Plastic changes that increase nociceptive transmission are observed in several brain regions under conditions of chronic pain. Synaptic plasticity in the anterior cingulate cortex (ACC) is particularly associated with neuropathic pain. Glial cells are considered candidates for the modulation of neural plastic changes in the central nervous system. In this study, we aimed to investigate the role of ACC glial cells in the development of neuropathic pain. First, we examined the expression of glial cells in the ACC of nerve-ligated mice. The expression of astrocytes and microglia was increased in the ACC of nerve-ligated mice, which was reversed by intracerebroventricular (i.c.v) treatment with the microglia inhibitor minocycline. Then, we examined the effect of minocycline on mechanical allodynia in nerve-ligated mice. I.c.v. and intra-ACC treatment with minocycline partially inhibited mechanical allodynia in the nerve-ligated mice. The expression of phosphorylated alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR1 subunit at Ser831, but not at Ser845, was increased in the ACC of the nerve-ligated mice compared to sham-operated mice, which was attenuated by minocycline administration. These results suggest that the activation of microglia in the ACC is involved in the development of hyperalgesia in mice with neuropathic pain.

Although the etiology of major depressive disorder remains poorly understood, reduced gamma oscillations is an emerging biomarker. Olfactory bulbectomy, an established model of depression that reduces limbic gamma oscillations, suffers from non-specific effects of structural damage. Here, we show that transient functional suppression of olfactory bulb neurons or their piriform cortex efferents decreased gamma oscillation power in limbic areas and induced depression-like behaviors in rodents. Enhancing transmission of gamma oscillations from olfactory bulb to limbic structures by closed-loop electrical neuromodulation alleviated these behaviors. By contrast, silencing gamma transmission by anti-phase closed-loop stimulation strengthened depression-like behaviors in naive animals. These induced behaviors were neutralized by ketamine treatment that restored limbic gamma power. Taken together, our results reveal a causal link between limbic gamma oscillations and depression-like behaviors in rodents. Interfering with these endogenous rhythms can affect behaviors in rodent models of depression, suggesting that restoring gamma oscillations may alleviate depressive symptoms.

The effect of diabetes on the emotional behavior of mice was examined using an automatic hole-board apparatus. Changes in the emotional state of mice were evaluated in terms of changes in exploratory activity; i.e., total locomotor activity, numbers and duration of rearing and head-dipping, and latency to the first head-dipping. The number and duration of head-dipping in diabetic mice were less than those in non-diabetic mice. Diazepam (0.1 - 0.56 mg/kg, i.p.) dose-dependently increased the number and duration of head-dipping at doses that did not produce sedation in both diabetic and non-diabetic mice. In contrast, methyl-β-carboline-3-carboxylate (1 and 2 mg/kg, i.p.) decreased the number and duration of head-dipping in non-diabetic mice, but not in diabetic mice. The number and duration of head-dipping in diabetic mice were increased by treatment with flumazenil (0.1 and 0.3 mg/kg, i.v.). These doses of flumazenil did not affect the number or duration of head-dipping in non-diabetic mice. The present data indicate that diabetic mice exhibited anxiety in the hole-board test and that a benzodiazepine receptor antagonist affected the attenuated number and duration of head-dipping in diabetic mice. The heightened anxiety in diabetic mice may be due to the dysfunction of the benzodiazepine receptor and/or of central inhibitory systems.