Exposure of male mice to perfluorooctanoic acid induces anxiety-like behaviors by increasing corticotropin-releasing factor in the basolateral amygdala complex.

Perfluorooctanoic acid (PFOA), a hazardous environmental pollutant, has been found to enhance hepatic synthesis of fibroblast growth factor 21 (FGF21). FGF21 can enter the brain and increase the expression of corticotropin-releasing factor (CRF) in the paraventricular nucleus (PVN). In this study, adult male mice were orally administered PFOA to evaluate how it regulates emotion. Exposure of mice to PFOA (1 mg kg-1 bw) for 10 consecutive days (PFOA-mice) caused anxiety-like behaviors and a peroxisome proliferator-activated receptor α (PPARα)-dependent increase in hepatic FGF21 synthesis. The levels of CRF expression in not only PVN but also basolateral amygdala complex (BLA) neurons of PFOA-mice were increased via FGF receptor 1 (FGF-R1) activation. However, the microinjection of FGF-R1 or CRF 1 receptor (CRF-R1) antagonist in the BLA rather than the PVN of PFOA-mice could relieve their anxiety-like behaviors. In addition, external capsule-BLA synaptic transmission in PFOA-mice was enhanced by increasing CRF-R1-mediated presynaptic glutamate release, which was corrected by the blockade of PPARα, FGF-R1 and CRF-R1 or the inhibition of PKA. Furthermore, the threshold of frequency-dependent long-term potentiation (LTP) induction was decreased in the BLA of PFOA-mice, which depended on the activation of PPARα, FGF-R1, CRF-R1, PKA and NMDA receptor (NMDAR), whereas long-term depression (LTD) induction was unchanged. Thus, the results indicate that the exposure of male mice to PFOA (1 mg kg-1 bw) enhances CRF expression in BLA neurons by increasing hepatic FGF21 synthesis, which then enhances CRF-R1-mediated presynaptic glutamate release to facilitate NMDAR-dependent BLA-LTP induction, leading to the production of anxiety-like behaviors.

Attention Impairment During the Interictal State in Migraineurs without Aura: A Cross-Sectional Study.

BACKGROUND AND PURPOSE: Migraine suffering is more than the onset of head pain. The broad non-painful clinical symptoms associated with migraine are not well recognized. Recent researches support that migraineurs suffer attention deficits, but these findings are not conclusive. The purpose of our study was to assess whether patients with migraine without aura (MwoA) during the interictal period have attention impairment and to identify the migraine characteristics related to attention deficits. METHODS: We enrolled subjects with MwoA during the interictal period and healthy controls matched for age, gender, and education level in this cross-sectional study. The attention network test (ANT) and a battery of neuropsychological tests, including the trail-making test (TMT), the digit span test (DST), and the Stroop test, were administered to the participants during the headache-free period. RESULTS: Forty-four subjects with MwoA (4 males, 40 females) and 20 controls matched for age, gender, and literacy education were included. Patients in MwoA were more anxious (P = 0.007) and depressed (P = 0.001) than healthy subjects. Significant differences between the two groups were detected in the executive network (P = 0.006) but not in the alerting and orienting networks of ANT. Mean reaction time of ANT in the MwoA group was significantly longer than that in the control group (P = 0.028). Patients showed worse performance on DST-forward (P < 0.001), DST-backward (P < 0.001), DS Total (P < 0.001), TMT-A (P < 0.001), TMT-B (P < 0.001) and TMT-d (P = 0.002). Differences found in executive functions between the two groups were unrelated to gender, age, literacy, anxiety, and depression. Multiple regression analysis revealed no relation between clinical characteristics of headache and scores on the executive function with MwoA. CONCLUSION: Our study suggested that patients in MwoA present worse performances on the executive control of attention networks during the headache-free period, which appear not be associated with measures of migraine severity. Although more studies are needed in this area, our results could be useful to find specific neuropsychological biomarker for migraine pathophysiology.

