Neuroinflammation and Neuronal Loss Precede Aβ Plaque Deposition in the hAPP-J20 Mouse Model of Alzheimer's Disease

Recent human trials of treatments for Alzheimer's disease (AD) have been largely unsuccessful, raising the idea that treatment may need to be started earlier in the disease, well before cognitive symptoms appear. An early marker of AD pathology is therefore needed and it is debated as to whether amyloid-βAβ? plaque load may serve this purpose. We investigated this in the hAPP-J20 AD mouse model by studying disease pathology at 6, 12, 24 and 36 weeks. Using robust stereological methods, we found there is no neuron loss in the hippocampal CA3 region at any age. However loss of neurons from the hippocampal CA1 region begins as early as 12 weeks of age. The extent of neuron loss increases with age, correlating with the number of activated microglia. Gliosis was also present, but plateaued during aging. Increased hyperactivity and spatial memory deficits occurred at 16 and 24 weeks. Meanwhile, the appearance of plaques and oligomeric Aβ were essentially the last pathological changes, with significant changes only observed at 36 weeks of age. This is surprising given that the hAPP-J20 AD mouse model is engineered to over-expresses Aβ. Our data raises the possibility that plaque load may not be the best marker for early AD and suggests that activated microglia could be a valuable marker to track disease progression. © 2013 Wright et al

A new mouse line with reduced GluA2 Q/R site RNA editing exhibits loss of dendritic spines, hippocampal CA1-neuron loss, learning and memory impairments and NMDA receptor-independent seizure vulnerability.

Calcium (Ca2+)-permeable AMPA receptors may, in certain circumstances, contribute to normal synaptic plasticity or to neurodegeneration. AMPA receptors are Ca2+-permeable if they lack the GluA2 subunit or if GluA2 is unedited at a single nucleic acid, known as the Q/R site. In this study, we examined mice engineered with a point mutation in the intronic editing complementary sequence (ECS) of the GluA2 gene, Gria2. Mice heterozygous for the ECS mutation (named GluA2+/ECS(G)) had a ~ 20% reduction in GluA2 RNA editing at the Q/R site. We conducted an initial phenotypic analysis of these mice, finding altered current-voltage relations (confirming expression of Ca2+-permeable AMPA receptors at the synapse). Anatomically, we observed a loss of hippocampal CA1 neurons, altered dendritic morphology and reductions in CA1 pyramidal cell spine density. Behaviourally, GluA2+/ECS(G) mice exhibited reduced motor coordination, and learning and memory impairments. Notably, the mice also exhibited both NMDA receptor-independent long-term potentiation (LTP) and vulnerability to NMDA receptor-independent seizures. These NMDA receptor-independent seizures were rescued by the Ca2+-permeable AMPA receptor antagonist IEM-1460. In summary, unedited GluA2(Q) may have the potential to drive NMDA receptor-independent processes in brain function and disease. Our study provides an initial characterisation of a new mouse model for studying the role of unedited GluA2(Q) in synaptic and dendritic spine plasticity in disorders where unedited GluA2(Q), synapse loss, neurodegeneration, behavioural impairments and/or seizures are observed, such as ischemia, seizures and epilepsy, Huntington's disease, amyotrophic lateral sclerosis, astrocytoma, cocaine seeking behaviour and Alzheimer's disease

Adar3 is involved in learning and memory in mice

© 2018 Mladenova, Barry, Konen, Pineda, Guennewig, Avesson, Zinn, Schonrock, Bitar, Jonkhout, Crumlish, Kaczorowski, Gong, Pinese, Franco, Walkley, Vissel and Mattick. The amount of regulatory RNA encoded in the genome and the extent of RNA editing by the post-transcriptional deamination of adenosine to inosine (A-I) have increased with developmental complexity and may be an important factor in the cognitive evolution of animals. The newest member of the A-I editing family of ADAR proteins, the vertebrate-specific ADAR3, is highly expressed in the brain, but its functional significance is unknown. In vitro studies have suggested that ADAR3 acts as a negative regulator of A-I RNA editing but the scope and underlying mechanisms are also unknown. Meta-analysis of published data indicates that mouse Adar3 expression is highest in the hippocampus, thalamus, amygdala, and olfactory region. Consistent with this, we show that mice lacking exon 3 of Adar3 (which encodes two double stranded RNA binding domains) have increased levels of anxiety and deficits in hippocampus-dependent short- and long-term memory formation. RNA sequencing revealed a dysregulation of genes involved in synaptic function in the hippocampi of Adar3-deficient mice. We also show that ADAR3 transiently translocates from the cytoplasm to the nucleus upon KCl-mediated activation in SH-SY5Y cells. These results indicate that ADAR3 contributes to cognitive processes in mammals

