Distribution pattern of the celiac, cranial mesenteric, and caudal mesenteric arteries to the gastrointestinal tract in the common marmoset (Callithrix jacchus).

Gastrointestinal diseases pose problems to captive common marmosets. Therefore, knowledge of the anatomy of the arterial supply to the gastrointestinal tract is an important prerequisite for implementing appropriate veterinary care. The common marmoset's intestinal tract has a well-developed cecum specialized for the fermentative digestion of tree gums. This specialized gastrointestinal tract may have a unique pattern of arterial distribution. This study aimed to elucidate the species-specific gastrointestinal tract arterial anatomy of the common marmoset. We traced the celiac, cranial mesenteric, and caudal mesenteric arteries in six male and nine female common marmosets using the latex injection method. We found that the celiac artery gave rise to the left gastric, common hepatic, splenic, and caudal pancreaticoduodenal arteries. In addition to these arteries, the celiac artery gave origin to the middle colic or jejunal arteries in seven or one cases, respectively. The branches of the cranial mesenteric artery consisted of 3-6 arteries, including the middle colic, caudal pancreaticoduodenal, jejunal, right colic, ileocolic, and ileal arteries, as well as a common trunk of the ventral cecal and ileal branches, and the dorsal cecal and colic branches. In four cases, the cranial mesenteric artery gave rise to the jejunal, ileocolic, and ileal arteries. In one of the 13 cases, the celiac and cranial mesenteric arteries formed a common trunk. The caudal mesenteric artery branched into the left colic, sigmoid, and cranial rectal arteries in all the cases. These findings provide an anatomical basis for gastrointestinal veterinary care of common marmosets.

Serotonergic regulation of cortical neurovascular coupling and hemodynamics upon awakening from sleep in mice.

Neurovascular coupling (NVC) is the functional hyperemia of the brain responding to local neuronal activity. It is mediated by astrocytes and affected by subcortical ascending pathways in the cortex that convey information, such as sensory stimuli and the animal condition. Here, we investigate the influence of the raphe serotonergic system, a subcortical ascending arousal system in animals, on the modulation of cortical NVC and cerebral blood flow (CBF). Raphe serotonergic neurons were optogenically activated for 30 s, which immediately awakened the mice from non-rapid eye movement sleep. This caused a biphasic cortical hemodynamic change: a transient increase for a few seconds immediately after photostimulation onset, followed by a large progressive decrease during the stimulation period. Serotonergic neuron activation increased intracellular Ca2+ levels in cortical pyramidal neurons and astrocytes, demonstrating its effect on the NVC components. Pharmacological inhibition of cortical neuronal firing activity and astrocyte metabolic activity had small hypovolemic effects on serotonin-induced biphasic CBF changes, while blocking 5-HT1B receptors expressed primarily in cerebral vasculature attenuated the decreasing CBF phase. This suggests that serotonergic neuron activation leading to animal awakening could allow the NVC to exert a hyperemic function during a biphasic CBF response, with a predominant decrease in the cortex.

Contribution of default mode network to game and delayed-response task performance: Power and connectivity analyses of theta oscillation in the monkey.

Neuroimaging studies have demonstrated the presence of a default mode network (DMN) which shows greater activity during rest, and an executive network (EN) which is activated during cognitive tasks. DMN and EN are thought to have competing functions. However, recent studies reported that the two networks show coactivation during some cognitive tasks. To clarify how DMN works and how DMN interacts with EN for cognitive control, we recorded EEG activities in the medial prefrontal (anterior DMN: aDMN), posterior cingulate/precuneus (posterior DMN: pDMN), and lateral prefrontal (EN) areas in the monkey. As cognitive tasks, we employed a monkey-monkey competitive video game (GAME) and a delayed-response (DR) task. We focused on theta oscillation because of its importance in cognitive control. We also examined theta band connectivity among the three network areas using the Granger causality analysis. DMN and EN were found to work cooperatively in both tasks. In all the three network areas, we found GAME-task-related, but no DR-task-related, increase in theta power from the resting level, maybe because of the higher cognitive demand associated with the GAME task performance. The information flow conveyed by the theta oscillation was directed more to aDMN than from aDMN for both tasks. The GAME-task-related increase in theta power in aDMN is supposed to be supported by more information flow conveyed by the theta oscillation from EN and pDMN.

