explore the relationship between astrocytic mitochondrial network dynamics and astrocytic mitochondrial Ca2+ signaling in a brain-region-selective manner.

Heterogeneous brain region-specific responses to astrocytic mitochondrial DNA damage in mice.

Astrocytes use Ca 2+ signals to regulate multiple aspects of normal and pathological brain function. Astrocytes display context-specific diversity in their functions, and in their response to noxious stimuli between brain regions. Indeed, astrocytic mitochondria have emerged as key players in governing astrocytic functional heterogeneity, given their ability to dynamically adapt their morphology to regional demands on their ATP generation and Ca 2+ buffering functions. Although there is reciprocal regulation between mitochondrial dynamics and mitochondrial Ca 2+ signaling in astrocytes, the extent of this regulation into the rich diversity of astrocytes in different brain regions remains largely unexplored. Brain-wide, experimentally induced mitochondrial DNA (mtDNA) loss in astrocytes showed that mtDNA integrity is critical for proper astrocyte function, however, few insights into possible diverse responses to this noxious stimulus from astrocytes in different brain areas were reported in these experiments. To selectively damage mtDNA in astrocytes in a brain-region-specific manner, we developed a novel adeno-associated virus (AAV)-based tool, Mito-PstI, which expresses the restriction enzyme PstI, specifically in astrocytic mitochondria. Here, we applied Mito-PstI to two distinct brain regions, the dorsolateral striatum, and the hippocampal dentate gyrus, and we show that Mito-PstI can induce astrocytic mtDNA loss in vivo , but with remarkable brain-region-dependent differences on mitochondrial dynamics, spontaneous Ca 2+ fluxes and astrocytic as well as microglial reactivity. Thus, AAV-Mito-PstI is a novel tool to explore the relationship between astrocytic mitochondrial network dynamics and astrocytic mitochondrial Ca 2+ signaling in a brain-region-selective manner.

Patterns of longitudinal cortical atrophy over 3 years in empirically derived MCI subtypes.

OBJECTIVE: We previously identified 4 empirically derived mild cognitive impairment (MCI) subtypes via cluster analysis within the Alzheimer's Disease Neuroimaging Initiative (ADNI) and demonstrated high correspondence between patterns of cortical thinning at baseline and each cognitive subtype. We aimed to determine whether our MCI subtypes demonstrate unique longitudinal atrophy patterns. METHODS: ADNI participants (295 with MCI and 134 cognitively normal [CN]) underwent annual structural MRI and neuropsychological assessments. General linear modeling compared vertex-wise differences in cortical atrophy rates between each MCI subtype and the CN group. Linear mixed models examined trajectories of cortical atrophy over 3 years within lobar regions of interest. RESULTS: Compared to the CN group, those with amnestic MCI (memory deficit) initially demonstrated greater atrophy rates within medial temporal lobe regions that became more widespread over time. Those with dysnomic/amnestic MCI (naming/memory deficits) showed greater atrophy rates largely localized to temporal lobe regions. The mixed MCI (impairment in all cognitive domains) group showed greater atrophy rates in widespread regions at all time points. The cluster-derived normal group, who had intact neuropsychological performance and normal cortical thickness at baseline despite their MCI diagnosis via conventional diagnostic criteria, continued to show normal cognition and minimal cortical atrophy over 3 years. CONCLUSIONS: ADNI's purported amnestic MCI sample produced more refined cognitive subtypes with unique longitudinal cortical atrophy rates. These novel MCI subtypes reliably reflect underlying atrophy, reduce false-positive diagnostic errors, and improve prediction of clinical course. Such improvements have implications for the selection of participants for clinical trials and for providing more precise risk assessment for individuals diagnosed with MCI.