Citations

Abstract The external globus pallidus (GPe) coordinates action-selection through GABAergic projections throughout the basal ganglia. GPe arkypallidal (arky) neurons project exclusively to the dorsal striatum, which regulates goal-directed and habitual reward-seeking. However, the role of GPe arky neurons in reward-seeking remains unknown. Here, we identified that a majority of arky neurons target the dorsolateral striatum (DLS). Using fiber photometry, we found that arky activities were higher during random interval (RI; habit) compared to random ratio (RR; goal) operant reward-seeking. Support vector machine analysis demonstrated that arky neuron activities have sufficient information to distinguish between RR and RI behavior. Genetic ablation of this arkyGPe◊DLS circuit facilitated a shift from goal-directed to habitual behavior. Conversely, chemogenetic activation reduced habitual seeking-behaviors, which was blocked by systemic D1R agonism. Our findings reveal a novel role of this arkyGPe◊DLS circuit in constraining habitual reward-seeking, which is relevant to addictive behaviors and other compulsive disorders.

Abstract Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a complex heterogeneous neurodegenerative disorder for which mechanisms are poorly understood. To explore transcriptional changes underlying FTLD-TDP, we performed RNA-sequencing on 66 genetically unexplained FTLD-TDP patients, 24 FTLD-TDP patients with GRN mutations and 24 control participants. Using principal component analysis, hierarchical clustering, differential expression and coexpression network analyses, we showed that GRN mutation carriers and FTLD-TDP-A patients without a known mutation shared a common transcriptional signature that is independent of GRN loss-of-function. After combining both groups, differential expression as compared to the control group and coexpression analyses revealed alteration of processes related to immune response, synaptic transmission, RNA metabolism, angiogenesis and vesicle-mediated transport. Deconvolution of the data highlighted strong cellular alterations that were similar in FTLD-TDP-A and GRN mutation carriers with NSF as a potentially important player in both groups. We propose several potentially druggable pathways such as the GABAergic, GDNF and sphingolipid pathways. Our findings underline new disease mechanisms and strongly suggest that affected pathways in GRN mutation carriers extend beyond GRN and contribute to genetically unexplained forms of FTLD-TDP-A.

Abstract Aims Accumulating evidence suggests that patients with frontotemporal lobar degeneration (FTLD) can have pathologic accumulation of multiple proteins, including tau and TDP‐43. This study aimed to determine the frequency and characteristics of concurrent tau pathology in FTLD with TDP‐43 pathology (FTLD‐TDP). Methods The study included 146 autopsy‐confirmed cases of FTLD‐TDP and 55 cases of FTLD‐TDP with motor neuron disease (FTLD‐MND). Sections from the basal forebrain were screened for tau pathology with phosphorylated‐tau immunohistochemistry. For cases with tau pathology on the screening section, additional brain sections were studied to establish a diagnosis. Genetic analysis of C9orf72 , GRN and MAPT was performed on select cases. Results We found 72 cases (36%) with primary age‐related tauopathy (PART), 85 (42%) with ageing‐related tau astrogliopathy (ARTAG), 45 (22%) with argyrophilic grain disease (AGD) and 2 cases (1%) with corticobasal degeneration (CBD). Patients with ARTAG or AGD were significantly older than those without these comorbidities. One of the patients with FTLD‐TDP and CBD had C9orf72 mutation and relatively mild tau pathology, consistent with incidental CBD. Conclusion The coexistence of TDP‐43 and tau pathologies was relatively common, particularly PART and ARTAG. Although rare, patients with FTLD can have multiple neurodegenerative proteinopathies. The absence of TDP‐43‐positive astrocytic plaques may suggest that CBD and FTLD‐TDP were independent disease processes in the two patients with both tau and TDP‐43 pathologies. It remains to be determined if mixed cases represent a unique disease process or two concurrent disease processes in an individual.

Abstract The external globus pallidus (GPe) is an integrative hub and gateway for behavioral flexibility in reward-related behaviors. However, it remains unknown whether enriched astrocytes in the GPe guide behavioral flexibility. Here, we trained mice to exhibit goal-directed and habitual reward-seeking behaviors using the behavior tasks with effort- and time-based reward delivery, respectively. Then, we examined the temporal dynamics of GPe astrocytes during goal-directed and habitual learning. Overall, GPe astrocytes were substantially silenced during habitual learning compared to goal-directed learning. In the timescale of action events, GPe astrocyte activities were increased immediately after termination of reward-taking behavior before the following action. However, during habitual learning, the increase of astrocyte activity was not evident. Moreover, support vector machine (SVM) analysis demonstrated that GPe astrocytes dynamics predicted whether mice perform goal-directed or habitual behaviors. Interestingly, chemogenetic activation of GPe astrocytes, which dampened GPe neuronal firings and habitual behaviors, exhibting goal-directed behaviors. Strikingly, brief and repeated attentional stimulations recapitulated the effect of chemogenetic activation of GPe in intervening the habitual reward-seeking behaviors with increased GPe astrocyte activities. Our findings reveal a novel insight that increasing GPe astrocytic activities attenuates habitual behavior and improves behavioral flexibility, which may provide a potential therapeutic target for decision-making-related disorders, such as obsessive-compulsive disorder and addiction.

