Comparison of the connectivity of the posterior intralaminar thalamic nucleus and peripeduncular nucleus in rats and mice.

The posterior intralaminar thalamic nucleus (PIL) and peripeduncular nucleus (PP) are two adjoining structures located medioventral to the medial geniculate nucleus. The PIL-PP region plays important roles in auditory fear conditioning and in social, maternal and sexual behaviors. Previous studies often lumped the PIL and PP into single entity, and therefore it is not known if they have common and/or different brain-wide connections. In this study, we investigate brain-wide efferent and afferent projections of the PIL and PP using reliable anterograde and retrograde tracing methods. Both PIL and PP project strongly to lateral, medial and anterior basomedial amygdaloid nuclei, posteroventral striatum (putamen and external globus pallidus), amygdalostriatal transition area, zona incerta, superior and inferior colliculi, and the ectorhinal cortex. However, the PP rather than the PIL send stronger projections to the hypothalamic regions such as preoptic area/nucleus, anterior hypothalamic nucleus, and ventromedial nucleus of hypothalamus. As for the afferent projections, both PIL and PP receive multimodal information from auditory (inferior colliculus, superior olivary nucleus, nucleus of lateral lemniscus, and association auditory cortex), visual (superior colliculus and ectorhinal cortex), somatosensory (gracile and cuneate nuclei), motor (external globus pallidus), and limbic (central amygdaloid nucleus, hypothalamus, and insular cortex) structures. However, the PP rather than PIL receives strong projections from the visual related structures parabigeminal nucleus and ventral lateral geniculate nucleus. Additional results from Cre-dependent viral tracing in mice have also confirmed the main results in rats. Together, the findings in this study would provide new insights into the neural circuits and functional correlation of the PIL and PP.

Recent Progress in Ferroptosis Induced Tumor Cell Death by Anti-tumor Metallic complexes.

Metal complexes represented by platinum complexes play a very important role in cancer treatment due to their diverse chemical structures and anti-tumor activities. Recently, ferroptosis has emerged as a newly occurring cell death form in the anti-tumor process. It has been reported that metal complexes could inhibit the proliferation and metastasis of tumors and combat chemotherapy resistance by targeting ferroptosis. In this review, we briefly describe ferroptosis as a fundamental process for tumor suppression and triggering anti-tumor immune responses. We summarize recent developments on metal complexes that induce ferroptosis. Finally, we outline the prospects for the application of metal complexes to the treatment of tumors based on ferroptosis and the associated problems that need to be solved, and discussed other potential research directions of metal complexes.

Possible rodent equivalent of the posterior cingulate cortex (area 23) interconnects with multimodal cortical and subcortical regions.

Posterior cingulate cortex (area 23, A23) in human and monkeys is a critical component of the default mode network and is involved in many diseases such as Alzheimer's disease, autism, depression, attention deficit hyperactivity disorder and schizophrenia. However, A23 has not yet identified in rodents, and this makes modeling related circuits and diseases in rodents very difficult. Using a comparative approach, molecular markers and unique connectional patterns this study has uncovered the location and extent of possible rodent equivalent (A23~) of the primate A23. A23 ~ but not adjoining areas in the rodents displays strong reciprocal connections with anteromedial thalamic nucleus. Rodent A23 ~ reciprocally connects with the medial pulvinar and claustrum as well as with anterior cingulate, granular retrosplenial, medial orbitofrontal, postrhinal, and visual and auditory association cortices. Rodent A23 ~ projects to dorsal striatum, ventral lateral geniculate nucleus, zona incerta, pretectal nucleus, superior colliculus, periaqueductal gray, and brainstem. All these findings support the versatility of A23 in the integration and modulation of multimodal sensory information underlying spatial processing, episodic memory, self-reflection, attention, value assessment and many adaptive behaviors. Additionally, this study also suggests that the rodents could be used to model monkey and human A23 in future structural, functional, pathological, and neuromodulation studies.

