Cognitive Reserve in Model Systems for Mechanistic Discovery: The Importance of Longitudinal Studies.

The goal of this review article is to provide a resource for longitudinal studies, using animal models, directed at understanding and modifying the relationship between cognition and brain structure and function throughout life. We propose that forthcoming longitudinal studies will build upon a wealth of knowledge gleaned from prior cross-sectional designs to identify early predictors of variability in cognitive function during aging, and characterize fundamental neurobiological mechanisms that underlie the vulnerability to, and the trajectory of, cognitive decline. Finally, we present examples of biological measures that may differentiate mechanisms of the cognitive reserve at the molecular, cellular, and network level

Cognitive reserve in model systems for mechanistic discovery: importance of longitudinal studies

The goal of this review article is to provide a resource for longitudinal studies, using animal models, directed at understanding and modifying the relationship between cognition and brain structure and function throughout life. We propose that forthcoming longitudinal studies will build upon a wealth of knowledge gleaned from prior cross-sectional designs to identify early predictors of variability in cognitive function during aging, and characterize fundamental neurobiological mechanisms that underlie the vulnerability to, and the trajectory of, cognitive decline. Finally, we present examples of biological measures that may differentiate mechanisms of the cognitive reserve at the molecular, cellular, and network level

A Ketogenic Diet Improves Cognition and Has Biochemical Effects in Prefrontal Cortex That Are Dissociable From Hippocampus

Age-related cognitive decline has been linked to a diverse set of neurobiological mechanisms, including bidirectional changes in proteins critical for neuron function. Importantly, these alterations are not uniform across the brain. For example, the hippocampus (HPC) and prefrontal cortex (PFC) show distinct patterns of dysfunction in advanced age. Because higher cognitive functions require large–scale interactions across prefrontal cortical and hippocampal networks, selectively targeting an alteration within one region may not broadly restore function to improve cognition. One mechanism for decline that the PFC and HPC share, however, is a reduced ability to utilize glucose for energy metabolism. Although this suggests that therapeutic strategies bypassing the need for neuronal glycolysis may be beneficial for treating cognitive aging, this approach has not been empirically tested. Thus, the current study used a ketogenic diet (KD) as a global metabolic strategy for improving brain function in young and aged rats. After 12 weeks, rats were trained to perform a spatial alternation task through an asymmetrical maze, in which one arm was closed and the other was open. Both young and aged KD-fed rats showed resilience against the anxiogenic open arm, training to alternation criterion performance faster than control animals. Following alternation testing, rats were trained to perform a cognitive dual task that required working memory while simultaneously performing a bi-conditional association task (WM/BAT), which requires PFC–HPC interactions. All KD-fed rats also demonstrated improved performance on WM/BAT. At the completion of behavioral testing, tissue punches were collected from the PFC for biochemical analysis. KD-fed rats had biochemical alterations within PFC that were dissociable from previous results in the HPC. Specifically, MCT1 and MCT4, which transport ketone bodies, were significantly increased in KD-fed rats compared to controls. GLUT1, which transports glucose across the blood brain barrier, was decreased in KD-fed rats. Contrary to previous observations within the HPC, the vesicular glutamate transporter (VGLUT1) did not change with age or diet within the PFC. The vesicular GABA transporter (VGAT), however, was increased within PFC similar to HPC. These data suggest that KDs could be optimal for enhancing large-scale network function that is critical for higher cognition

Regionally Distinct Responses of Microglia and Glial Progenitor Cells to Whole Brain Irradiation in Adult and Aging Rats