Narcolepsy type I-associated DNA methylation and gene expression changes in the human leukocyte antigen region.

Narcolepsy type 1 (NT1) is caused by a loss of hypothalamic orexin-producing cells, and autoreactive CD4+ and CD8+ T cells have been suggested to play a role in the autoimmune mechanism. Although NT1 showed a strong association with human leukocyte antigen (HLA)-DQB1*06:02, the responsible antigens remain unidentified. We analyzed array-based DNA methylation and gene expression data for the HLA region in CD4+ and CD8+ T cells that were separated from the peripheral blood mononuclear cells of Japanese subjects (NT1, N = 42; control, N = 42). As the large number of SNPs in the HLA region might interfere with the affinity of the array probes, we conducted a comprehensive assessment of the reliability of each probe. The criteria were based on a previous study reporting that the presence of frequent SNPs, especially on the 3' side of the probe, makes the probe unreliable. We confirmed that 90.3% of the probes after general filtering in the HLA region do not include frequent SNPs, and are thus suitable for analysis, particularly in Japanese subjects. We then performed an association analysis, and found that several CpG sites in the HLA class II region of the patients were significantly hypomethylated in CD4+ and CD8+ T cells. This association was not detected when the effect of HLA-DQB1*06:02 was considered, suggesting that the hypomethylation was possibly derived from HLA-DQB1*06:02. Further RNA sequencing revealed reduced expression levels of HLA-DQB1 alleles other than HLA-DQB1*06:02 in the patients with NT1. Our results suggest the involvement of epigenetic and expressional changes in HLA-DQB1 in the pathogenesis of NT1.

Low carnitine palmitoyltransferase 1 activity is a risk factor for narcolepsy type 1 and other hypersomnia.

STUDY OBJECTIVES: Narcolepsy type 1 (NT1) is associated with metabolic abnormalities but their etiology remains largely unknown. The gene for carnitine palmitoyltransferase 1B (CPT1B) and abnormally low serum acylcarnitine levels have been linked to NT1. To elucidate the details of altered fatty acid metabolism, we determined levels of individual acylcarnitines and evaluated CPT1 activity in patients with NT1 and other hypersomnia. METHODS: Blood samples from 57 NT1, 51 other hypersomnia patients, and 61 healthy controls were analyzed. The levels of 25 major individual acylcarnitines were determined and the C0/(t[C16] + t[C18]) ratio was used as a CPT1 activity marker. We further performed transcriptome analysis using independent blood samples from 42 NT1 and 42 healthy controls to study the relevance of fatty acid metabolism. NT1-specific changes in CPT1 activity and in expression of related genes were investigated. RESULTS: CPT1 activity was lower in patients with NT1 (p = 0.00064) and other hypersomnia (p = 0.0014) than in controls. Regression analysis revealed that CPT1 activity was an independent risk factor for NT1 (OR: 1.68; p = 0.0031) and for other hypersomnia (OR: 1.64; p = 0.0042). There was a significant interaction between obesity (BMI <25, ≥25) and the SNP rs5770917 status such that nonobese NT1 patients without risk allele had better CPT1 activity (p = 0.0089). The expression levels of carnitine-acylcarnitine translocase (CACT) and CPT2 in carnitine shuttle were lower in NT1 (p = 0.000051 and p = 0.00014, respectively). CONCLUSIONS: These results provide evidences that abnormal fatty acid metabolism is involved in the pathophysiology of NT1 and other hypersomnia.

Hippocampal Connectivity of the Presubiculum in the Common Marmoset (Callithrix jacchus).

The marmoset (a New World monkey) has recently received much attention as an experimental animal model; however, little is known about the connectivity of limbic regions, including cortical and hippocampal memory circuits, in the marmoset. Here, we investigated the neuronal connectivity of the marmoset, especially focusing on the connectivity between the hippocampal formation and the presubiculum, using retrograde and anterograde tracers (cholera toxin-B subunit and biotin dextran amine). We demonstrated the presence of a direct projection from the CA1 pyramidal cell layer to the deep layers of the presubiculum in the marmoset, which was previously identified in the rabbit brain, but not in the rat. We also found that the cells of origin of the subiculo-presubicular projections were localized in the middle part along the superficial-to-deep axis of the pyramidal cell layer of the distal subiculum in the marmoset, which was similar to that in both rats and rabbits. Our results suggest that, compared to the rat and rabbit brains, connections between the hippocampal formation and presubiculum are highly organized and characteristic in the marmoset brain.

