The day-night differences in cognitive and anxiety-like behaviors of mice after chronic sleep restriction.

Animal behavioral tests are often conducted during the day. However, rodents are nocturnal animals and are primarily active at night. The aim of this study was to determine whether there are diurnal changes in cognitive and anxiety-like performance of mice following chronic sleep restriction (SR). We also investigated whether this phenotypic difference is related to the diurnal variation of glymphatic clearance of metabolic wastes. Mice received 9-day SR by the use of the modified rotating rod method, followed by the open field, elevated plus maze, and Y-maze tests conducted during the day and at night, respectively. Brain ß-amyloid (Aß) and tau protein levels, the polarity of aquaporin4 (AQP4), a functional marker of the glymphatic system, and glymphatic transport ability were also analyzed. SR mice exhibited cognitive impairment and anxiety-like behaviors during the day, but not at night. AQP4 polarity and glymphatic transport ability were higher during the day, with lower Aß1-42 , Aß1-40 , and P-Tau levels in the frontal cortex. These day-night differences were totally disrupted after SR. These results reveal the diurnal changes in behavioral performance after chronic SR, which may be related to circadian control of AQP4-mediated glymphatic clearance of toxic macromolecules from the brain.

Experimental Approaches Used to Investigate Voluntary Behavioral Thermoregulatory Responses.

A new behavioral test was developed to investigate the neural mechanisms of voluntary, behavioral thermoregulatory responses. The apparatus used in this test consisted of a thermostatic chamber that maintained the ambient temperature at a chosen level and two side-by-side floor plates that were placed in the thermostatic chamber and could be set to different temperatures. As the three temperatures, ambient temperature and two plate temperatures, can be controlled independently, we term this behavioral test the three-temperature (3 T) test. When the ambient temperature was 28 °C with floor plate temperatures of 25 °C and 35 °C, mice showed preference to the warm plate over the cool one. By contrast, when the ambient temperature was 40 °C, the mice showed preference to the cool plate, that is, a cool-seeking behavior. Detailed analyses of the time courses of the plate preference and core body temperature revealed that this cool-seeking behavior contributed to the regulation of body temperature. By using the 3 T test in combination with the latest in vivo imaging techniques for real-time measurement of neuronal activities and neurotransmitter releases in the brain of freely-moving animals, the neural mechanisms of voluntary, behavioral thermoregulatory responses could be elucidated in the near future.

Effects of Transcranial Ultrasound Stimulation on Blood Oxygen Metabolism and Brain Rhythms in Nitroglycerin-Induced Migraine Mice.

OBJECTIVES: In this study, we aimed to investigate the regulatory mechanism of transcranial ultrasound stimulation (TUS) on nitroglycerin-induced migraine in mice. MATERIALS AND METHODS: The experiment was divided into four groups, namely, the normal saline control group (n = 9), ultrasound stimulation control group (n = 6), nitroglycerin-induced migraine group (n = 9), and ultrasound stimulation group (n = 9). The behavior, blood oxygen metabolism, and brain rhythm distribution of the four groups were analyzed. RESULTS: We found that after TUS, the movement time and speed of mice with migraine are modulated to those of the control groups, and the number of head scratching and grooming events is significantly reduced. TUS increased the deoxygenated hemoglobin, and the power of the 4-to-40 Hz frequency band of local field potentials in the cortex of migraine mice. TUS also decreased the expression of plasma calcitonin gene-related peptide and cortical c-Fos protein. CONCLUSIONS: Ultrasound stimulation can regulate brain rhythm and blood oxygen metabolism and reduce migraine symptoms in mice. The regulatory mechanism may be related to reducing calcitonin gene-related peptide in blood vessels.

Tooth loss in young mice is associated with cognitive decline and femur-bone mineral density.