The effects of bilateral prostriata lesions on spatial learning and memory in the rat.

Area prostriata is the primary limbic structure for rapid response to the visual stimuli in the far peripheral visual field. Recent studies have revealed that the prostriata receives inputs not only from the visual and auditory cortices but also from many structures critical for spatial processing and navigation. To gain insight into the functions of the prostriata in spatial learning and memory the present study examines the effects of bilateral lesions of the prostriata on motor ability, exploratory interest and spatial learning and memory using the open field, elevated plus-maze and Morris water maze tests. Our results show that the spatial learning and memory abilities of the rats with bilateral prostriata lesions are significantly reduced compared to the control and sham groups. In addition, the lesion rats are found to be less interested in space exploration and more anxious while the exercise capacity of the rats is not affected based on the first two behavioral tests. These findings suggest that the prostriata plays important roles in spatial learning and memory and may be involved in anxiety as well.

Chemoarchitecture of area prostriata in adult and developing mice: Comparison with presubiculum and parasubiculum.

Retrosplenial area 29e, which was a cortical region described mostly in earlier rodent literature, is often included in the dorsal presubiculum (PrSd) or postsubiculum (PoS) in modern literature and commonly used brain atlases. Recent anatomical and molecular studies have revealed that retrosplenial area 29e belongs to the superficial layers of area prostriata, which in primates is found to be important in fast analysis of quickly moving objects in far peripheral visual field. As in primates, the prostriata in rodents adjoins area 29 (granular retrosplenial area), area 30 (agranular retrosplenial area), medial visual cortex, PrSd/PoS, parasubiculum (PaS), and postrhinal cortex (PoR). The present study aims to reveal the chemoarchitecture of the prostriata versus PrSd/PoS or PaS by means of a systematic survey of gene expression patterns in adult and developing mouse brains. First, we find many genes that display differential expression across the prostriata, PrSd/PoS, and PaS and that show obvious laminar expression patterns. Second, we reveal subsets of genes that selectively express in the dorsal or ventral parts of the prostriata, suggesting the existence of at least two subdivisions. Third, we detect some genes that shows differential expression in the prostriata of postnatal mouse brains from adjoining regions, thus enabling identification of the developing area prostriata. Fourth, gene expression difference of the prostriata from the medial primary visual cortex and PoR is also observed. Finally, molecular and connectional features of the prostriata in rodents and nonhuman primates are discussed and compared.

Rodent Area Prostriata Converges Multimodal Hierarchical Inputs and Projects to the Structures Important for Visuomotor Behaviors.

Area prostriata is a limbic structure critical to fast processing of moving stimuli in far peripheral visual field. Neural substrates underlying this function remain to be discovered. Using both retrograde and anterograde tracing methods, the present study reveals that the prostriata in rat and mouse receives inputs from multimodal hierarchical cortical areas such as primary, secondary, and association visual and auditory cortices and subcortical regions such as the anterior and midline thalamic nuclei and claustrum. Surprisingly, the prostriata also receives strong afferents directly from the rostral part of the dorsal lateral geniculate nucleus. This shortcut pathway probably serves as one of the shortest circuits for fast processing of the peripheral vision and unconscious blindsight since it bypasses the primary visual cortex. The outputs of the prostriata mainly target the presubiculum (including postsubiculum), pulvinar, ventral lateral geniculate nucleus, lateral dorsal thalamic nucleus, and zona incerta as well as the pontine and pretectal nuclei, most of which are heavily involved in subcortical visuomotor functions. Taken together, these results suggest that the prostriata is poised to quickly receive and analyze peripheral visual and other related information and timely initiates and modulates adaptive visuomotor behaviors, particularly in response to unexpected quickly looming threats.

Artemisinin improves neurocognitive deficits associated with sepsis by activating the AMPK axis in microglia.