Clinical characteristics of older Japanese patients with acute appendicitis: A post hoc analysis.

BACKGROUND: Acute appendicitis (AA) in older patients can look different from AA in younger patients. Although it is crucial that primary care physicians can recognize AA in patients of any age, few Japanese studies have examined the characteristics of older AA patients. To address this, we evaluated the clinical characteristics of older Japanese patients with AA. METHODS: We performed a post hoc analysis of the data from a previous Japanese single-center study. We analyzed the clinical information of both younger (age: 16-64 years) and older patients (age: ≥65 years). RESULTS: A cohort of 236 patients consisting of 219 (92.8%) younger patients and 17 (7.2%) older patients was evaluated. The median ages of the younger and older patients were 34 (interquartile range [IR], 24-45) and 78 years (IR, 74-81), respectively. The prevalence of complicated appendicitis (CA) (older: 41.2% vs. younger: 14.2%), comorbidities (70.6% vs. 13.2%), and thrombocytopenia (17.7% vs. 4.1%), along with serum C-reactive protein (CRP) level (6.7 mg/dl vs. 1.0 mg/dl), was significantly higher in older patients. Significantly fewer older patients had epigastric pain (17.7% vs. 53.0%). Logistic regression evaluating the characteristics of older AA patients showed that CRP >5 mg/dl had a high odds ratio (OR) (5.01; 95% CI, 1.73-14.54), while epigastric pain had a low OR (0.24; 95% CI, 0.06-0.90). CONCLUSION: Our study reveals a higher prevalence of CA and comorbidities in older patients, and suggests that a lack of epigastric pain, thrombocytopenia, and higher serum CRP level are characteristics of older AA patients.

A variant in orexin receptor-2 is associated with self-reported daytime sleepiness in the Japanese population.

Excessive daytime sleepiness is characterized by a persistent feeling of having trouble staying awake, typically with inappropriate sleep episodes. Orexin (hypocretin) is a neuropeptide that regulates sleep-wake cycles and rapid eye movement sleep. Several large-scale genome-wide association studies (GWASs) in European populations have found genetic variants in orexin receptor-1 (OX1R) and -2 (OX2R) that are associated with sleep traits including daytime sleepiness. To identify genetic variants associated with daytime sleepiness, we performed an association study of genetic variants in prepro-orexin, OX1R, and OX2R in 14,329 Japanese individuals from the Tohoku Medical Megabank Project cohort. A genetic variant in OX2R was significantly associated with self-reported daytime sleepiness after Bonferroni correction (rs188018846: P = 8.4E-05). In addition, a missense variant in OX2R identified by the European GWASs showed a nominally significant association with daytime sleepiness in a Japanese population (p.Ile308Val, rs2653349: P = 0.044). Multiple genetic variants in OX2R can affect daytime sleepiness in general populations.

Clinical prediction of complicated appendicitis: A case-control study utilizing logistic regression.