<div><p>Radiation therapy has proven efficacy for treating brain tumors and metastases. Higher doses and larger treatment fields increase the probability of eliminating neoplasms and preventing reoccurrence, but dose and field are limited by damage to normal tissues. Normal tissue injury is greatest during development and in populations of proliferating cells but also occurs in adults and older individuals and in non-proliferative cell populations. To better understand radiation-induced normal tissue injury and how it may be affected by aging, we exposed young adult, middle-aged, and old rats to 10 Gy of whole brain irradiation and assessed in gray- and white matter the responses of microglia, the primary cellular mediators of radiation-induced neuroinflammation, and oligodendrocyte precursor cells, the largest population of proliferating cells in the adult brain. We found that aging and/or irradiation caused only a few microglia to transition to the classically “activated” phenotype, e.g., enlarged cell body, few processes, and markers of phagocytosis, that is seen following more damaging neural insults. Microglial changes in response to aging and irradiation were relatively modest and three markers of reactivity - morphology, proliferation, and expression of the lysosomal marker CD68- were regulated largely independently within individual cells. Proliferation of oligodendrocyte precursors did not appear to be altered during normal aging but increased following irradiation. The impacts of irradiation and aging on both microglia and oligodendrocyte precursors were heterogeneous between white- and gray matter and among regions of gray matter, indicating that there are regional regulators of the neural response to brain irradiation. By several measures, the CA3 region of the hippocampus appeared to be differentially sensitive to effects of aging and irradiation. The changes assessed here likely contribute to injury following inflammatory challenges like brain irradiation and represent important end-points for analysis in studies of therapeutic strategies to protect patients from neural dysfunction.</p> </div

Density and fraction of proliferating microglia.

<p>A, B. Density and percentage, respectively, of Iba1⁺ cells expressing Ki-67 in normally aging rats in the young adult (open bars), middle-aged (light gray bars) and old (dark gray bars) groups (values combined for sham irradiated, control rats of each age from the 1- and 10-week survival groups). Mean values (+sem) are indicated. Results of post-hoc comparisons are indicated as described for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052728#pone-0052728-g002" target="_blank">Figure 2</a>. C–F. WBI-induced changes in the density and percentage of Iba1⁺ cells expressing Ki-67 at 1 (C, D) and 10 (E, F) weeks after WBI. Asterisks indicate that the mean for irradiated animals was significantly different from that for age-matched, sham irradiated controls.</p

Density and fraction of ED1⁺ microglia.

<p>A, B. Density of ED1⁺ cells (A) and estimated percentage of Iba1⁺ cells expressing ED1 antigen (B) in normally aging rats in the young adult (open bars), middle-aged (light gray bars) and old (dark gray bars) groups (values combined for sham irradiated, control rats of each age from the 1- and 10-week survival groups). Mean values (+sem) are indicated. Results of post-hoc comparisons are indicated as described for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052728#pone-0052728-g002" target="_blank">Figure 2</a>. C–F. WBI-induced changes in the density and percentage of ED1⁺ microglia at 1 (C, D) and 10 (E, F) weeks after WBI. Mean values (+sem) are indicated. Asterisks indicate that the mean for irradiated animals was significantly different from that for age-matched, sham irradiated controls.</p

Results of two-way ANOVAs testing for effects of age and region on the WBI-induced change in each dependent variable (results of post-hoc tests provided in Figures 2, 3, 6 and 7).

<p>Results of two-way ANOVAs testing for effects of age and region on the WBI-induced change in each dependent variable (results of post-hoc tests provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052728#pone-0052728-g002" target="_blank">Figures 2</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052728#pone-0052728-g003" target="_blank">3</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052728#pone-0052728-g006" target="_blank">6</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052728#pone-0052728-g007" target="_blank">7</a>).</p

IHC labeling with ED1.

<p>Images illustrating ED1 labeling in the CC and CA1 (A, B) and CA3 (C, D) of young adult, middle-aged and old rats following sham irradiation (A, C) or at 1 week after WBI (B, D), Scale bar = 250 µm.</p

Results of two-way ANOVAs testing for effects of age and region on baseline measures of each dependent variable in sham irradiated, control rats (results of post-hoc tests provided in Figures 2, 3, 6 and 7).

<p>Results of two-way ANOVAs testing for effects of age and region on baseline measures of each dependent variable in sham irradiated, control rats (results of post-hoc tests provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052728#pone-0052728-g002" target="_blank">Figures 2</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052728#pone-0052728-g003" target="_blank">3</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052728#pone-0052728-g006" target="_blank">6</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052728#pone-0052728-g007" target="_blank">7</a>).</p