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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.

The disconnection of neuronal circuitry through synaptic loss is presumed to be a major driver of age‐related cognitive decline. Age‐related cognitive decline is heterogeneous, yet whether genetic mechanisms differentiate successful from unsuccessful cognitive decline through maintenance or vulnerability of synaptic connections remains unknown. Previous work using rodent and primate models leveraged various techniques to imply that age‐related synaptic loss is widespread on pyramidal cells in prefrontal cortex (PFC) circuits but absent on those in area CA1 of the hippocampus. Here, we examined the effect of aging on synapses on projection neurons forming a hippocampal‐cortico‐thalamic circuit important for spatial working memory tasks from two genetically distinct mouse strains that exhibit susceptibility (C57BL/6J) or resistance (PWK/PhJ) to cognitive decline during aging. Across both strains, synapse density on CA1‐to‐PFC projection neurons appeared completely intact with age. In contrast, we found synapse loss on PFC‐to‐nucleus reuniens (RE) projection neurons from aged C57BL/6J but not PWK/PhJ mice. Moreover, synapses from aged PWK/PhJ mice but not from C57BL/6J exhibited altered morphologies that suggest increased efficiency to drive depolarization in the parent dendrite. Our findings suggest resistance to age‐related cognitive decline results in part by age‐related synaptic adaptations, and identification of these mechanisms in PWK/PhJ mice could uncover new therapeutic targets for promoting successful cognitive aging and extending human health span. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Human data suggest susceptibility and resilience to features of Alzheimer's disease (AD) such as microglia activation and synaptic dysfunction are under genetic control. However, causal relationships between these processes, and how genomic diversity modulates them remain systemically underexplored in mouse models. METHODS: AD‐vulnerable hippocampal neurons were virally labeled in inbred (C57BL/6J) and wild‐derived (PWK/PhJ) APP/PS1 and wild‐type mice, and brain microglia depleted from 4 to 8 months of age. Dendrites were assessed for synapse plasticity changes by evaluating spine densities and morphologies. RESULTS: In C57BL/6J, microglia depletion blocked amyloid‐induced synaptic density and morphology changes. At a finer scale, synaptic morphology on individual branches was dependent on microglia–dendrite physical interactions. Conversely, synapses from PWK/PhJ mice showed remarkable stability in response to amyloid, and no evidence of microglia contact‐dependent changes on dendrites. DISCUSSION: These results demonstrate that microglia‐dependent synaptic alterations in specific AD‐vulnerable projection pathways are differentially controlled by genetic context. [ABSTRACT FROM AUTHOR]

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 neurobi-ological evidence that standard hormone therapy in women is unlikely to yield the synaptic benefit presumed to underlie the cognitive enhancement reported in animal models. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Neuronal networks in the prefrontal cortex mediate the highest levels of cognitive processing and decision making, and the capacity to perform these functions is among the cognitive features most vulnerable to aging. Despite much research, the neurobiological basis of age-related compromised prefrontal function remains elusive. Many investigators have hypothesized that exposure to stress may accelerate cognitive aging, though few studies have directly tested this hypothesis and even fewer have investigated a neuronal basis for such effects. It is known that in young animals, stress causes morphological remodeling of prefrontal pyramidal neurons that is reversible. The present studies sought to determine whether age influences the reversibility of stress-induced morphological plasticity in rat prefrontal neurons. We hypothesized that neocortical structural resilience is compromised in normal aging. To directly test this hypothesis we used a well characterized chronic restraint stress paradigm, with an additional group allowed to recover from the stress paradigm, in 3-, 12-, and 20-month-old male rats. In young animals, stress induced reductions of apical dendritic length and branch number, which were reversed with recovery; in contrast, middle-aged and aged rats failed to show reversible morphological remodeling when subjected to the same stress and recovery paradigm. The data presented here provide evidence that aging is accompanied by selective impairments in long-term neocortical morphological plasticity. [ABSTRACT FROM AUTHOR]

Introduction: Human data suggest susceptibility and resilience to features of Alzheimer's disease (AD) such as microglia activation and synaptic dysfunction are under genetic control. However, causal relationships between these processes, and how genomic diversity modulates them remain systemically underexplored in mouse models., Methods: AD-vulnerable hippocampal neurons were virally labeled in inbred (C57BL/6J) and wild-derived (PWK/PhJ) APP/PS1 and wild-type mice, and brain microglia depleted from 4 to 8 months of age. Dendrites were assessed for synapse plasticity changes by evaluating spine densities and morphologies., Results: In C57BL/6J, microglia depletion blocked amyloid-induced synaptic density and morphology changes. At a finer scale, synaptic morphology on individual branches was dependent on microglia-dendrite physical interactions. Conversely, synapses from PWK/PhJ mice showed remarkable stability in response to amyloid, and no evidence of microglia contact-dependent changes on dendrites., Discussion: These results demonstrate that microglia-dependent synaptic alterations in specific AD-vulnerable projection pathways are differentially controlled by genetic context., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)