BACKGROUND: Since high-quality evidence on conservative treatment of acute appendicitis using antibiotics has increased, differentiation of patients with complicated appendicitis (CA) from those with simple appendicitis (SA) has become increasingly important. Previous studies have revealed that male gender, advanced age, comorbid conditions, prehospital delay, fever, and anorexia are risk factors of perforated appendicitis. Elevated serum C-reactive protein (CRP) level and hyponatremia have also been reported as predictive biomarkers of CA. However, confounding between various factors is problematic because most previous studies were limited to univariate analysis. AIM: To evaluate non-laboratory and laboratory predictive factors of CA using logistic regression analyses. METHODS: We performed an exploratory, single-center, retrospective case-control study that evaluated 198 patients (83.9%) with SA and 38 patients (16.1%) with CA. Diagnoses were confirmed by computed tomography images for all cases. We compared age, sex, onset-to-visit interval, epigastric/periumbilical pain, right lower quadrant pain, nausea/vomiting, diarrhea, anorexia, medical history (of previous non-surgically treated appendicitis, diabetes, hypertension, dyslipidemia, liver cirrhosis, hemodialysis, chronic lung diseases, malignant tumors, immunosuppressant use, and antiplatelet use), vital signs, physical findings, and laboratory data to select the explanatory variates for logistic regression. Based on the univariate comparisons, we performed logistic regression for clinical differentiation between CA and SA using only non-laboratory factors and also including both non-laboratory and laboratory factors. RESULTS: The 236 eligible patients consisted of 198 patients (83.9%) with SA and 38 patients (16.1%) with CA. The median ages were 34 years old [interquartile ranges (IR), 24-45 years] in the SA group and 49 years old (IR, 35-63 years) in the CA group (P < 0.001). The median onset-to-visit interval was 1 d (IR, 0-1) and 1 d (IR, 1-2) in the SA and CA groups, respectively (P < 0.001). Heart rate, body temperature, and serum CRP level in the CA group were significantly higher than in the SA group; glomerular filtration rate and serum sodium were significantly lower in the CA group. Anorexia was significantly more prevalent in the CA group. The regression model including age, onset-to-visit interval, anorexia, tachycardia, and fever as non-laboratory predictive factors of CA (Model 1) showed that age ≥ 65 years old, longer onset-to-visit interval, and anorexia had significantly high odds ratios. The logistic regression for prediction of CA including age, onset-to-visit interval, anorexia, serum CRP level, hyponatremia (serum sodium < 135 mEq/L), and glomerular filtration rate < 60 mL/min/1.73 m2 (Model 2) showed that only elevated CRP levels had significantly high odds ratios. Under the curve values of receiver operating characteristics curves of each regression model were 0.74 for Model 1 and 0.87 for Model 2. CONCLUSION: Our logistic regression analysis on differentiating factors of CA from SA showed that high CRP level was a strong dose-dependent predictor of CA.

A Susceptible Period of Photic Day-Night Rhythm Loss in Common Marmoset Social Behavior Development.

The prevalence of neurodevelopmental psychiatric disorders such as pervasive developmental disorders is rapidly increasing worldwide. Although these developmental disorders are known to be influenced by an individual's genetic background, the potential biological responses to early life's environmental exposure to both physical and psychological factors must also be considered. Many studies have acknowledged the influence of shorter time for rest at night and the simultaneous occurrence of various kinds of complications involving developmental disorders. In a prior study, we examined how a common marmoset's (Callithrix jacchus) psychosocial development was affected when it was reared under constant daylight from birth and then reared individually by humans nursing them under constant light (LL) during their juvenile development stages. The behaviors of these marmosets were compared with those of normal day-night cycle (LD) marmosets using a multivariate analysis based on principal component analysis (PCA). That study found that LL marmosets relatively elicited egg-like calls (Ecall) and side-to-side shakes of the upper body with rapid head rotation through adulthood frequently. Based on the PCA, these behaviors were interpreted as "alert" or "hyperactive" states. However, we did not clarify susceptible periods of the photic rhythm loss experience and the psychological development output. In this study we summarize the following studies in our model animal colonies involving 30 animals (11 female, 19 males) to further explore critical age states of inquiry about each social behavior profiling. We compared social behaviors of three age stages, juvenile, adolescent and young adult equivalent to one another in four LL experience conditions, LL (postnatal day (P) 0 to around 150), Middle (P60-149, 90 days), Late (P150-239, 90 days), and LD (no experience). In the most representative 1st and 2nd principal component scores, the shifting to higher frequency of alert behaviors developed at the adult stage in LL, Middle, then Late in turn. The no LL experience group, LD, generally featured higher frequency of local preference of high position compared to LL experience present groups, in adulthood. This limited model primate study might inspire different developmental age sensitive mechanisms of neuronal network to control socio-emotional functions by utilizing the multivariate visualization method, BOUQUET. This study could potentially contribute to nurturing educational designs for social developmental disorders.

The Effects of Frankincense Essential Oil on Stress in Rats.