Sepsis is life-threatening organ dysfunction due to dysregulated systemic inflammatory and immune response to infection, often leading to cognitive impairments. Growing evidence shows that artemisinin, an antimalarial drug, possesses potent anti-inflammatory and immunoregulatory activities. In this study we investigated whether artemisinin exerted protective effect against neurocognitive deficits associated with sepsis and explored the underlying mechanisms. Mice were injected with LPS (750 µg · kg-1 · d-1, ip, for 7 days) to establish an animal model of sepsis. Artemisinin (30 mg · kg-1 · d-1, ip) was administered starting 4 days prior LPS injection and lasting to the end of LPS injection. We showed that artemisinin administration significantly improved LPS-induced cognitive impairments assessed in Morris water maze and Y maze tests, attenuated neuronal damage and microglial activation in the hippocampus. In BV2 microglial cells treated with LPS (100 ng/mL), pre-application of artemisinin (40 µΜ) significantly reduced the production of proinflammatory cytokines (i.e., TNF-α, IL-6) and suppressed microglial migration. Furthermore, we revealed that artemisinin significantly suppressed the nuclear translocation of NF-κB and the expression of proinflammatory cytokines by activating the AMPKα1 pathway; knockdown of AMPKα1 markedly abolished the anti-inflammatory effects of artemisinin in BV2 microglial cells. In conclusion, atemisinin is a potential therapeutic agent for sepsis-associated neuroinflammation and cognitive impairment, and its effect is probably mediated by activation of the AMPKα1 signaling pathway in microglia.

Afferent Projections to Area Prostriata of the Mouse.

Area prostriata plays important roles in fast detection and analysis of peripheral visual information. It remains unclear whether the prostriata directly receives and integrates information from other modalities. To gain insight into this issue, we investigated brain-wide afferent projections to mouse prostriata. We find convergent projections to layer 1 of the prostriata from primary and association visual and auditory cortices; retrosplenial, lateral entorhinal, and anterior cingulate cortices; subiculum; presubiculum; and anterior thalamic nuclei. Innervation of layers 2-3 of the prostriata mainly originates from the presubiculum (including postsubiculum) and anterior midline thalamic region. Layer 5 of the prostriata mainly receives its inputs from medial entorhinal, granular retrosplenial, and medial orbitofrontal cortices and anteromedial thalamic nucleus while layer 6 gets its major inputs from ectorhinal, postrhinal, and agranular retrosplenial cortices. The claustrum, locus coeruleus, and basal forebrain provide relatively diffuse innervation to the prostriata. Moreover, Cre-dependent tracing in cortical areas reveals that the cells of origin of the prostriata inputs are located in layers 2-4 and 5 of the neocortical areas, layers 2 and 5 of the medial entorhinal cortex, and layer 5 of the retrosplenial cortex. These results indicate that the prostriata is a unique region where primary and association visual and auditory inputs directly integrate with many limbic inputs.

Homotopic Commissural Projections of Area Prostriata in Rat and Mouse: Comparison With Presubiculum and Parasubiculum.

Area prostriata in primates has recently been found to play important roles in rapid detection and processing of peripheral visual, especially fast-moving visual information. The prostriata in rodents was not discovered until recently and its connectivity is largely unknown. As a part of our efforts to reveal brain-wide connections of the prostriata in rat and mouse, this study focuses on its commissural projections in order to understand the mechanisms underlying interhemispheric integration of information, especially from peripheral visual field. Using anterograde, retrograde and Cre-dependent tracing techniques, we find a unique commissural connection pattern of the prostriata: its layers 2-3 in both hemispheres form strong homotopic commissural connections with few heterotopic projections to bilateral medial entorhinal cortex. This projection pattern is in sharp contrast to that of the presubiculum and parasubiculum, two neighbor regions of the prostriata. The latter two structures project very strongly to bilateral medial entorhinal cortex and to their contralateral counterparts. Our results also suggest the prostriata is a distinct anatomical structure from the presubiculum and parasubiculum and probably plays differential roles in interhemispheric integration and the balancing of spatial information between two hemispheres.

