@article {49256, title = {Cell-type specific changes in glial morphology and glucocorticoid expression during stress and aging in the medial prefrontal cortex.}, journal = {Frontiers in Aging Neuroscience}, volume = {10}, year = {2018}, month = {2018 May 23}, abstract = {

Repeated exposure to stressors is known to produce large-scale remodeling of neurons within the prefrontal cortex (PFC). Recent work suggests stress-related forms of structural plasticity can interact with aging to drive distinct patterns of pyramidal cell morphological changes. However, little is known about how other cellular components within PFC might be affected by these challenges. Here, we examined the effects of stress exposure and aging on medial prefrontal cortical glial subpopulations. Interestingly, we found no changes in glial morphology with stress exposure but a profound morphological change with aging. Furthermore, we found an upregulation of non-nuclear glucocorticoid receptors (GR) with aging, while nuclear levels remained largely unaffected. Both changes are selective for microglia, with no stress or aging effect found in astrocytes. Lastly, we show that the changes found within microglia inversely correlated with the density of dendritic spines on layer III pyramidal cells. These findings suggest microglia play a selective role in synaptic health within the aging brain.

}, doi = {10.3389/fnagi.2018.00146}, author = {Chan, Thomas E and Grossman, Yael S and Bloss, Erik B and Janssen, William G and Lou, Wendy and McEwen, Bruce S and Dumitriu, Dani and Morrison, John H} } @article {46044, title = {Morphological and molecular changes in aging rat prelimbic prefrontal cortical synapses.}, journal = {Neurobiology of Aging}, volume = {34}, year = {2013}, month = {2013 Jan}, pages = {200-10}, abstract = {

Age-related impairments of executive functions appear to be related to reductions of the number and plasticity of dendritic spine synapses in the prefrontal cortex (PFC). Experimental evidence suggests that synaptic plasticity is mediated by the spine actin cytoskeleton, and a major pathway regulating actin-based plasticity is controlled by phosphorylated LIM kinase (pLIMK). We asked whether aging resulted in altered synaptic density, morphology, and pLIMK expression in the rat prelimbic region of the PFC. Using unbiased electron microscopy, we found an approximate 50\% decrease in the density of small synapses with aging, while the density of large synapses remained unchanged. Postembedding immunogold revealed that pLIMK localized predominantly to the postsynaptic density where it was increased in aging synapses by approximately 50\%. Furthermore, the age-related increase in pLIMK occurred selectively within the largest subset of prelimbic PFC synapses. Because pLIMK is known to inhibit actin filament plasticity, these data support the hypothesis that age-related increases in pLIMK may explain the stability of large synapses at the expense of their plasticity.

}, keywords = {Age Factors, Aging, Analysis of Variance, Animals, Gene Expression Regulation, Lim Kinases, Male, Microscopy, Electron, Transmission, Microscopy, Immunoelectron, Neurons, Post-Synaptic Density, Prefrontal Cortex, Rats, Rats, Sprague-Dawley, Synapses}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2012.05.014}, author = {Bloss, Erik B and Puri, Rishi and Yuk, Frank and Punsoni, Michael and Hara, Yuko and Janssen, William G and McEwen, Bruce S and Morrison, John H} } @article {46045, title = {Clinically relevant hormone treatments fail to induce spinogenesis in prefrontal cortex of aged female rhesus monkeys.}, journal = {Journal of Neuroscience}, volume = {32}, year = {2012}, month = {2012 Aug 22}, pages = {11700-5}, abstract = {

Preclinical animal models have provided strong evidence that estrogen (E) therapy (ET) enhances cognition and induces spinogenesis in neuronal circuits. However, clinical studies have been inconsistent, with some studies revealing adverse effects of ET, including an increased risk of dementia. In an effort to bridge this disconnect between the preclinical and clinical data, we have developed a nonhuman primate (NHP) model of ET combined with high-resolution dendritic spine analysis of dorsolateral prefrontal cortical (dlPFC) neurons. Previously, we reported cyclic ET in aged, ovariectomized NHPs increased spine density on dlPFC neurons. Here, we report that monkeys treated with cyclic E treatment paired with cyclic progesterone (P), continuous E combined with P (either cyclic or continuous), or unopposed continuous E failed to increase spines on dlPFC neurons. Given that the most prevalent form of ET prescribed to women is a combined and continuous E and P, these data bring into convergence the human neuropsychological findings and preclinical neurobiological evidence that standard hormone therapy in women is unlikely to yield the synaptic benefit presumed to underlie the cognitive enhancement reported in animal models.