Frankincense essential oil, obtained from Boswellia carteri, is a popular essential oil, which is widely used in many parts of the world. While some of its properties are known, its effects on stress and sleep have not been studied. The effects of frankincense essential oil and its major components, limonene and α-pinene, on plasma corticosterone and glutathione (GSH) levels, as well as on sleep and wakefulness behaviour, were studied in sleep-deprived rats. The substances were applied topically after dilution in jojoba oil (vehicle). As compared to vehicle, frankincense essential oil at a dilution of 1/1000 (1:103) significantly reduced corticosterone levels (p < 0.05). In contrast, its major constituents (α-pinene and limonene), elevated levels of this stress hormone. Frankincense, limonene and α-pinene, all led to significant reductions in plasma GSH levels. Although frankincense dose-dependently reduced plasma concentrations of antioxidant ions albeit to levels insufficient to neutralize oxidative stress; levels of products of oxidative metabolism metabolites were decreased by the frankincense. In sleep-deprived rats, frankincense 1:103 respectively increased and decreased the amount of wakefulness and non-rapid eye movement sleep. Frankincense essential oil can counter the effects of stress by effectively relieving sleep debt and maintaining antioxidant capacity without increasing oxidative stress, and, therefore, may be beneficial in the management of stress.

Clinical differentiation of acute appendicitis and right colonic diverticulitis: A case-control study.

BACKGROUND: Acute right colonic diverticulitis (ARCD) is an important differential diagnosis of acute appendicitis (AA) in Asian countries because of the unusually high prevalence of right colonic diverticula. Due to qualitative improvement and the high penetration rate of computed tomography (CT) scanning in Japan, differentiation of ARCD and AA mainly depends on this modality. But cost, limited availability, and concern for radiation exposure make CT scanning problematic. Differential findings of ARCD from AA are based on several small studies that used univariate comparisons from Korea and Taiwan. Previous studies on clinical and laboratory differences between AA and ARCD are limited. AIM: To determine clinical differences between AA and ARCD for differentiation of these two diagnoses by creating a logistic regression model. METHODS: We performed an exploratory single-center retrospective case-control study evaluating 369 Japanese patients (age ≥ 16 years), 236 (64.0%) with AA and 133 (36.0%) with ARCD, who were hospitalized between 2012 and 2016. Diagnoses were confirmed by CT images. We compared age, sex, onset-to-visit interval, epigastric/periumbilical pain, right lower quadrant (RLQ) pain, nausea/vomiting, diarrhea, anorexia, medical history, body temperature, blood pressure, heart rate, RLQ tenderness, peritoneal signs, leukocyte count, and levels of serum creatinine, serum C-reactive protein (CRP), and serum alanine aminotrans-ferase. We subsequently performed logistic regression analysis for differentiating AA from ARCD based on the results of the univariate analyses. RESULTS: In the AA and ARCD groups, median ages were 35.5 and 41.0 years, respectively (p=0.011); median onset-to-visit intervals were 1 [interquartile range (IQR): 0-1] and 2 (IQR: 1-3) days, respectively (P < 0.001); median leukocyte counts were 12600 and 11500/mm3, respectively (P = 0.002); and median CRP levels were 1.1 (IQR: 0.2-4.1) and 4.9 (IQR: 2.9-8.5) mg/dL, respectively (P < 0.001). In the logistic regression model, odds ratios (ORs) were significantly high in nausea/vomiting (OR: 3.89, 95%CI: 2.04-7.42) and anorexia (OR: 2.13, 95%CI: 1.06-4.28). ORs were significantly lower with a longer onset-to-visit interval (OR: 0.84, 95%CI: 0.72-0.97), RLQ pain (OR: 0.28, 95%CI: 0.11-0.71), history of diverticulitis (OR: 0.034, 95%CI: 0.005-0.20), and CRP level > 3.0 mg/dL (OR: 0.25, 95%CI: 0.14-0.43). The regression model showed good calibration, discrimination, and optimism. CONCLUSION: Clinical findings can differentiate AA and ARCD before imaging studies; nausea/vomiting and anorexia suggest AA, and longer onset-to-visit interval, RLQ pain, previous diverticulitis, and CRP level > 3.0 mg/dL suggest ARCD.

Multiple Patterns of Axonal Collateralization of Single Layer III Neurons of the Rat Presubiculum.

