Exercise Increases Neural Stem Cell Number in a GH-Dependent Manner, Augmenting the Regenerative Response in Aged Mice

The exercise-induced enhancement of learning and memory, and its ability to slow age-related cognitive decline in humans led us to investigate whether running stimulates periventricular (PVR) neural stem cells (NSCs) in aging mice, thereby augmenting the regenerative capacity of the brain. To establish a benchmark of normal aging on endogenous NSCs, we harvested the PVR from serial vibratome sections through the lateral ventricles of juvenile (6-8 weeks), 6, 12, 18, and 24-month-old mice, culturing the cells in the neural colony forming cell assay. A significant decline in NSC frequency was apparent by 6-months (~40%) ultimately resulting in a ~90% reduction by 24-months. Concurrent with this decline was a progressive loss in regenerative capacity, as reflected by an incomplete repopulation of neurosphere-forming cells following gamma cell irradiation-induced depletion of the PVR. However voluntary exercise (i.e. 21 days of running) significantly increased NSC frequency in mic

Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and meta-analysis

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Mutations in neuroligin-3 in male mice impact behavioral flexibility but not relational memory in a touchscreen test of visual transitive inference

Cognitive dysfunction including disrupted behavioral flexibility is central to neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). A cognitive measure that assesses relational memory, and the ability to flexibly assimilate and transfer learned information is transitive inference. Transitive inference is highly conserved across vertebrates and disrupted in cognitive disorders. Here, we examined how mutations in the synaptic cell-adhesion molecule neuroligin-3 (Nlgn3) that have been documented in ASD impact relational memory and behavioral flexibility. We first refined a rodent touchscreen assay to measure visual transitive inference, then assessed two mouse models of Nlgn3 dysfunction (Nlgn3−/y and Nlgn3R451C). Deep analysis of touchscreen behavioral data at a trial level established we could measure trajectories in flexible responding and changes in processing speed as cognitive load increased. We show that gene mutations in Nlgn3 do not disrupt relational memory, but significantly impact flexible responding. Our study presents the first analysis of reaction times in a rodent transitive inference test, highlighting response latencies from the touchscreen system are useful indicators of processing demands or decision-making processes. These findings expand our understanding of how dysfunction of key components of synaptic signaling complexes impact distinct cognitive processes disrupted in neurodevelopmental disorders, and advance our approaches for dissecting rodent behavioral assays to provide greater insights into clinically relevant cognitive symptoms

Rethinking the reserve with a translational approach: novel ideas on the construct and the interventions

The concept of brain, cognitive, and neural reserves has been introduced to account for the apparent discrepancies between neurological damage and clinical manifestations. However, these ideas are yet theoretical suggestions that are not completely assimilated in the clinical routine. The mechanisms of the reserves have been extensively studied in neurodegenerative pathologies, in particular in Alzheimer's disease. Both human and animal studies addressed this topic by following two parallel pathways. The specific aim of the present review is to attempt to combine the suggestions derived from the two different research fields to deepen the knowledge about reserves. In fact, the achievement of a comprehensive theoretical framework on reserve mechanisms is an essential step to propose well-timed interventions tailored to the clinical characteristics of patients. The present review highlights the importance of addressing three main aspects: the definition of reserve proxy measures, the interaction between reserve level and therapeutic interventions, and the specific time-window of reserve efficacy

MicroRNA-210 regulates dendritic morphology and behavioural flexibility in mice

MicroRNAs are known to be critical regulators of neuronal plasticity. The highly-conserved, hypoxia- regulated microRNA-210 (miR-210) has been shown to be associated with long term memory in invertebrates and dysregulated in neurodevelopmental and neurodegenerative disease models. However, the role of miR-210 in mammalian neuronal function and cognitive behavior remains unexplored. Here we generated Nestin-cre driven miR-210 neuronal knockout mice to characterise miR-210 regulation and function using in vitro and in vivo methods. We identified miR-210 localisation throughout neuronal somas and dendritic processes and increased levels of mature miR- 210 in response to neural activity in vitro. Loss of miR-210 in neurons resulted in higher oxidative phosphorylation and ROS production following hypoxia and increased dendritic arbour density in hippocampal cultures. Additionally, miR-210 knockout mice displayed altered behavioral flexibility in rodent touchscreen tests, particularly during early reversal learning suggesting processes underlying updating of information and feedback were impacted. Our findings support a conserved, activity- dependent role for miR-210 in neuroplasticity and cognitive function.Australian Research Council (ARC: DP120104117)ARC Future Fellowships (FT110100292; FT140101327)Australian Government Research Training Program StipendAccepte

Evolution of GluN2A/B cytoplasmic domains diversified vertebrate synaptic plasticity and behavior

Two genome duplications early in the vertebrate lineage expanded gene families, including GluN2 subunits of the NMDA receptor. Diversification between the four mammalian GluN2 proteins occurred primarily at their intracellular C−terminal domains (CTDs). To identify shared ancestral functions and diversified subunit−specific functions, we exchanged the exons encoding the GluN2A (also known as Grin2a) and GluN2B (also known as Grin2b) CTDs in two knock−in mice and analyzed the mice's biochemistry, synaptic physiology, and multiple learned and innate behaviors. The eight behaviors were genetically separated into four groups, including one group comprising three types of learning linked to conserved GluN2A/B regions. In contrast, the remaining five behaviors exhibited subunit−specific regulation. GluN2A/B CTD diversification conferred differential binding to cytoplasmic MAGUK proteins and differential forms of long−term potentiation. These data indicate that vertebrate behavior and synaptic signaling acquired increased complexity from the duplication and diversification of ancestral GluN2 gene

Arc requires PSD95 for assembly into postsynaptic complexes involved with neural dysfunction and intelligence

Arc is an activity-regulated neuronal protein, but little is known about its interactions, assembly into multiprotein complexes, and role in human disease and cognition. We applied an integrated proteomic and genetic strategy by targeting a tandem affinity purification (TAP) tag and Venus fluorescent protein into the endogenous Arc gene in mice. This allowed biochemical and proteomic characterization of native complexes in wild-type and knockout mice. We identified many Arc-interacting proteins, of which PSD95 was the most abundant. PSD95 was essential for Arc assembly into 1.5-MDa complexes and activity-dependent recruitment to excitatory synapses. Integrating human genetic data with proteomic data showed that Arc-PSD95 complexes are enriched in schizophrenia, intellectual disability, autism, and epilepsy mutations and normal variants in intelligence. We propose that Arc-PSD95 postsynaptic complexes potentially affect human cognitive function