Altered anxiety and social behaviors in a mouse model of Fragile X syndrome treated with hyperbaric oxygen therapy.

Fragile X syndrome (FXS) is a common mental retardation syndrome. Anxiety and abnormal social behaviors are prominent features of FXS in humans. To better understand the effects of hyperbaric oxygen therapy (HBOT) on these behaviors, we analyzed anxiety-related and social behaviors in Fmr1 knockout mice treated by HBOT. In the open field test, HBOT group mice preferred the periphery to central areas and tended to run or walk along the wall. The results suggested that thigmotaxis was significantly increased in the HBOT group compared with the control group. In the elevated plus maze test, the percentage of distance traveled was significantly increased in the open arm and significantly decreased in the closed arm for HBOT group mice compared with control group mice. These results suggested that HBOT group mice displayed enhanced motor activity in the open arm and exhibited fewer anxiety-related behaviors. In the three-chambered social approach test, the HBOT group mice made more approaches to the wire cup containing an acquaintance mouse than control group mice in the sociability test and made more approaches to the wire cup containing a stranger mouse than control group mice in the social novelty preference test. The results suggested that HBOT group mice showed increased levels of social interaction and decreased "social anxiety" than the control group to partner mice in this test. Our findings indicated that HBOT resulted in altered anxiety and social behavior in Fmr1 knockout mice and could possibly be used as a treatment for FXS.

[Placental Foxp3 expression in patients with preeclampsia and correlation of Foxp3 gene locus 924 (rs2232365) polymorphism with preeclampsia].

OBJECTIVE: To detect changes of Foxp3 expression in the decidua in patients with preeclampsia and investigate the correlation of Foxp3-924 (rs2232365) polymorphisms with preeclampsia. METHODS: From October 2011 to December 2012, 252 normal pregnant women and 156 preeclampsia patients of Han nationality from the same geographic region were tested for Foxp3-924 genotypes by polymerase chain reaction with sequence-specific primer (PCR-SSP). Sixty-eight of the patients with preeclampsia (33 with mild and 35 with severe preeclampsia) and 30 of the normal pregnant women were also examined for Foxp3 expression in the decidua using immunohistochemical method. RESULTS: Foxp3 positive expression rates in the decidua was 51.52% in mild preeclampsia and 28.57% in severe preeclampsia cases, significantly lower than that in the control group (86.67%, P<0.05). In preeclampsia patients, the frequencies of Foxp3-924G/G, G/A, and A/A genotypes were 0.1346, 0.4615 and 0.4038, respectively, and the frequencies of Foxp3-924A and Foxp3-924 G were 0.6346 and 0.3654, respectively. The genotype frequencies of Foxp3-924G/G, G/A and A/A in the control group were 0.1508, 0.4087 and 0.4405, respectively, and the frequencies of Foxp3-924 A and Foxp3-924 G were 0.6448 and 0.3552, respectively. No significant differences were found in the gene frequencies of Foxp3-924G/A between preeclampsia patients and the control group (P>0.05). CONCLUSION: The expression level of Foxp3 in the placental tissue of preeclampsia patients is significantly lower than that in normal pregnant women, suggesting that lowered Foxp3 expression decreases the immunosuppressive function and causes imbalance of immune tolerance between maternal-fetal to induce preeclampsia. Foxp3-924 polymorphisms is not significantly correlated with the occurrence of preeclampsia.

[Expression of iNOS in the testis of Fmr1 knockout mice in different developmental stages].