The presubiculum plays a key role in processing and integrating spatial and head-directional information. Layer III neurons of the presubiculum provide strong projections to the superficial layers of the medial entorhinal cortex (MEC) in the rat. Our previous study revealed that the terminal distribution of efferents from layer III cells of the presubiculum was organized in a band-like fashion within the MEC, and the transverse axis of these zones ran parallel to the rhinal fissure. Identifying axonal branching patterns of layer III neurons of the presubiculum is important to further elucidate the functional roles of the presubiculum. In the present study, we visualized all axonal processes and terminal distributions of single presubicular layer III neurons in the rat, using in vivo injection of a viral vector expressing membrane-targeted palmitoylation site-attached green fluorescent protein (GFP). We found that layer III of the rat presubiculum comprised multiple types of neurons (n = 12) with characteristic patterns of axonal collateralization, including cortical projection neurons (n = 6) and several types of intrinsic connectional neurons (n = 6). Two of six cortical projection neurons provided two or three major axonal branches to the MEC and formed elaborate terminal arbors within the superficial layers of the MEC. The width and axis of the area of their terminal distribution resembled that of the band-like terminal field seen in our massive-scale observation. Two of the other four cortical projection neurons gave off axonal branches to the MEC and also to the subiculum, and each of the other two neurons sent axons to the subiculum or parasubiculum. Patterns of axonal arborization of six intrinsic connectional neurons were distinct from each other, with four neurons sending many axonal branches to both superficial and deep layers of the presubiculum and the other two neurons showing sparse axonal branches with terminations confined to layers III-V of the presubiculum. These data demonstrate that layer III of the rat presubiculum consists of multiple types of cortical projection neurons and interneurons, and also suggest that inputs from a single presubicular layer III neuron can directly affect a band-like zone of the MEC.

Involvement of PLAGL1/ZAC1 in hypocretin/orexin transcription.

The hypocretin/orexin neuropeptide system coordinates the regulation of various physiological processes. Our previous study reported that a reduction in the expression of pleomorphic adenoma gene­like 1 (Plagl1), which encodes a C2H2 zinc­finger transcription factor, occurs in hypocretin neuron­ablated transgenic mice, suggesting that PLAGL1 is co­expressed in hypocretin neurons and regulates hypocretin transcription. The present study examined whether canonical prepro­hypocretin transcription is functionally modulated by PLAGL1. Double immunostaining indicated that the majority of hypocretin neurons were positive for PLAGL1 immunoreactivity in the nucleus. Notably, PLAGL1 immunoreactivity in hypocretin neurons was altered in response to several conditions affecting hypocretin function. An uneven localization of PLAGL1 was detected in the nuclei of hypocretin neurons following sleep deprivation. Chromatin immunoprecipitation revealed that endogenous PLAGL1 may bind to a putative PLAGL1­binding site in the proximal region of the hypocretin gene, in the murine hypothalamus. In addition, electroporation of the PLAGL1 expression vector into the fetal hypothalamus promoted hypothalamic hypocretin transcription. These results suggested that PLAGL1 may regulate hypothalamic hypocretin transcription.

Anatomical variations of the torcular Herophili: macroscopic study and clinical aspects.

The anatomical variations of the confluence of sinuses were examined, focusing on the continuity of the superior sagittal sinus (SSS) and the transverse sinuses (TSs). In the 142 specimens studied, there were 72 symmetric cases (50.7%) and 70 asymmetric cases (49.3%). The symmetric group (no dominant type) was categorized into 34 cases of bifurcation (23.9%) and 38 cases of confluence (26.8%). The asymmetric group was categorized into 54 cases of the right-dominant type (38.0%) and 16 cases of the left-dominant type (11.3%). The right-dominant type was further categorized into 38 partially-communicating (26.8%) and 16 non-communicating types (11.3%). The left-dominant type was categorized into 11 partially-communicating (7.7%) and 5 non-communicating types (3.5%). In summary, the SSS asymmetrically drained into one TS in about half of the cases studied. The right-dominant type was about three to four times as common as the left-dominant type. The draining pattern shown by the asymmetric group could provoke intracranial hypertension due to unilateral jugular vein obstruction. In order to avoid this risk in cases of neck dissection, jugular vein catheterization, or hypercoagulopathy, preoperative evaluations of the dural sinus variations via MR venography, three-dimensional CT, or plain X-ray of the skull are recommended.

