Microglia Drive Pockets of Neuroinflammation in Middle Age.

During aging, microglia produce inflammatory factors, show reduced tissue surveillance, altered interactions with synapses, and prolonged responses to CNS insults, positioning these cells to have profound impact on the function of nearby neurons. We and others recently showed that microglial attributes differ significantly across brain regions in young adult mice. However, the degree to which microglial properties vary during aging is largely unexplored. Here, we analyze and manipulate microglial aging within the basal ganglia, brain circuits that exhibit prominent regional microglial heterogeneity and where neurons are vulnerable to functional decline and neurodegenerative disease. In male and female mice, we demonstrate that VTA and SNc microglia exhibit unique and premature responses to aging, compared with cortex and NAc microglia. This is associated with localized VTA/SNc neuroinflammation that may compromise synaptic function as early as middle age. Surprisingly, systemic inflammation, local neuron death, and astrocyte aging do not appear to underlie these early aging responses of VTA and SNc microglia. Instead, we found that microglial lysosome status was tightly linked to early aging of VTA microglia. Microglial ablation/repopulation normalized VTA microglial lysosome swelling and suppressed increases in VTA microglial density during aging. In contrast, CX3CR1 receptor KO exacerbated VTA microglial lysosome rearrangements and VTA microglial proliferation during aging. Our findings reveal a previously unappreciated regional variation in onset and magnitude of microglial proliferation and inflammatory factor production during aging and highlight critical links between microglial lysosome status and local microglial responses to aging.SIGNIFICANCE STATEMENT Microglia are CNS cells that are equipped to regulate neuronal health and function throughout the lifespan. We reveal that microglia in select brain regions begin to proliferate and produce inflammatory factors in late middle age, months before microglia in other brain regions. These findings demonstrate that CNS neuroinflammation during aging is not uniform. Moreover, they raise the possibility that local microglial responses to aging play a critical role in determining which populations of neurons are most vulnerable to functional decline and neurodegenerative disease.

Reduced perineuronal net expression in Fmr1 KO mice auditory cortex and amygdala is linked to impaired fear-associated memory.

Fragile X Syndrome (FXS) is a leading cause of heritable intellectual disability and autism. Humans with FXS show anxiety, sensory hypersensitivity and impaired learning. The mechanisms of learning impairments can be studied in the mouse model of FXS, the Fmr1 KO mouse, using tone-associated fear memory paradigms. Our previous study reported impaired development of parvalbumin (PV) positive interneurons and perineuronal nets (PNN) in the auditory cortex of Fmr1 KO mice. A recent study suggested PNN dynamics in the auditory cortex following tone-shock association is necessary for fear expression. Together these data suggest that abnormal PNN regulation may underlie tone-fear association learning deficits in Fmr1 KO mice. We tested this hypothesis by quantifying PV and PNN expression in the amygdala, hippocampus and auditory cortex of Fmr1 KO mice following fear conditioning. We found impaired tone-associated memory formation in Fmr1 KO mice. This was paralleled by impaired learning-associated regulation of PNNs in the superficial layers of auditory cortex in Fmr1 KO mice. PV cell density decreased in the auditory cortex in response to fear conditioning in both WT and Fmr1 KO mice. Learning-induced increase of PV expression in the CA3 hippocampus was only observed in WT mice. We also found reduced PNN density in the amygdala and auditory cortex of Fmr1 KO mice in all conditions, as well as reduced PNN intensity in CA2 hippocampus. There was a positive correlation between tone-associated memory and PNN density in the amygdala and auditory cortex, consistent with a tone-association deficit. Altogether our studies suggest a link between impaired PV and PNN regulation within specific regions of the fear conditioning circuit and impaired tone memory formation in Fmr1 KO mice.

The role of physico-chemical interactions in the seasonality of toxic dinoflagellate cyst assemblages: The case of the NW Patagonian fjords system.