Oligomer ß-amyloid Induces Hyperactivation of Ras to Impede NMDA Receptor-Dependent Long-Term Potentiation in Hippocampal CA1 of Mice.

The activity of Ras, a small GTPase protein, is increased in brains with Alzheimer's disease. The objective of this study was to determine the influence of oligomeric Aß1-42 on the activation of Ras, and the involvement of the Ras hyperactivity in Aß1-42-induced deficits in spatial cognition and hippocampal synaptic plasticity. Herein, we show that intracerebroventricular injection of Aß1-42 in mice (Aß-mice) enhanced hippocampal Ras activation and expression, while 60 min incubation of hippocampal slices in Aß1-42 (Aß-slices) only elevated Ras activity. Aß-mice showed deficits in spatial cognition and NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) in hippocampal CA1, but basal synaptic transmission was enhanced. The above effects of Aß1-42 were corrected by the Ras inhibitor farnesylthiosalicylic acid (FTS). ERK2 phosphorylation increased, and Src phosphorylation decreased in Aß-mice and Aß1-42-slices. Both were corrected by FTS. In CA1 pyramidal cells of Aß1-42-slices, the response of AMPA receptor and phosphorylation of GluR1 were enhanced with dependence on Ras activation rather than ERK signaling. In contrast, NMDA receptor (NMDAR) function and GluN2A/2B phosphorylation were downregulated in Aß1-42-slices, which was recovered by application of FTS or the Src activator ouabain, and mimicked in control slices treated with the Src inhibitor PP2. The administration of PP2 impaired the spatial cognition and LTP induction in control mice and FTS-treated Aß-mice. The treatment of Aß-mice with ouabain rescued Aß-impaired spatial cognition and LTP. Overall, the results indicate that the oligomeric Aß1-42 hyperactivates Ras and thereby causes the downregulation of Src which impedes NMDAR-dependent LTP induction resulting in cognitive deficits.

Akt3 deletion in mice impairs spatial cognition and hippocampal CA1 long long-term potentiation through downregulation of mTOR.

AIM: Loss-of-function mutation of Akt3 in humans has been associated with microcephaly and cognitive defects. Two Akt isoforms, Akt1 and Akt3, are highly expressed in hippocampal pyramidal cells. We explored the roles of Akt1 and Akt3, respectively, in spatial cognition and underlying mechanisms. METHODS: We used Akt1 knockout (Akt1-KO) and Akt3 knockout (Akt3-KO) mice to examine the influence of Akt1 and Akt3 deficiency on spatial memory, as well as induction and maintenance of hippocampal CA1 NMDA receptor-dependent and protein synthesis-dependent long-term potentiation (LTP). RESULTS: Long-term spatial memory was impaired in Akt3-KO mice, but not in Akt1-KO mice, as assessed by the Morris water maze task. Akt3-KO and Akt1-KO mice displayed reductions in brain size without concurrent changes in the number of pyramidal cells or basal properties of synaptic transmission. One-train high-frequency stimulation (HFS × 1) induced NMDA receptor-dependent LTP in Akt3-KO mice and Akt1-KO mice. Four-train HFS (HFS × 4) induced rapamycin-sensitive long-LTP in Akt1-KO mice, but not Akt3-KO mice. Basal level of mTOR phosphorylation was reduced in Akt3-KO mice rather than Akt1-KO mice. HFS × 4 induced an elevation of mTOR and p70S6K phosphorylation in Akt1-KO mice, which led to enhanced 4EBP2 and eIF4E phosphorylation along with an increase in AMPA receptor protein. However, the same protocol of HFS × 4 failed to trigger the mTOR-p70S6K signalling cascade or increase 4EBP2 and eIF4E phosphorylation in Akt3-KO mice. CONCLUSION: The Akt3 deficiency via inactivation of mTOR suppresses HFS × 4-induced mTOR-p70S6K signalling to reduce phosphorylation of 4EBP and eIF4E, which impairs protein synthesis-dependent long-LTP and long-term spatial cognitive function.