Abstract Aims To assess the burden of transactive response DNA‐binding protein of 43 kDa (TDP‐43) inclusions in a unique cohort of old‐age patients with genetic frontotemporal lobar degeneration (gFTLD‐TDP) and compare these patients with sporadic old‐age individuals with TDP‐43, either in the presence of Alzheimer's disease (AD‐TDP) or in isolation (pure‐TDP). Methods The brain bank at Mayo Clinic‐Jacksonville was searched for cases ≥75 years old at death with TDP‐43 extending into middle frontal cortex. Cases were split into the following groups: (1) gFTLD‐TDP ( n = 15) with progranulin ( GRN )/ C9ORF72 mutations; (2) AD‐TDP ( n = 10)—cases with median Braak neurofibrillary tangle (NFT) stage VI, Thal phase V; (3) pure‐TDP ( n = 10)—cases with median Braak NFT stage I, Thal phase I. Clinical data were abstracted; TDP‐43 burden was calculated using digital pathology. Results Amnestic Alzheimer's dementia was the clinical diagnosis in ≥50% patients in each group. The distribution of TDP‐43 burden in gFTLD‐TDP and AD‐TDP, but not pure‐TDP, was limbic‐predominant targeting CA1 and subiculum. Patients with gFTLD‐TDP had higher burden in entorhinal cortex compared to AD‐TDP. TDP‐43 burden in middle frontal cortex did not differ between the three groups. Conclusions In old age it is challenging to clinically and pathologically differentiate gFTLD‐TDP from AD‐TDP and pure‐TDP‐43 based on burden. Like AD‐TDP, old age gFTLD‐TDP have a limbic predominant TDP‐43 distribution. The finding that amnestic Alzheimer's dementia was the most common clinical diagnosis regardless of group suggests that TDP‐43 directly and indirectly targets limbic regions.

AbstractTo examine the length of a hexanucleotide expansion in C9orf72, which represents the most frequent genetic cause of frontotemporal lobar degeneration and motor neuron disease, we employed a targeted amplification-free long-read sequencing technology: No-Amp sequencing. In our cross-sectional study, we assessed cerebellar tissue from 28 well-characterized C9orf72 expansion carriers. We obtained 3507 on-target circular consensus sequencing reads, of which 814 bridged the C9orf72 repeat expansion (23%). Importantly, we observed a significant correlation between expansion sizes obtained using No-Amp sequencing and Southern blotting (P = 5.0 × 10−4). Interestingly, we also detected a significant survival advantage for individuals with smaller expansions (P = 0.004). Additionally, we uncovered that smaller expansions were significantly associated with higher levels of C9orf72 transcripts containing intron 1b (P = 0.003), poly(GP) proteins (P = 1.3 × 10− 5), and poly(GA) proteins (P = 0.005). Thorough examination of the composition of the expansion revealed that its GC content was extremely high (median: 100%) and that it was mainly composed of GGGGCC repeats (median: 96%), suggesting that expanded C9orf72 repeats are quite pure. Taken together, our findings demonstrate that No-Amp sequencing is a powerful tool that enables the discovery of relevant clinicopathological associations, highlighting the important role played by the cerebellar size of the expanded repeat in C9orf72-linked diseases.

ObjectiveThe objective of this study was to describe clinical features, [18F]‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET) metabolism and digital pathology in patients with logopenic progressive aphasia (LPA) and pathologic diagnosis of diffuse Lewy body disease (DLBD) and compare to patients with LPA with other pathologies, as well as patients with classical features of probable dementia with Lewy bodies (pDLB).MethodsThis is a clinicopathologic case‐control study of 45 patients, including 20 prospectively recruited patients with LPA among whom 6 were diagnosed with LPA‐DLBD. We analyzed clinical features and compared FDG‐PET metabolism in LPA‐DLBD to an independent group of patients with clinical pDLB and regional α‐synuclein burden on digital pathology to a second independent group of autopsied patients with DLBD pathology and antemortem pDLB (DLB‐DLBD).ResultsAll patients with LPA‐DLBD were men. Neurological, speech, and neuropsychological characteristics were similar across LPA‐DLBD, LPA‐Alzheimer's disease (LPA‐AD), and LPA‐frontotemporal lobar degeneration (LPA‐FTLD). Genetic screening of AD, DLBD, and FTLD linked genes were negative with the exception of APOE ε4 allele present in 83% of LPA‐DLBD patients. Seventy‐five percent of the patients with LPA‐DLBD showed a parietal‐dominant pattern of hy pometabolism; LPA‐FTLD – temporal‐dominant pattern, whereas LPA‐AD showed heterogeneous patterns of hypometabolism. LPA‐DLBD had more asymmetrical hypometabolism affecting frontal lobes, with relatively spared occipital lobe in the nondominantly affected hemisphere, compared to pDLB. LPA‐DLBD had minimal atrophy on gross brain examination, higher cortical Lewy body counts, and higher α‐synuclein burden in the middle frontal and inferior parietal cortices compared to DLB‐DLBD.InterpretationWhereas AD is the most frequent underlying pathology of LPA, DLBD can also be present and may contribute to the LPA phenotype possibly due to α‐synuclein‐associated functional impairment of the dominant parietal lobe. ANN NEUROL 2021;89:520–533