Anatomical variations of the recurrent artery of Heubner: number, origin, and course.

The clinical anatomy of the recurrent artery of Heubner (RAH) was examined, focusing on its number, origin, and course, in a large number of brain specimens. We studied 724 RAH in total from 357 brain specimens (714 hemispheres). In 98.74 % of 714 cases there were one or more RAHs, while it was absent in 1.26 % of cases. There was a single RAH in 96.22 % of cases, double in 2.38 % of cases, and triple in 0.14 % of cases. In this study, three origin types of the RAH were defined. We defined A1 and A2 segment of the anterior cerebral artery (ACA) as the artery from the origin of the ACA to the junction of the anterior communicating artery (AComA) and the artery from the junction of the AComA to the anterior border of the corpus callosum, respectively. In 76.2 % of 724 arteries, the RAH originated from the junction of the A1 and A2 segment of the ACA. In 16.3 %, the RAH originated from the A2 segment of the ACA. In 7.5 %, the RAH originated from the A1 segment of the ACA. The course of the RAH was superior to the A1 segment of the ACA in 30.1 % of 724 arteries, anterior in 62.2 %, and posterior in 7.7 %. It is of great importance for neurosurgeons to understand the detailed anatomical variations of the RAH before operating to prevent operative complications resulting in neurological deficits.

Narcolepsy susceptibility gene CCR3 modulates sleep-wake patterns in mice.

Narcolepsy is caused by the loss of hypocretin (Hcrt) neurons and is associated with multiple genetic and environmental factors. Although abnormalities in immunity are suggested to be involved in the etiology of narcolepsy, no decisive mechanism has been established. We previously reported chemokine (C-C motif) receptor 3 (CCR3) as a novel susceptibility gene for narcolepsy. To understand the role of CCR3 in the development of narcolepsy, we investigated sleep-wake patterns of Ccr3 knockout (KO) mice. Ccr3 KO mice exhibited fragmented sleep patterns in the light phase, whereas the overall sleep structure in the dark phase did not differ between Ccr3 KO mice and wild-type (WT) littermates. Intraperitoneal injection of lipopolysaccharide (LPS) promoted wakefulness and suppressed both REM and NREM sleep in the light phase in both Ccr3 KO and WT mice. Conversely, LPS suppressed wakefulness and promoted NREM sleep in the dark phase in both genotypes. After LPS administration, the proportion of time spent in wakefulness was higher, and the proportion of time spent in NREM sleep was lower in Ccr3 KO compared to WT mice only in the light phase. LPS-induced changes in sleep patterns were larger in Ccr3 KO compared to WT mice. Furthermore, we quantified the number of Hcrt neurons and found that Ccr3 KO mice had fewer Hcrt neurons in the lateral hypothalamus compared to WT mice. We found abnormalities in sleep patterns in the resting phase and in the number of Hcrt neurons in Ccr3 KO mice. These observations suggest a role for CCR3 in sleep-wake regulation in narcolepsy patients.

Organizational connectivity among the CA1, subiculum, presubiculum, and entorhinal cortex in the rabbit.

The laminar and topographical organization of connections between the hippocampal formation and parahippocampal regions was investigated in the rabbit following in vivo injection of cholera toxin B subunit as a retro- and antero-grade tracer and biotinylated dextran amine as an anterograde tracer. We confirmed several connectional features different from those of the rat, that is, the rabbit presubiculum received abundant afferents from CA1 and had many reciprocal connections with the entorhinal cortex. On the other hand, we identified many similarities with the rat: both the CA1 and subicular afferents that originated from the entorhinal cortex were abundant; moreover, the presubiculum received many inputs from the subiculum and sent massive projections to the entorhinal cortex. By plotting retrograde and anterograde labels in two-dimensional unfolded maps of the entire hippocampal and parahippocampal regions, we found that each group of entorhinal cells that project to CA1, subiculum, and presubiculum, and also the termination of the presubiculo-entorhinal projection, was distributed in band-like zones in layers II-III, extending across the medial and lateral entorhinal cortex. Our results suggest that the rabbit has a basic connectivity that is common with that of the rat, and also has additional hippocampal-presubicular and entorhino-presubicular connections that may reflect functional evolution in learning and memory.