Harmful algal blooms (HABs) are recurrent in the NW Patagonia fjords system and their frequency has increased over the last few decades. Outbreaks of HAB species such as Alexandrium catenella, a causal agent of paralytic shellfish poisoning, and Protoceratium reticulatum, a yessotoxins producer, have raised considerable concern due to their adverse socioeconomic consequences. Monitoring programs have mainly focused on their planktonic stages, but since these species produce benthic resting cysts, the factors influencing cyst distributions are increasingly gaining recognition as potentially important to HAB recurrence in some regions. Still, a holistic understanding of the physico-chemical conditions influencing cyst distribution in this region is lacking, especially as it relates to seasonal changes in drivers of cyst distributions, as the characteristics that favor cyst preservation in the sediment may change through the seasons. In this study, we analyzed the physico-chemical properties of the sediment (temperature, pH, redox potential) and measured the bottom dissolved oxygen levels in a "hotspot" area of southern Chile, sampling during the spring and summer as well as the fall and winter, to determine the role these factors may play as modulators of dinoflagellate cyst distribution, and specifically for the cysts of A. catenella and P. reticulatum. A permutational analysis of variance (PERMANOVA) showed the significant effect of sediment redox conditions in explaining the differences in the cyst assemblages between spring-summer and fall-winter periods (seasonality). In a generalized linear model (GLM), sediment redox potential and pH were associated with the highest abundances of A. catenella resting cysts in the spring-summer, however it was sediment temperature that most explained the distribution of A. catenella in the fall-winter. For P. reticulatum, only spring-summer sediment redox potential and temperature explained the variation in cyst abundances. The implications of environmental (physico-chemical) seasonality for the resting cysts dynamics of both species are discussed.

Effects of developmental noise exposure on inhibitory cell densities and perineuronal nets in A1 and AAF of mice.

Within the auditory cortex, there are two primary-like regions considered to be 'core' cortical fields, the primary auditory cortex (A1) and the anterior auditory field (AAF). Both fields have sharp frequency tuning, tonotopic organization, and inputs from the ventral division of the medial geniculate body of the thalamus. AAF seems to be more specialized for faster spectrotemporal processing than A1, but the underlying mechanisms are unclear. A1 has been studied extensively in developmental plasticity, but how AAF changes with developmental experience is less clear. To address potential cellular correlates of processing differences between the two fields, we used immunohistochemistry to quantify the density of GABA, parvalbumin (PV), and somatostatin (SOM) cells in A1 and AAF of mice. We also compared the density of perineuronal nets (PNN) between A1 and AAF. PNNs are a specialized assembly of extracellular matrix involved in network maturation and plasticity. Finally, we compared the effects of developmental noise exposure on inhibitory and PNN cell density in these two core regions. In adult mice, there were more PV cells and PNNs surrounding cell bodies in AAF than in A1. Moderate level noise exposure during early development leads to 1) increased GABA and SOM cell density in both A1 and AAF, and 2) decreased PNN cell density in A1, but not AAF. Inhibitory cells without PNN appear to be more susceptible to changes following developmental noise exposure in both fields. Deep layers (5/6) are more susceptible to change in PNN density compared to superficial layers (1-4) of A1. Results are consistent with altered cortical gain control models and impaired maturation of cortex in response to noisy environments, and suggest that PNNs may be more prone to modification in A1 than AAF.

Revisión Bibliográfica: Disfunción Eréctil y Enfermedad Periodontal / literature Review: Erectile Dysfunction and Periodontal Disease

La asociación entre Enfermedad Periodontal y Disfunción Eréctil se ha estudiado limitadamente. Sin embargo, hoy en día los estudios disponibles han reportado una posible asociación en base a factores de riesgo compartidos entre ambas patologías, pero fundamentalmente se atribuye la asociación al fenómeno de disfunción endotelial que se vincula con ambas enfermedades. Se ha propuesto que la enfermedad periodontal crónica puede inducir una respuesta inflamatoria sistémica que resulta en el deterioro de las condiciones fisiológicas y bioquímicas del endotelio generando disfunción endotelial. Por otro lado, se reconoce a la disfunción eréctil como una enfermedad de origen multifactorial, en la que prevalece la condición vasculogénica como el factor etiológico más frecuente, esto atribuido a un defecto vascular (disfunción endotelial). Es así como el punto de enlace más fuerte es la alteración de la función vascular, que sin duda demuestra argumento sólido de asociación entre las dos enfermedades. El objetivo de esta revisión bibliográfica es informar sobre los posibles mecanismos de asociación entre enfermedad periodontal y disfunción eréctil, enfocándose en el proceso de disfunción endotelial como el principal vínculo existente.(au)

The association between periodontal disease and erectile dysfunction has not been sufficiently studied. However, recent studies have reported a possible link based on mutually shared risks factors between both pathologies, but the association is fundamentally attributed to endothelial dysfunction, phenomenon that is related to both diseases. It has been suggested that chronic periodontal disease can induce systemic inflammatory response that results in deterioration of the physiological and biochemical conditions of the endothelium causing endothelial dysfunction. On the other hand, erectile dysfunction is a multifactorial disease, but the vasculogenic factor is considered as the most frequent one, attributed to a vascular defect (endothelial dysfunction). So, the strongest link is the vascular function alteration, which undoubtedly demonstrates demonstrates a solid argument of association between both diseases. The objective of this literature review is to report the possible mechanisms of association between periodontal disease and erectile dysfunction, focusing mainly on endothelial dysfunction as the main existing link.(au)