Osteoporosis is a prevalent disease that is associated with increased hip fractures which cause significant decline in quality of life. Tooth loss affects systemic condition such as cognitive function through various mechanism, but the link between tooth loss and femoral bone mineral density is still uncertain. This study aims to investigate whether tooth loss in young mice affects memory function and femoral bone mineral density. Eight-week-old male C57BL/6 J mice were allocated randomly into the control group with sham operation and the tooth-loss group extracted all maxillary molar. Step-through passive avoidance test as cognitive function test, micro-CT analysis and western blotting analysis were performed after 1- and 2-month observation period. Step-through passive avoidance test revealed that the tooth-loss group in 2-month observation period impaired cognitive function. Additionally, micro-CT analysis revealed a significant decrease in both the length of the mandible and bone mineral density in the femur of the tooth-loss group compared to the control group. Claudin-5 level in the hippocampus, which is one of the tight junction markers in blood-brain-barrier, was significantly decreased in the tooth-loss group. The findings of our present study suggested that tooth loss impair cognitive function accompanied by reduced tight-junction marker, mandibular growth and bone mineral density of femur.

Mitigating the Functional Deficit after Neurotoxic Motoneuronal Loss by an Inhibitor of Mitochondrial Fission.

Amyotrophic lateral sclerosis (ALS) is an extremely complex neurodegenerative disease involving different cell types, but motoneuronal loss represents its main pathological feature. Moreover, compensatory plastic changes taking place in parallel to neurodegeneration are likely to affect the timing of ALS onset and progression and, interestingly, they might represent a promising target for disease-modifying treatments. Therefore, a simplified animal model mimicking motoneuronal loss without the other pathological aspects of ALS has been established by means of intramuscular injection of cholera toxin-B saporin (CTB-Sap), which is a targeted neurotoxin able to kill motoneurons by retrograde suicide transport. Previous studies employing the mouse CTB-Sap model have proven that spontaneous motor recovery is possible after a subtotal removal of a spinal motoneuronal pool. Although these kinds of plastic changes are not enough to counteract the functional effects of the progressive motoneuron degeneration, it would nevertheless represent a promising target for treatments aiming to postpone ALS onset and/or delay disease progression. Herein, the mouse CTB-Sap model has been used to test the efficacy of mitochondrial division inhibitor 1 (Mdivi-1) as a tool to counteract the CTB-Sap toxicity and/or to promote neuroplasticity. The homeostasis of mitochondrial fission/fusion dynamics is indeed important for cell integrity, and it could be affected during neurodegeneration. Lesioned mice were treated with Mdivi-1 and then examined by a series of behavioral test and histological analyses. The results have shown that the drug may be capable of reducing functional deficits after the lesion and promoting synaptic plasticity and neuroprotection, thus representing a putative translational approach for motoneuron disorders.

Developing a novel quantitative parameter for characterizing spatial distribution of fish following exposure to chemicals and wastewater: Behavioral Gini coefficient.

While the spatial distribution pattern of fish is increasingly used for toxicological test of chemicals or wastewater, no ideal parameter is available for quantitative assessment of spatial distribution, especially uneven distribution with multiple hotspots. Here, to develop a quantitative assessment parameter for spatial distribution, the zebrafish were exposed to ethanol, pentylenetetrazole (PTZ), paraquat dichloride (paraquat) and wastewater, followed by a behavioral test in a narrow tank. Behavioral data was acquired and analyzed by idTracker and MATLAB. By comparing the effects of all treatments on behavior parameters, we confirmed that the spatial distribution was more easily altered rather than general locomotor parameters, e.g. 0.7-70 mg/L PTZ and 5-20 mg/L paraquat being effective for altering spatial distribution but having little effects on general locomotor parameters. Based on the heatmap, i.e., the cumulative proportion of grids and that of frequency in grids, we calculated the behavioral Gini coefficient (Gb) for quantitative assessment of fish spatial distribution. The Gini coefficient ranged from zero to 1, with larger values meaning poorer evenness of spatial distribution. Of note, Gb showed smaller coefficient of variations (CV) with 3%-19% between replicate tanks in all treatments than the highest frequency (4%-79%), displaying well robustness. Especially, Gb addressed the challenge of the complicated heatmap with multiple hotspots. Overall, the behavioral Gini coefficient we established is an ideal parameter to quantitatively assess spatial distribution of fish shoal, which is expected to be applied in toxicity testing for chemicals and wastewater and automatic quality monitoring for surface water and aquaculture water.

