Selective Vulnerability of Neurons in Layer II of the Entorhinal Cortex during Aging and Alzheimer's Disease

All neurons are not created equal. Certain cell populations in specific brain regions are more susceptible to age-related changes that initiate regional and system-level dysfunction. In this respect, neurons in layer II of the entorhinal cortex are selectively vulnerable in aging and Alzheimer's disease (AD). This paper will cover several hypotheses that attempt to account for age-related alterations among this cell population. We consider whether specific developmental, anatomical, or biochemical features of neurons in layer II of the entorhinal cortex contribute to their particular sensitivity to aging and AD. The entorhinal cortex is a functionally heterogeneous environment, and we will also review data suggesting that, within the entorhinal cortex, there is subregional specificity for molecular alterations that may initiate cognitive decline. Taken together, the existing data point to a regional cascade in which entorhinal cortical alterations directly contribute to downstream changes in its primary afferent region, the hippocampus

Cortical gene transcription response patterns to water maze training in aged mice

<p>Abstract</p> <p>Background</p> <p>The hippocampus mediates the acquisition of spatial memory, but the memory trace is eventually transferred to the cortex. We have investigated transcriptional activation of pathways related to cognitive function in the cortex of the aged mouse by analyzing gene expression following water maze training.</p> <p>Results</p> <p>We identified genes that were differentially responsive in aged mice with accurate spatial performance during probe trials or repeated swimming sessions, relative to home cage conditions. Effective learners exhibited significantly greater activation of several pathways, such as the mitogen-activated protein kinase and insulin receptor signaling pathways, relative to swimmers. The genes encoding activity-related cytoskeletal protein (Arc) and brain-derived neurotrophic factor (BDNF) were upregulated in proficient learners, relative to swimmers and home cage controls, while the gene encoding Rho GTPase activating protein 32 (GRIT) was downregulated. We explored the regulation of Arc, BDNF, and GRIT expression in greater morphological detail using in situ hybridization. Recall during probe trials enhanced Arc expression across multiple cortical regions involved in the cognitive component of water maze learning, while BDNF expression was more homogeneously upregulated across cortical regions involved in the associational and sensorimotor aspects of water maze training. In contrast, levels of GRIT expression were uniformly reduced across all cortical regions examined.</p> <p>Conclusions</p> <p>These results suggest that cortical gene transcription is responsive to learning in aged mice that exhibit behavioral proficiency, and support a distributed hypothesis of memory storage across multiple cortical compartments.</p

Changes in Brain Neuroimmunology Following Injury and Disease

The nervous and immune systems are intimately related in the brain and in the periphery, where changes to one affect the other and vice-versa. Immune cells are responsible for sculpting and pruning neuronal synapses, and play key roles in neuro-development and neurological disease pathology. The immune composition of the brain is tightly regulated from the periphery through the blood-brain barrier (BBB), whose maintenance is driven to a significant extent by extracellular matrix (ECM) components. After a brain insult, the BBB can become disrupted and the composition of the ECM can change. These changes, and the resulting immune infiltration, can have detrimental effects on neurophysiology and are the hallmarks of several diseases. In this review, we discuss some processes that may occur after insult, and potential consequences to brain neuroimmunology and disease progression. We then highlight future research directions and opportunities for further tool development to probe the neuro-immune interface.</jats:p

Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons

Many organ systems are adversely affected by diabetes, including the brain, which undergoes changes that may increase the risk of cognitive decline. Although diabetes influences the hypothalamic-pituitary-adrenal axis, the role of this neuroendocrine system in diabetes-induced cognitive dysfunction remains unexplored. Here we demonstrate that, in both insulin-deficient rats and insulin-resistant mice, diabetes impairs hippocampus-dependent memory, perforant path synaptic plasticity and adult neurogenesis, and the adrenal steroid corticosterone contributes to these adverse effects. Rats treated with streptozocin have reduced insulin and show hyperglycemia, increased corticosterone, and impairments in hippocampal neurogenesis, synaptic plasticity and learning. Similar deficits are observed in db/db mice, which are characterized by insulin resistance, elevated corticosterone and obesity. Changes in hippocampal plasticity and function in both models are reversed when normal physiological levels of corticosterone are maintained, suggesting that cognitive impairment in diabetes may result from glucocorticoid-mediated deficits in neurogenesis and synaptic plasticity