OBJECTIVE: To analyze the expression of inducible nitric oxide synthase (iNOS) in the testis tissues of Fmr1 (fragile X mental retardation 1) knockout and wild-type male mice in different developmental stages, and provide background information for researches on fragile X syndrome. METHODS: This study included 4, 6, 8 and 10 weeks old Fmr1 knockout and wild-type male mice, 6 in each age group. We identified the genotype of the mice by PCR, and detected and compared the expression of iNOS in the testis tissues of the Fmr1 knockout and wild-type mice by immunohistochemistry. RESULTS: The iNOS expression was weakly positive in the Leydig cells of the 4-week-old mice, moderately positive in the 6-week-old ones, and strongly positive in 8- and 10-week-old ones, significantly weaker in the Fmr1 knockout than in the wild-type ones. CONCLUSION: The expression of iNOS significantly decreases in the testis of Fmr1 knockout mice, suggesting that iNOS may be involved in the pathogenesis of fragile X syndrome.

Early continuous inhibition of group 1 mGlu signaling partially rescues dendritic spine abnormalities in the Fmr1 knockout mouse model for fragile X syndrome.

RATIONALE: Abnormal dendritic spine morphology is a significant neuroanatomical defect in fragile X mental retardation. It has been suggested that overactive group 1 metabotropic glutamate receptor (mGlu) signaling is associated with the spine dysmorphology occurring in fragile X syndrome (FXS). Thus, group 1 mGlu became a new therapeutic target for the treatment of FXS. OBJECTIVE: The purpose of this study was to identify the effect of inhibition of mGlu signaling in FXS. METHODS: We observed the changes in dendritic spines after pharmacological modulation of mGlu signaling in an Fmr1 knockout (KO) mouse model. RESULTS: The activation of group 1 mGlu resulted in elongation of dendritic spines in the cultured neurons derived from Fmr1 KO mice and wild-type (WT) mice. Antagonism of group 1 mGlu reduced the average spine length of Fmr1 KO neurons. Furthermore, systemic administration of the selective group 1 mGlu5 antagonist 2-methyl-6-phenylethynyl pyridine (MPEP) reduced the average spine length and density in the cortical neurons of Fmr1 KO mice at developmental age. For the adult mice, MPEP administration was less effective for the restoration of spine length. The percentage of immature spines showed a similar reduction in parallel to the changes of spine length. Temporary MPEP intervention with single-dose treatment did not show any effect. CONCLUSION: These results show that MPEP administration could partially rescue the morphological deficits of dendritic spines in Fmr1 KO mice at developmental age.

[Clinical manifestations and detection of pantothenate kinase 2 gene mutation in a patient with Hallervorden-Spatz syndrome].

OBJECTIVE: To investigate the clinical features and detection of pantothenate kinase 2 (PANK2) gene mutation in a Chinese patient with Hallervorden-Spatz syndrome (HSS). METHODS: The clinical features were analyzed in one HSS patient. PANK2 gene mutations were detected by polymerase chain reaction (PCR) and DNA sequence analysis in this patient, her parents and 50 unrelated healthy persons. RESULTS: The main symptoms of this patient were involuntary movements, dysarthria and progressive course. MRI scans showed hypointensity with a central region of hyperintensity in medial globus pallidus on T2 and T2-weighted fluid attenuated inversion recovery (FLAIR) images, i.e. "eye-of-the-tiger" sign. Novel compound heterozygous PANK2 gene mutations, G115T and A803G, were found in this patient, leading to substitution of a glutamic acid for a premature stop codon at amino acid 39 (E39X) and an aspartic acid for glycine codon at amino acid 268 (D268G) respectively. The father was a heterozygote for G115T mutation and the mother a heterozygote for A803G mutation. CONCLUSION: PANK2 gene mutations are present in Chinese HSS patients. And A803G mutation of PANK2 gene is probably a hot spot.

Neuroprotection of lamotrigine on hypoxic-ischemic brain damage in neonatal rats: Relations to administration time and doses.