Anti-Tribbles Pseudokinase 2 (TRIB2)-Immunization Modulates Hypocretin/Orexin Neuronal Functions.

Study Objectives: Recent findings showed that 16%-26% of narcolepsy patients were positive for anti-tribbles pseudokinase 2 (TRIB2) antibody, and the intracerebroventricular administration of immunoglobulin-G purified from anti-TRIB2 positive narcolepsy patients caused hypocretin/orexin neuron loss. We investigated the pathophysiological role of TRIB2 antibody using TRIB2-immunized rats and hypocretin/ataxin-3 transgenic (ataxin-3) mice. Methods: Plasma, cerebrospinal fluid (CSF), and hypothalamic tissues from TRIB2-immunized rats were collected. Anti-TRIB2 titers, hypocretin contents, mRNA expressions, the cell count of hypocretin neurons, and immunoreactivity of anti-TRIB2 antibodies on hypocretin neurons were investigated. The plasma from ataxin-3 mice was also used to determine the anti-TRIB2 antibody titer changes following the loss of hypocretin neurons. Results: TRIB2 antibody titers increased in the plasma and CSF of TRIB2-immunized rats. The hypothalamic tissue immunostained with the sera from TRIB2-immunized rats revealed positive signals in the cytoplasm of hypcretin neurons. While no changes were found regarding hypothalamic hypocretin contents or cell counts, but there were significant decreases of the hypocretin mRNA level and release into the CSF. The plasma from over 26-week-old ataxin-3 mice, at the advanced stage of hypocretin cell destruction, showed positive reactions against TRIB2 antigen, and positive plasma also reacted with murine hypothalamic hypocretin neurons. Conclusions: Our results suggest that the general activation of the immune system modulates the functions of hypocretin neurons. The absence of a change in hypocretin cell populations suggested that factors other than anti-TRIB2 antibody play a part in the loss of hypocretin neurons in narcolepsy. The increased anti-TRIB2 antibody after the destruction of hypocretin neurons suggest that anti-TRIB2 antibody in narcolepsy patients is the consequence rather than the inciting cause of hypocretin cell destruction.

Oral Administration of Methylphenidate (Ritalin) Affects Dopamine Release Differentially Between the Prefrontal Cortex and Striatum: A Microdialysis Study in the Monkey.

Methylphenidate (MPH; trade name Ritalin) is a widely used drug for the treatment of attention deficit hyperactivity disorder (ADHD) and is often used as a cognitive enhancer. Because MPH increases dopamine (DA) release by blocking the DA transporter in the human striatum, MPH is supposed to work on attention and cognition through a DA increase in the striatum. However, ADHD patients show impaired prefrontal cortex (PFC) function and MPH administration is associated with increased neural activity in the PFC. Although MPH is indicated to increase DA release in the rat PFC, there has been no study to examine MPH-induced DA changes in the human PFC because of technical difficulties associated with the low level of PFC DA receptors. Using the microdialysis technique, we examined the effects of oral administration of MPH on DA release in both the PFC and striatum in the monkey. We also tested the effect of MPH on cognitive task performance. As in human studies, in the striatum, both high and low doses of MPH induced consistent increases in DA release ∼30 min after their administrations. In the PFC, a consistent increase in DA release was observed 1 h after a high dose, but not low doses, of MPH. Low doses of MPH improved cognitive task performance, but a high dose of MPH made the monkey drowsy. Therefore, low-dose MPH-induced cognitive enhancement is supported by striatum DA increase.SIGNIFICANCE STATEMENT Methylphenidate (MPH) is a widely used drug for the treatment of attention deficit hyperactivity disorder and is often used as a cognitive enhancer. Although human positron emission tomography studies suggest that MPH works on attention and cognition through dopamine (DA) changes in the striatum, there has been no study to examine MPH-induced DA changes in the human prefrontal cortex (PFC). Using the microdialysis technique in monkeys, we found, for the first time, that low doses of MPH consistently increased DA release in the striatum but did not in the PFC. Cognitive enhancement effects of low doses of MPH are supposed to be supported by the striatum DA increase.