Prefrontal Cortex Lesions Impair Object-Spatial Integration

How and where object and spatial information are perceptually integrated in the brain is a central question in visual cognition. Single-unit physiology, scalp EEG, and fMRI research suggests that the prefrontal cortex (PFC) is a critical locus for object-spatial integration. To test the causal participation of the PFC in an object-spatial integration network, we studied ten patients with unilateral PFC damage performing a lateralized object-spatial integration task. Consistent with single-unit and neuroimaging studies, we found that PFC lesions result in a significant behavioral impairment in object-spatial integration. Furthermore, by manipulating inter-hemispheric transfer of object-spatial information, we found that masking of visual transfer impairs performance in the contralesional visual field in the PFC patients. Our results provide the first evidence that the PFC plays a key, causal role in an object-spatial integration network. Patient performance is also discussed within the context of compensation by the non-lesioned PFC

Self-Reported Time in Bed and Sleep Quality in Association with Internalizing and Externalizing Symptoms in School-Age Youth

This study investigated the relationship between self-reported time in bed and sleep quality in association with self-reported internalizing and externalizing symptoms in a sample of 285 elementary school students (52% female) recruited from a rural Midwestern elementary school. Path models were used to estimate proposed associations, controlling for grade level and gender. Curvilinear associations were found between time in bed and anxiety, depressive symptoms, and irritability. Marginal curvilinear trends were found between time in bed and emotion dysregulation, reactive aggression, and proactive aggression. Sleep quality was negatively associated with anxiety, depressive symptoms, irritability, reactive aggression, and delinquency engagement. Gender and grade differences were found across models. Findings suggest that examining self-reported time in bed (both linear and quadratic) and sleep quality is important for understanding internalizing and externalizing symptoms associated with sleep in school-age youth. Incorporating self-reported sleep assessments into clinical practice and school-based evaluations may have implications for a child’s adjustment

Visuomotor Cerebellum in Human and Nonhuman Primates

In this paper, we will review the anatomical components of the visuomotor cerebellum in human and, where possible, in non-human primates and discuss their function in relation to those of extracerebellar visuomotor regions with which they are connected. The floccular lobe, the dorsal paraflocculus, the oculomotor vermis, the uvula–nodulus, and the ansiform lobule are more or less independent components of the visuomotor cerebellum that are involved in different corticocerebellar and/or brain stem olivocerebellar loops. The floccular lobe and the oculomotor vermis share different mossy fiber inputs from the brain stem; the dorsal paraflocculus and the ansiform lobule receive corticopontine mossy fibers from postrolandic visual areas and the frontal eye fields, respectively. Of the visuomotor functions of the cerebellum, the vestibulo-ocular reflex is controlled by the floccular lobe; saccadic eye movements are controlled by the oculomotor vermis and ansiform lobule, while control of smooth pursuit involves all these cerebellar visuomotor regions. Functional imaging studies in humans further emphasize cerebellar involvement in visual reflexive eye movements and are discussed

Tactile localization biases are modulated by gaze direction

Identifying the spatial location of touch on the skin surface is a fundamental function of our somatosensory system. Despite the fact that stimulation of even single mechanoreceptive afferent fibres is sufficient to produce clearly localised percepts, tactile localisation can be modulated also by higher-level processes such as body posture. This suggests that tactile events are coded using multiple representations using different coordinate systems. Recent reports provide evidence for systematic biases on tactile localisation task, which are thought to result from a supramodal representation of the skin surface. While the influence of non-informative vision of the body and gaze direction on tactile discrimination tasks has been extensively studied, their effects on tactile localisation tasks remain largely unexplored. To address this question, participants performed a tactile localization task on their left hand under different visual conditions by means of a mirror box; in the mirror condition a single stimulus was delivered on participants’ hand while the reflexion of the right hand was seen through the mirror; in the object condition participants looked at a box through the mirror, and in the right hand condition participants looked directly at their right hand. Participants reported the location of the tactile stimuli using a silhouette of a hand. Results showed a shift in the localization of the touches towards the tip of the fingers (distal bias) and the thumb (radial biases) across conditions. Critically, distal biases were reduced when participants looked towards the mirror compared to when they looked at their right hand suggesting that gaze direction reduces the typical proximo-distal biases in tactile localization. Moreover, vision of the hand modulates the internal configuration of points’ locations, by elongating it, in the radio-ulnar axis