Physiological Corticosterone Attenuates gp120-Mediated Microglial Activation and Is Associated with Reduced Anxiety-Like Behavior in gp120-Expressing Mice

Abstract

Despite the benefits of combinatorial antiretroviral therapies (cART), virotoxic HIV proteins are still detectable within the central nervous system. Approximately half of all cART-treated patients contend with neurological impairments. The mechanisms underlying these effects likely involve virotoxic HIV proteins, including glycoprotein 120 (gp120). Glycoprotein-120 is neurotoxic due to its capacity to activate microglia. Corticosterone has been found to attenuate neuronal death caused by gp120-induced microglial cytokine production in vitro. However, the concentration-dependent effects of corticosterone on microglial activation states and the associated behavioral outcomes are unclear. Herein, we conducted parallel in vitro and in vivo studies to assess gp120-mediated effects on microglial activation, motor function, anxiety- and depression-like behavior, and corticosterone's capacity to attenuate these effects. We found that gp120 activated microglia in vitro, and corticosterone attenuated this effect at an optimal concentration of 100 nM. Transgenic mice expressing gp120 demonstrated greater anxiety-like behavior on an elevated plus maze, and a greater duration of gp120 exposure was associated with motor deficits and anxiety-like behavior. Circulating corticosterone was lower in gp120-expressing males and diestrous females. Greater circulating corticosterone was associated with reduced anxiety-like behavior. These findings may demonstrate a capacity for glucocorticoids to attenuate gp120-mediated neuroinflammation and anxiety-like behavior.

Keywords: affective behavior; glucocorticoids; glycoprotein 120; human immunodeficiency virus; microglia.

Figure 1

The proportion of surveillant microglia at 2 h (A), 6 h (B) and 24 h post-treatment (C). The proportion of active/reactive microglia at 2 h (D), 6 h (E) and 24 h post-treatment (F). The proportion of amoeboid/phagocytic microglia at 2 h (G), 6 h (H) and 24 h post-treatment (I). Figure (A,D,G) contain inset representative images of a surveillant, active/reactive, and amoeboid microglia, respectively (scale bare in A = 20 µm). † main effect of incubation time wherein 6 h significantly differs from 2 h; ‡ main effect time wherein the indicated time significantly differs from all other time-points; * main effect for gp120 to significantly differ from media control; § time × gp120 interaction wherein gp120 significantly differs from media control at 6 and 24 h only; ^ main effect of incubation time wherein the indicated time point is significantly different from all other time points; p < 0.05.

Figure 2

The average activation score of microglia at 2 h (A), 6 h (B) and 24 h post-treatment (C) and the mean activation score across all time-points (D). § time × gp120 interaction wherein gp120 significantly differs from media control at 6 and 24 h only; * gp120 × corticosterone interaction wherein gp120-exposure significantly increases activation of all microglia except those exposed to 100 nM corticosterone; p < 0.05.

Figure 3

Mice were behaviorally assessed in an open field (A), light-dark transition task (B), elevated plus maze (C,D) and a tail suspension test (E). Circulating corticosterone was assessed from whole trunk blood (F). * main effect of genotype; + main effect of sex, wherein females are significantly different from males, irrespective of estrous cycle phase; § gp120 × sex interaction, wherein gp120(+) diestrous females and males significantly differ from their respective gp120(−) controls, p < 0.05.

Figure 4

Simple linear regressions between circulating corticosterone among gp120(−) and gp120(+) females and males.