The Single-Dose Application of Interleukin-4 Ameliorates Secondary Brain Damage in the Early Phase after Moderate Experimental Traumatic Brain Injury in Mice.

Activation of the interleukin-4 (IL-4) pathway ameliorates secondary injury mechanisms after experimental traumatic brain injury (TBI); therefore, we assessed the effect of a therapeutic IL-4 administration on secondary brain damage after experimental TBI. We subjected 100 C57/Bl6 wildtype mice to controlled cortical impact (CCI) and administered IL-4 or a placebo control subcutaneously 15 min thereafter. Contusion volume (Nissl staining), neurological function (hole board, video open field, and CatWalkXT®), and the immune response (immunofluorescent staining) were analyzed up to 28 days post injury (dpi). Contusion volumes were significantly reduced after IL-4 treatment up to 14 dpi (e.g., 6.47 ± 0.41 mm3 vs. 3.80 ± 0.85 mm3, p = 0.011 3 dpi). Macrophage invasion and microglial response were significantly attenuated in the IL-4 group in the acute phase after CCI (e.g., 1.79 ± 0.15 Iba-1+/CD86+ cells/sROI vs. 1.06 ± 0.21 Iba-1/CD86+ cells/sROI, p = 0.030 in the penumbra 3 dpi), whereas we observed an increased neuroinflammation thereafter (e.g., mean GFAP intensity of 3296.04 ± 354.21 U vs. 6408.65 ± 999.54 U, p = 0.026 in the ipsilateral hippocampus 7 dpi). In terms of functional outcome, several gait parameters were improved in the acute phase following IL-4 treatment (e.g., a difference in max intensity of -7.58 ± 2.00 U vs. -2.71 ± 2.44 U, p = 0.041 3 dpi). In conclusion, the early single-dose administration of IL-4 significantly reduces secondary brain damage in the acute phase after experimental TBI in mice, which seems to be mediated by attenuation of macrophage and microglial invasion.

Ranuncoside's attenuation of scopolamine-induced memory impairment in mice via Nrf2 and NF-ĸB signaling.

Scopolamine is a well-known pharmacological agent responsible for causing memory impairment in animals, as well as oxidative stress and neuroinflammation inducer which lead to the development of Alzheimer disease. Although a cure for Alzheimer's disease is unavailable. Ranuncoside, a metabolite obtained from a medicinal plant has demonstrated antioxidant and anti-inflammatory properties in vitro, making it a promising treatment with potential anti-Alzheimer disease properties. However, as ranuncoside has not been evaluated for its antioxidant and anti-neuroinflammatory properties in any in vivo model, our study aimed to evaluate its neurotherapeutic efficacy against scopolamine-induced memory impairment in adult male albino mice. Mice were randomly divided into four experimental groups. Mice of group I was injected with saline, group II was injected with scopolamine (1 mg/kg/day) for 3 weeks. After receiving a daily injection of scopolamine for 1 week, the mice of group III were injected with ranuncoside (10 mg/kg) every other day for 2 weeks along with scopolamine daily and group IV were injected with ranuncoside on 5th alternate days. Behavioral tests (i.e., Morris water maze and Y-maze) were performed to determine the memory-enhancing effect of ranuncoside against scopolamine's memory deleterious effect. Western blot analysis was also performed to further elucidate the anti-neuroinflammatory and antioxidant effects of ranuncoside against scopolamine-induced neuroinflammation and oxidative stress. Our results showed memory-enhancing, anti-neuroinflammatory effect, and antioxidant effects of ranuncoside against scopolamine by increasing the expression of the endogenous antioxidant system (i.e., Nrf2 and HO-1), followed by blocking neuroinflammatory markers such as NF-κB, COX-2, and TNF-α. The results also revealed that ranuncoside possesses hypoglycemic and hypolipidemic effects against scopolamine-induced hyperglycemia and hyperlipidemia in mice as well as scopolamine's hyperglycemic effect. In conclusion, our findings suggest that ranuncoside could be a potential agent for the management of Alzheimer's disease, hyperglycemia, and hyperlipidemia.

