The purinergic P2X7 receptor is a key mediator in (neuro)inflammation, a process that is associated with neurodegeneration and excitotoxicity in Parkinson’s disease (PD). Recently, P2X7 imaging has become possible with [ 11 C]JNJ-(54173)717. We investigated P2X7 availability, in comparison with availability of the translocator protein (TSPO), in two well-characterized rat models of PD using in vitro autoradiography at multiple time points throughout the disease progression. Rats received either a unilateral injection with 6-hydroxydopamine (6-OHDA) in the striatum, or with recombinant adeno-associated viral vector overexpressing human A53T alpha-synuclein (α-SYN) in the substantia nigra. Transverse cryosections were incubated with [ 11 C]JNJ-717 for P2X7 or [ 18 F]DPA-714 for TSPO. [ 11 C]JNJ-717 binding ratios were transiently elevated in the striatum of 6-OHDA rats at day 14–28 post-injection, with peak P2X7 binding at day 14. This largely coincided with the time course of striatal [ 18 F]DPA-714 binding which was elevated at day 7–21, with peak TSPO binding at day 7. Increased P2X7 availability co-localized with microglial, but not astrocyte or neuronal markers. In the chronic α-SYN model, no significant differences were found in P2X7 binding, although in vitro TSPO overexpression was reported previously. This first study showed an increased P2X7 availability in the acute PD model in a time window corresponding with elevated TSPO binding and motor behavior changes. In contrast, the dynamics of TSPO and P2X7 were divergent in the chronic α-SYN model where no P2X7 changes were detectable. Overall, extended P2X7 phenotyping is warranted prior to implementation of P2X7 imaging for monitoring of neuroinflammation.
Abnormalities of adrenal gland function have been described in survivors of prolonged critical illness, but whether an acute inflammatory illness such as sepsis causes lasting changes in adrenal function is unknown. Critically ill patients with sepsis are often treated with high doses of corticosteroids for their vasoactive properties, which may also affect adrenal function. To examine the effect of sepsis and corticosteroid treatment on adrenal function, we used a naturalistic mouse model of sepsis, cecal ligation and puncture (CLP). Male and female C57Bl/6 mice (N = 20 per group, 10 male/10 female) underwent CLP or sham surgery and were treated with daily injections of either corticosterone (13 mg/kg) or vehicle for five days. Mice were maintained on a 14:10 light-dark cycle with lights on at 6 AM. Three weeks after surgery, mice were sacrificed at baseline (between 9:00 and 12:00) or after stress (6-minute swim) and blood collected for hormone measurements. Adrenal weights, adrenal gland histology, and gene expression analysis were performed on a subset of mice. The results showed that female mice had higher adrenal weights and higher plasma corticosterone, but lower plasma ACTH, when compared to males. Corticosterone and CLP had sex-dependent effects on adrenal function. Specifically, corticosterone-treated male sepsis survivors had higher morning ACTH/corticosterone ratios than the other groups without any difference in stress ACTH/corticosterone, and this group had heavier adrenal weights. These findings were not explained by adrenal histology. Gene expression analysis of male adrenals showed that corticosterone treatment increased adrenal expression of Sonic Hedgehog, Disabled-2, and COUP-TF in the sham mice, but this effect was absent in sepsis survivors. We conclude that corticosterone treatment during sepsis causes a defect in adrenal function after recovery only in males. The increased ACTH/corticosterone ratio suggests a compensatory increase in pituitary activity, while the gene expression analysis shows an absence of the normal recovery process from corticosterone treatment in the sepsis survivors. These novel findings could have clinical implications for the maintenance of appropriate adrenal function after corticosteroid treatment during acute illness. This work was supported by grants from the NIMH, NIDDK, Office of Naval Research, Hope for Depression Research Foundation, and the Brain and Behavior Research Foundation.
Stress hormone signaling via the glucocorticoid receptor (GR) modulates vulnerability to stress-related disorders, but whether GR influences how the brain encodes contextual experience is unknown. Mice with lifelong GR overexpression in forebrain glutamatergic neurons (GRov) show increased sensitivity to environmental stimuli. This phenotype is developmentally programmed and associated with profound changes in hippocampal gene expression. We hypothesized that GR overexpression influences hippocampal encoding of experiences. To test our hypothesis, we performed in vivo microendoscopic calcium imaging of 1359 dorsal CA1 pyramidal cells in freely behaving male and female WT and GRov mice during exploration of a novel open field. We compared calcium amplitude and event rate as well as sensitivity to center location and mobility between genotypes. GRov neurons exhibited higher average calcium activity than WT neurons in the novel open field. While most neurons showed sensitivity to center location and/or mobility, GRov neurons were more likely to be sensitive to center location and less likely to be sensitive to mobility, as compared to WT neurons. More than one-third of behavior-selective GRov neurons were uniquely sensitive to location without mobility sensitivity; these uniquely center-sensitive neurons were rare in WT. We conclude that dorsal CA1 pyramidal cells in GRov mice show increased activity in a novel environment and preferentially encode emotionally salient behavior. This heightened sensitivity to a novel environment and preferential encoding of emotionally salient elements of experience could underlie differential stress vulnerability in humans with increased glucocorticoid sensitivity.
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