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Fluoxetine (Flx), a selective serotonin reuptake inhibitor, is extensively used to treat mood and anxiety disorders. Previous animal studies have shown that early-life exposure to Flx results in long-lasting behavioral alterations and neuroplasticity in the hippocampus and cortex, which may persist into adulthood. It remains unclear whether repeated Flx treatment in normal adult animals can induce lasting neuroplasticity and behavioral alterations persisting long beyond the treatment period. In this study, young adult rats (about 9 weeks old) were treated with Flx (10 mg/kg body weight, twice daily) for 15 consecutive days, and the effects of Flx on medial prefrontal cortex (mPFC) neuroplasticity and mPFC-related behaviors were assessed 20 days after the last injection. It was observed that the mPFC of Flx-treated rats had significant increases in the number of 5-bromodeoxyuridine-positive (BrdU+) cells, dendritic complexity/spine density in layer II/III pyramidal neurons, and brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) expression levels, as well as a significant decrease in the number of parvalbumin-positive (PV+) interneurons. The Flx-treated rats exhibited higher motivation to explore new environments, evidenced by a significantly increased number of entries into the novel arm in the Y-maze test. However, they did not show any significant changes in the anhedonia and anxiety levels measured by sucrose preference and elevated plus maze tests respectively. In conclusion, repeated Flx treatment, with the paradigm used, induces long-lasting neuroplastic changes in the mPFC of normal adult rats; such changes and related behavioral manifestations may persist up to 20 days after the last dose.

NMDAR antagonist treatments in adolescent/young adult rodents are associated with augmented glutamate (Glu) release and perturbed Glu/glutamine (Gln) metabolism in the medial prefrontal cortex (mPFC) resembling those found in first-episode schizophrenia. Few studies, however, investigated NMDAR antagonist-induced changes in the adult mPFC and whether there is an age-dependence to this end. In this study, the effects of acute/repeated (+)-MK801 treatment on Glu release/metabolism were measured in the mPFC of male adolescent (postnatal day 30) and adult (14 weeks) rats. Acute (+)-MK801 treatment at 0.5 mg/kg body weight induced an approximately 4-fold increase of extracellular Glu concentration in the adolescent rats, and repeated treatment for 6 consecutive days significantly increased the levels of Glu + Gln (Glx) and glial metabolites 7 days after the last dose. Histologically (+)-MK801 treatments induced reactive astrocytosis and elevated oxidative stress in the mPFC of adolescent rats, without causing evident neuronal degeneration in the region. All (+)-MK801-induced changes observed in the mPFC of adolescent rats were not present or evident in the adult rats, suggesting that the treatments might have caused less disinhibition in the adult mPFC than in the adolescent mPFC. In conclusion, the effects of (+)-MK801 treatments on the Glu release/metabolism in the mPFC were found to be age-dependent; and the adult mPFC is likely equipped with more robust neurobiological mechanisms to preserve excitatory-inhibitory balance in response to NMDAR hypofunction.

We established hypoglycemic rat models and divided them into three groups (the sham group, the acute hypoglycemia group and the recovery group). The brain water diffusion was examined using DWI. Thereafter, neuropathologic examinations were performed in order to evaluate the distribution of brain damage. The expression of AQP4 and Caspase3 was also examined using Western blot. We aimed to determine the specific brain regions which were vulnerable to hypoglycemia in relation to the water diffusion and neuropathology. The DWI scanning showed abnormal water diffusion in the cortex, hippocampus and hypothalamus during each stage of hypoglycemia. In the acute hypoglycemia group, the apparent diffusion coefficient (ADC) of the dentate gyrus (DG) and the hypothalamus was increased, while the ADC of the somatosensory cortex (SSc), subcortex and striatum (Str) was decreased. After glucose reperfusion and a 7-day recovery period, most of the hypoglycemia-induced changes in ADC returned to normal, except in the hypothalamus, posterior SSc and DG, which demonstrated increased ADC levels. The lowest AQP4 expression was observed in the cortex of the acute hypoglycemia group. Furthermore, there was increased Caspase3 expression in the hippocampus of the recovery group. The expression of Caspase3 in the hypothalamus was most prominent in the acute hypoglycemia group. Our work revealed that hypoglycemia significantly influenced the water diffusion of the brain. The decrease of AQP4 was associated with the formation of cytotoxic edema in acute hypoglycemia. Hypoglycemia primarily tends to damage the cerebral cortex, hippocampus and hypothalamus and may result in permanent injury to the brain.

Fluoxetine (Flx)-induced neuronal plasticity plays an important role in the effective treatment of depression and mood disorders. It is less understood whether repeated Flx treatment induces astrocytic plasticity that outlasts the presence of the drug in the body. We showed previously that Flx-induced neuronal plasticity in the medial prefrontal cortex (mPFC) persisted up to 20 days after the treatment. In this study, adult rats were subjected to a 15-day repeated Flx treatment at a daily dose of 20 mg/kg body weight. Astrocytic metabolites and markers were assessed in the mPFC at day 1 (d1) and day 20 (d20) after the treatment. Significant transient reductions in the concentrations of astrocytic metabolites taurine and myo-inositol and the expressions of glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQP4) were observed in the mPFC of Flx-treated rats at d1, which recovered to the control levels at d20. Further, Flx treatment resulted in long-lasting changes in Kir4.1 expression in the mPFC, which remained downregulated at d20. The expression of 5-HT1A receptor in the mPFC of Flx-treated rats was downregulated at d1 but became upregulated at d20. In summary, repeated Flx treatment induces both transient and long-term astrocytic plasticity in the mPFC of adult rats. The changes observed at d1 are consistent with disturbed water homeostasis and astrocytic de-maturation in the mPFC. The persistent changes in the expressions of Kir4.1 and 5-HT1A at d20, presumably of the astrocytic origin, might have contributed to the long-term neurotrophic effects of repeated Flx treatment in the mPFC.

Many neurological/psychiatric disorders are associated with metabolic abnormalities in the brain observable with in vivo proton MRS (1 H-MRS). The underlying molecular/cellular mechanisms and functional correlations of such metabolic alterations, however, are yet to be understood fully. The rodent prefrontal cortex (PFC) is comprised of multiple sub-regions with distinctive cytoarchitecture and functions, providing a good model system to study the correlations among cerebral metabolism, regional cytoarchitecture and connectivity. In this study, the metabolic profiles in two voxels containing mainly the medial PFC (mPFC) and posterior part of the cingulate cortex (pCG), respectively, were measured with single-voxel in vivo 1 H-MRS in adult male rats. The levels of glutamine synthetase and glutamatergic synaptic proteins, including vesicular glutamate transporter 1, vesicular glutamate transporter 2 (VGLUT2) and post-synaptic density protein 95 (PSD95), as well as the density of astrocytes, in these two regions were also compared semi-quantitatively. It was shown that, relative to the pCG voxel, the mPFC voxel had significantly higher N-acetyl aspartate, glutamate (Glu), glutamine (Gln), Glx (Glu + Gln), myo-inositol and taurine levels. The VGLUT2/PSD95 levels and astrocyte density were also higher in the mPFC voxel than in the pCG voxel. Taken together, these results indicated that regional metabolic variations in the PFC of the adult male rat may reflect regional differences in the density of astrocytes and glutamatergic terminals associated with subcortical projections. The study provided a link between the Glu concentration measured with localized in vivo 1 H-MRS and regional glutamatergic activities/connections in the rat PFC.