Synaptic loss and progression in mice infected with Angiostrongylus cantonensis in the early stage.

BACKGROUND: Angiostrongylus cantonensis is also known as rat lungworm. Infection with this parasite is a zoonosis that can cause eosinophilic meningitis and/or eosinophilic meningoencephalitis in humans and may lead to fatal outcomes in severe cases. In this study, we explored the mechanisms of the impairments in the cognitive functions of mice infected with A. cantonensis. METHODS: In infected mice with different infective intensities at different timepoint postinfection, loss and recovery of cognitive functions such as learning and memory abilities were determined. Neuronal death and damage to synaptic structures were analyzed by Western blotting and IHC in infected mice with different infection intensities at different timepoint postinfection. RESULTS: The results of behavioral tests, pathological examinations, and Golgi staining showed that nerve damage caused by infection in mice occurred earlier than pathological changes of the brain. BDNF was expressed on 14 day post-infection. Cleaved caspase-3 increased significantly in the late stage of infection. However, IHC on NeuN indicated that no significant changes in the number of neurons were found between the infected and uninfected groups. CONCLUSIONS: The synaptic loss caused by the infection of A. cantonensis provides a possible explanation for the impairment of cognitive functions in mice. The loss of cognitive functions may occur before severe immunological and pathological changes in the infected host.

Low-Intensity Pulsed Ultrasound Stimulation Inhibits Cortical Spreading Depression.

Cortical spreading depression (CSD), which is closely correlated with migraine aura, cerebral ischemia, seizure, and brain injury, is a spreading wave of neuronal and glial depolarization. The purpose of this study is to investigate whether low-intensity pulsed ultrasound stimulation (PUS) inhibits CSD by modulating neural activity and hemodynamics. Behavioral test, intrinsic signal optical imaging and western blot analysis were used for evaluating the inhibition effect of PUS on CSD in rat. We found that: 1) 30 min of PUS can significantly improve motor activity of rat with CSD. 2) Both 30 s and 30 min of PUS can significantly reduce count and propagation speed of CSD in rat and the inhibitory effect was enhanced with increase of ultrasound intensity. 3) 30 min of PUS significantly enhanced levels of brain-derived neurotrophic factor protein in brain tissue with CSD. These results suggest that PUS has the potential to treat brain disorders associated with CSD.

Microinjection of Reelin into the mPFC prevents MK-801-induced recognition memory impairment in mice.

Reelin, a large extracellular matrix protein, helps to regulate neuronal plasticity and cognitive function. Several studies have shown that Reelin dysfunction, resulting from factors such as mutations in gene RELN or low Reelin expression, is associated with schizophrenia (SCZ). We previously reported that microinjection of Reelin into cerebral ventricle prevents phencyclidine-induced cognitive and sensory-motor gating deficits. However, it remains unclear whether and how Reelin ameliorates behavioral abnormalities in the animal model of SCZ. In the present study, we evaluated the effect of recombinant Reelin microinjection into the medial prefrontal cortex (mPFC) on abnormal behaviors induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Microinjection of Reelin into the mPFC prevented impairment of recognition memory of MK-801-treated mice in the novel object recognition test (NORT). On the other hand, the same treatment had no effect on deficits in sensory-motor gating and short-term memory in the pre-pulse inhibition and Y-maze tests, respectively. To establish the neural substrates that respond to Reelin, the number of c-Fos-positive cells in the mPFC was determined. A significant increase in c-Fos-positive cells in the mPFC of MK-801-treated mice was observed when compared with saline-treated mice, and this change was suppressed by microinjection of Reelin into the mPFC. A K2360/2467A Reelin that cannot bind to its receptor failed to ameliorate MK-801-induced cognitive deficits in NORT. These results suggest that Reelin prevents MK-801-induced recognition memory impairment by acting on its receptors to suppress neural activity in the mPFC of mice.

