Region and task-specific activation of Arc in primary motor cortex of rats following motor skill learning

Motor learning requires protein synthesis within the primary motor cortex (M1). Here, we show that the immediate early gene Arc/Arg3.1 is specifically induced in M1 by learning a motor skill. Arc mRNA was quantified using a fluorescent in situ hybridization assay in adult Long-Evans rats learning a skilled reaching task (SRT), in rats performing reaching-like forelimb movement without learning (ACT) and in rats that were trained in the operant but not the motor elements of the task (controls). Apart from M1, Arc expression was assessed within the rostral motor area (RMA), primary somatosensory cortex (S1), striatum (ST) and cerebellum. In SRT animals, Arc mRNA levels in M1 contralateral to the trained limb were 31% higher than ipsilateral (p<0.001), 31% higher than in the contralateral M1 of ACT animals (p<0.001) and 48% higher than in controls (p<0.001). Arc mRNA expression in SRT was positively correlated with learning success between two sessions (r=0.52; p=0.026). For RMA, S1, ST or cerebellum no significant differences in Arc mRNA expression were found between hemispheres or across behaviors. As Arc expression has been related to different forms of cellular plasticity, these findings suggest a link between M1 Arc expression and motor skill learning in rats

Prominent microglial inclusions in transgenic mouse models of α-synucleinopathy that are distinct from neuronal lesions.

Alpha-synucleinopathies are a group of progressive neurodegenerative disorders, characterized by intracellular deposits of aggregated α-synuclein (αS). The clinical heterogeneity of these diseases is thought to be attributed to conformers (or strains) of αS but the contribution of inclusions in various cell types is unclear. The aim of the present work was to study αS conformers among different transgenic (TG) mouse models of α-synucleinopathies. To this end, four different TG mouse models were studied (Prnp-h[A53T]αS; Thy1-h[A53T]αS; Thy1-h[A30P]αS; Thy1-mαS) that overexpress human or murine αS and differed in their age-of-symptom onset and subsequent disease progression. Postmortem analysis of end-stage brains revealed robust neuronal αS pathology as evidenced by accumulation of αS serine 129 (p-αS) phosphorylation in the brainstem of all four TG mouse lines. Overall appearance of the pathology was similar and only modest differences were observed among additionally affected brain regions. To study αS conformers in these mice, we used pentameric formyl thiophene acetic acid (pFTAA), a fluorescent dye with amyloid conformation-dependent spectral properties. Unexpectedly, besides the neuronal αS pathology, we also found abundant pFTAA-positive inclusions in microglia of all four TG mouse lines. These microglial inclusions were also positive for Thioflavin S and showed immunoreactivity with antibodies recognizing the N-terminus of αS, but were largely p-αS-negative. In all four lines, spectral pFTAA analysis revealed conformational differences between microglia and neuronal inclusions but not among the different mouse models. Concomitant with neuronal lesions, microglial inclusions were already present at presymptomatic stages and could also be induced by seeded αS aggregation. Although nature and significance of microglial inclusions for human α-synucleinopathies remain to be clarified, the previously overlooked abundance of microglial inclusions in TG mouse models of α-synucleinopathy bears importance for mechanistic and preclinical-translational studies

Orchestrated experience-driven Arc responses are disrupted in a mouse model of Alzheimer's disease

Experience-induced expression of immediate-early gene Arc/Arg3.1 is known to play a pivotal role in the consolidation of memory. Here we use in-vivo longitudinal multiphoton imaging to show orchestrated activity-dependent expression of Arc in the mouse extrastriate visual cortex in response to a structured visual stimulation. In wild-type mice, the amplitude of the Arc response in individual neurons strongly predicts the probability of reactivation by a subsequent presentation of the same stimulus. In a mouse model of Alzheimer’s disease, this association is markedly disrupted in the cortex specifically near senile plaques. Neurons in the vicinity of plaques are less likely to respond but, paradoxically, there is stronger response in those few neurons around plaques that do respond. To the extent that the orchestrated pattern of Arc expression reflects nervous system responses to, and physiological consolidation of, behavioral experience, the disruption in Arc patterns reveals plaque-associated interference with neural network integration

The molecular lifecycle of amyloid – Mechanism of assembly, mesoscopic organisation, polymorphism, suprastructures, and biological consequences

The formation of a diverse range of amyloid structures from normally soluble proteins and peptides is a hallmark of devastating human disorders as well as biological functions. The current molecular understanding of the amyloid lifecycle reveals four processes central to their growth and propagation: primary nucleation, elongation, secondary nucleation and division. However, these processes result in a wide range of cross-β packing and filament arrangements, including diverse assemblies formed from identical monomeric precursors with the same amino acid sequences. Here, we review current structural and mechanistic understanding of amyloid self-assembly, and discuss how mesoscopic, i.e. micrometre to nanometre, organisation of amyloid give rise to suprastructural features that may be the key link between the polymorphic amyloid structures and the biological response they elicit. A greater understanding of the mechanisms governing suprastructure formation will guide future strategies to combat amyloid associated disorders and to use and control the amyloid quaternary structure in synthetic biology and materials applications

Distinct Spacing Between Anionic Groups: An Essential Chemical Determinant for Achieving Thiophene-Based Ligands to Distinguish Beta-Amyloid or Tau Polymorphic Aggregates

The accumulation of protein aggregates is associated with many devastating neurodegenerative diseases and the existence of distinct aggregated morphotypes has been suggested to explain the heterogeneous phenotype reported for these diseases. Thus, the development of molecular probes able to distinguish such morphotypes is essential. We report an anionic tetrameric oligothiophene compound that can be utilized for spectral assignment of different morphotypes of -amyloid or tau aggregates present in transgenic mice at distinct ages. The ability of the ligand to spectrally distinguish between the aggregated morphotypes was reduced when the spacing between the anionic substituents along the conjugated thiophene backbone was altered, which verified that specific molecular interactions between the ligand and the protein aggregate are necessary to detect aggregate polymorphism. Our findings provide the structural and functional basis for the development of new fluorescent ligands that can distinguish between different morphotypes of protein aggregates.Funding Agencies|Swedish Foundation for Strategic Research; Swedish Alzheimer Foundation; European Research Council Starting Independent Researcher Grant (MUMID)</p

Label-free imaging of cerebral beta-amyloidosis with extended-focus optical coherence microscopy

We demonstrate label-free imaging of cerebral $beta$-amyloidosis ex vivo and in a living mouse model of Alzheimer's disease using extended-focus Fourier domain optical coherence microscopy (xfOCM). xfOCM provides 3D, high-resolution images of individual $beta$-amyloid plaques in the brain parenchyma and vasculature and requires no staining of the Alzheimeric sample under investigation. xfOCM also opens the possibility to perform minimally invasive studies of $beta$-amyloid pathology in vivo, without the use of labeling methods, which potentially confound experimental findings.info:eu-repo/semantics/publishe