Lamotrigine (LTG), an antiepileptic drug, has been shown to be able to improve cerebral ischemic damage by limiting the presynaptic release of glutamate. The present study investigated further the neuroprotective effect of LTG on hypoxic-ischemic brain damage (HIBD) in neonatal rats and its relations to administration time and doses. The HIBD model was produced in 7-days old SD rats by left common carotid artery ligation followed by 2 h hypoxic exposure (8% oxygen). LTG was administered intraperitoneally with the doses of 5, 10, 20, and 40 mg/kg 3 h after operation and the dose of 20 mg/kg 1 h before and 3 h, 6 h after operation. Blood and brain were sampled 24 h after operation. Nissl staining, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL), and neuron-specific enolase (NSE) immunohistochemical staining were used for morphological studies. Water content in left cortex and NSE concentration in serum were determined. LTG significantly reduced water content in the cerebral cortex, as well as the number of TUNEL staining neurons in the dentate gyrus and cortex in hypoxic-ischemia (HI) model. Furthermore, LTG significantly decreased the NSE level in serum and increased the number of NSE staining neurons in the cortex. These effects, except that on water content, were dose-dependent and were more remarkable in the pre-treated group than in the post-treated groups. These results demonstrate that LTG may have a neuroprotective effect on acute HIBD in neonates. The effect is more prominent when administrated with higher doses and before HI.

[HLA-DM gene polymorphism in Cantonese with condyloma acuminata].

OBJECTIVE: To study the polymorphism of HLA-DM gene in Cantonese patients with condyloma acuminata(CA) and determine the susceptible genetic factors of CA. METHODS: DMA and DMB typing was performed in 98 Cantonese patients with CA and 93 healthy controls using restriction fragment length polymorphism method. RESULTS: The gene frequencies of DMA*0101 and DMB*0101 were significantly higher in the patients than in the controls (P<0.05 and P<0.01, respectively), and gene frequency of DMA*0102 was lower in patients than in the controls (P<0.01). Genotype frequencies of HLA-DM showed no significant difference between CA patients and the controls (P>0.05). CONCLUSION: DMA*0101 and DMB*0101 alleles may be the susceptibility genes or closely linked to the susceptibility gene in Cantonese patients with CA.

[Investigating the correlation between polymorphisms with couple sharing rate of TAP gene and hypertensive disorder complicating pregnancy].

OBJECTIVE: To investigate and clarify whether the genetic susceptibility to women with hypertensive disorder complicating pregnancy or pre-eclampsia is associated with polymorphisms and couple sharing rate of transporter associate with antigen processing genes(TAP). METHODS: One hundred and two severe pre-eclampsia women and their spouses served as study group, and 200 normal pregnant women and their spouses were selected as control group. All pregnant women were primipara with single fetus. Genomic DNA was extracted from 2 mL cubital venous blood. We used the amplification refractory mutation system polymerase chain reaction(ARMS-PCR) to characterize TAP gene locus 333, 637, 379, 565, 665. RESULTS: We observed eleven TAP haplotypes. There were four kinds of haplotypes(1A-1D) existing in TAP1, and seven kinds of haplotypes(2A-2G) existing in TAP2. The gene frequencies of TAP2B(Chi2=9.19, P<0.01, RR=4.18) and TAP2F(Chi2=5.34, P<0.05, RR=4.63) of patient group with pre-eclampsia were significantly higher as compared with control group. The analyses of some TAP haplotypes such as TAP1B(Chi2=4.87, P<0.05, RR=3.14), TAP1C(Chi2=5.42, P<0.05, RR=4.90), TAP2B(Chi2=9.65, P<0.01, RR=5.39) showed that the couple sharing rate of pre-eclampsia women and their spouses had statistically a highly significant increase in comparison with that of controls. CONCLUSION: Our data suggest that the presence of TAP2B or TAP2F haplotypes should be considered as a risk increased to pregnant women being susceptible to hypertensive disorder complicating pregnancy; and also the elevated couple sharing rates of TAP1B, TAP1C and TAP2B genes will increase the opportunity or possibility of pregnant women suffering from pre-eclampsia disease.