}, keywords = {Aging, Analysis of Variance, Animals, Dendritic Spines, Estrogens, Female, Macaca mulatta, Microscopy, Confocal, Neurons, Ovariectomy, Prefrontal Cortex, Progesterone}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.1881-12.2012}, author = {Ohm, Daniel T and Bloss, Erik B and Janssen, William G and Dietz, Karen C and Wadsworth, Shannon and Lou, Wendy and Gee, Nancy A and Lasley, Bill L and Rapp, Peter R and Morrison, John H} } @article {46042, title = {Disruption of circadian clocks has ramifications for metabolism, brain, and behavior.}, journal = {Proceedings of the National Academy of Sciences USA}, volume = {108}, year = {2011}, month = {2011 Jan 25}, pages = {1657-62}, abstract = {

Circadian (daily) rhythms are present in almost all plants and animals. In mammals, a brain clock located in the hypothalamic suprachiasmatic nucleus maintains synchrony between environmental light/dark cycles and physiology and behavior. Over the past 100 y, especially with the advent of electric lighting, modern society has resulted in a round-the-clock lifestyle, in which natural connections between rest/activity cycles and environmental light/dark cycles have been degraded or even broken. Instances in which rapid changes to sleep patterns are necessary, such as transmeridian air travel, demonstrate negative effects of acute circadian disruption on physiology and behavior. However, the ramifications of chronic disruption of the circadian clock for mental and physical health are not yet fully understood. By housing mice in 20-h light/dark cycles, incongruous with their endogenous \~{}24-h circadian period, we were able to model the effects of chronic circadian disruption noninvasively. Housing in these conditions results in accelerated weight gain and obesity, as well as changes in metabolic hormones. In the brain, circadian-disrupted mice exhibit a loss of dendritic length and decreased complexity of neurons in the prelimbic prefrontal cortex, a brain region important in executive function and emotional control. Disrupted animals show decreases in cognitive flexibility and changes in emotionality consistent with the changes seen in neural architecture. How our findings translate to humans living and working in chronic circadian disruption is unknown, but we believe that this model can provide a foundation to understand how environmental disruption of circadian rhythms impacts the brain, behavior, and physiology.

}, keywords = {Animals, Behavior, Animal, Biological Clocks, Blood Glucose, Body Temperature, Brain, Circadian Clocks, Circadian Rhythm, Energy Metabolism, Humans, Insulin, Leptin, Male, Maze Learning, Mice, Mice, Inbred C57BL, Motor Activity, Neurons, Photoperiod, Prefrontal Cortex, Weight Gain}, issn = {1091-6490}, doi = {10.1073/pnas.1018375108}, author = {Karatsoreos, Ilia N and Bhagat, Sarah and Bloss, Erik B and Morrison, John H and McEwen, Bruce S} } @article {46043, title = {Evidence for reduced experience-dependent dendritic spine plasticity in the aging prefrontal cortex.}, journal = {Journal of Neuroscience}, volume = {31}, year = {2011}, month = {2011 May 25}, pages = {7831-9}, abstract = {

Cognitive functions that require the prefrontal cortex are highly sensitive to aging in humans, nonhuman primates, and rodents, although the neurobiological correlates of this vulnerability remain largely unknown. It has been proposed that dendritic spines represent the primary site of structural plasticity in the adult brain, and recent data have supported the hypothesis that aging is associated with alterations of dendritic spine morphology and plasticity in prefrontal cortex. However, no study to date has directly examined whether aging alters the capacity for experience-dependent spine plasticity in aging prefrontal neurons. To address this possibility, we used young, middle-aged, and aged rats in a behavioral stress paradigm known to produce spine remodeling in prefrontal cortical neurons. In young rats, stress resulted in dendritic spine loss and altered patterns of spine morphology; in contrast, spines from middle-aged and aged animals were remarkably stable and did not show evidence of remodeling. The loss of stress-induced spine plasticity observed in aging rats occurred alongside robust age-related reductions in spine density and shifts in remaining spine morphology. Together, the data presented here provide the first evidence that experience-dependent spine plasticity is altered by aging in prefrontal cortex, and support a model in which dendritic spines become progressively less plastic in the aging brain.

}, keywords = {Aging, Animals, Cognition, Dendritic Spines, Learning, Male, Neuronal Plasticity, Prefrontal Cortex, Rats, Rats, Sprague-Dawley}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.0839-11.2011}, author = {Bloss, Erik B and Janssen, William G and Ohm, Daniel T and Yuk, Frank J and Wadsworth, Shannon and Saardi, Karl M and McEwen, Bruce S and Morrison, John H} }