Abnormal mitochondrial dynamics and impaired mitochondrial biogenesis in trigeminal ganglion neurons in a rat model of migraine.

Accumulating evidence has demonstrated a possible role of mitochondrial dysfunction in migraine pathophysiology. Migraine sufferers exhibit impaired metabolic capacity, with an increased formation of reactive oxygen species (ROS). Mitochondrial dynamics and mitochondrial biogenesis are key processes regulating mitochondrial homeostasis. The aim of this study was to explore the alterations of mitochondrial regulatory networks in a rat model of migraine induced by repeated dural stimulation with inflammatory soup (IS). Ultrastructural, protein, gene and mitochondrial DNA analysis were applied to assess mitochondrial dynamics and biogenesis in trigeminal ganglion (TG) neurons. Mitochondria in TG neurons exhibited small and fragmented morphology after repeated dural stimulation. Further investigations showed that mitochondrial fission protein dynamin-related protein 1 (Drp1) was increased while mitochondrial fusion protein Mitofusin1 (Mfn1) was reduced in TG neurons. In addition, our results also presented that mitochondrial DNA copy number in TG neurons was reduced significantly, accompanied by alterations in mRNA and protein levels of regulatory factors related to mitochondrial biogenesis including peroxisome proliferator-activated receptor-gamma coactivator-1a (PGC-1α) and its downstream regulators in TG neurons in the IS-induced migraine model. These findings suggest that the mitochondrial dynamic regulatory networks are maladjusted in TG neurons in a rat model of migraine. Regulation of mitochondrial dynamics and biogenesis signaling may indicate a new mitochondria-targeted therapeutic strategy for migraine.

Na+/HCO3- cotransporter is expressed on ß and α cells during rat pancreatic development.

AIM: To determine the expression and localization of the electrogenic Na+/HCO3- cotransporter (NBC1) in rat pancreas during development. METHODS: The rat pancreas from postnatal and embryos removed from the uterus of pregnant rats that had been sacrificed by CO2 asphyxiation were used. Rat pancreas from embryonic day (E) 15.5 and E18.5 rat embryos was isolated under a stereomicroscope. Rat pancreas from postnatal (P) days 0, 7, 14, 21 and adult was directly isolated by the unaided eye. The RT-PCR analysis of the NBC1 specific region on rat pancreas tissues from different developmental stages. The two antibodies which target the NBC1 common COOH-terminal region and NH2-terminal region detected a clear band of about 145 kDa in the Western blot analysis. The localization of NBC1 was examined by immuno-fluorescence detection. RESULTS: The results revealed the first peak of NBC1 expression at E18.5 and the second peak at P14. Meanwhile, the low NBC1 expression occurred at P7 and adult stages. Our results demonstrated, for the first time, the presence of NBC1 in the plasma membrane of ß and α cells, as well as in the basolateral membrane of acinar cells of the rat pancreas at different stages of development. CONCLUSION: The data strongly suggests that NBC1 is diversely expressed in the pancreas at different developmental stages, where it may exert its functions in pancreatic development especially islet cell growth through HCO3- transport and pH regulation.

Cervical sympathectomy reduces neurogenic vasodilation in dura mater of rats.

Migraine may affect the autonomic nervous system, but the mechanisms remain unclear. The sympathetic and parasympathetic nervous systems may play different roles in the attack. To explore the effect of blocking the cervical sympathetic nerve on vasodilation of the meningeal vessels, jugular vein calcitonin gene-related peptide (CGRP) and meningeal blood flow changes were measured before and after transection of the cervical sympathetic nerve by electrically stimulating the trigeminal ganglion in Sprague-Dawley (SD) rats. We found that CGRP level and meningeal blood flow increased in both the sham-operated and sympathectomized groups (p<0.05). Compared with the sham-operated group, dural blood flow decreased significantly in the cervical sympathectomy group, but CGRP level was not significantly different between these two groups. The cervical sympathetic nerve may play an important role in the process of neurogenic dural vasodilation in rats; this effect is not entirely dependent on CGRP level.