The attractive effects of amino acids and some classical substances on grass carp (Ctenopharyngodon idellus).

Grass carp (Ctenopharyngodon idellus) is one of the most essential fishing species in China. The bait for this fish is rapidly developing. However, the study on the attractants in the bait for this fish lacks. This study was designed to systematically investigate the effects of 16 kinds of test substances on the perspective of behaviour and physiology of grass carp by using different kinds of methods, including behavioral tests (maze test and biting-balls test) and electro-olfactogram (EOG). Our experiment's idea is mainly to imitate: in addition to vision, fish in nature also use smell to find food and finally swallow under the action of olfaction, taste, and other sensory systems. Firstly, the behavioral maze test was used to screen the attractive or suppressive effect of 16 test substances on grass carp, and the electronic olfactory recording method was used to further evaluate the olfactory response of grass carp to the eight stimuli selected from the maze test. Then, the best concentrations of these eight stimuli and their combination were investigated by the biting-balls test to compound a formula with the strongest appetite for grass carp. The results of behavioral maze test showed that dimethyl-ß-propiothetin (DMPT), dimethylthetin (DMT), glycine, taurine, L-glutamic, L-alanine, L-proline, and L-arginine have different degrees of usefulness in attracting grass carp. The electro-olfactogram recoding showed that the EOG response of grass carp to the stimuli is a transient biphasic potential change and all of the eight stimuli could induce the EOG response of grass carp. The biting-balls test showed that glycine, L-glutamic, and L-arginine at 10-2 mol/L had significant feeding stimulation and DMT at 10-1 mol/L had significant feeding stimulation than the other groups. Finally, formula 9 composed of DMT, glycine, L-glutamic acid, and L-arginine has the greatest attraction for grass carp. The results of this study verified the attractive effect of some amino acids and other chemicals on grass carp fishing, and would provide support for the production of specific grass carp attractants.

Creative, Antagonistic, and Angry? Exploring the Roots of Malevolent Creativity with a Real-World Idea Generation Task.

Research is currently witnessing more investigations into malevolent creativity-creativity that is used to intentionally harm others. Inspired by previous methods to measure malevolent creativity, in the present study, we introduce a real-world behavioral task designed to capture individuals' capacity for using creativity for the purpose of attaining malevolent goals in response to everyday, provocative situations. In a sample of 105 students, we found malevolent creativity positively correlated with fluency in conventional creative ideation, as well as with self-reported typical malevolent creativity behavior in daily life. Moreover, performance on the malevolent creativity task showed positive correlations with the maladaptive personality trait of antagonism (PID-5) as well as individuals' state anger at the beginning of the experiment. Further, our multiple regression analysis revealed that conventional creative ideation, antagonistic personality, and state anger all explained unique, non-overlapping variance in the capacity for implementing malevolent creativity. As a whole, these findings suggest that different cognitive and affective factors, along with specific personality traits may each contribute to the expression of malevolent creativity in distinct ways. Future investigations striving to further decode the destructive potential of individuals toward others may benefit from this validated behavioral measurement approach to malevolent creativity.

Development of a novel gripping test for the evaluation of the finger fine motor ability in MPTP-treated monkeys.

Assessing the finger fine motor ability is extremely important. However, conventional behavioral tests in monkeys are complicated and costly. We attempted to develop a new task to assess the precise finger grip in Parkinson's disease monkeys based on the principles of objectification, multipurpose, and simplification. This study involved seven adult male cynomolgus monkeys. A gripping test based on the previous food reaching test was developed. Parallel experiments of food reaching test and gripping test affected by the treatments of levodopa and deep brain stimulation of the subthalamic nucleus were performed to verify the utility of the gripping test. We found that gross motor ability (measured by food reaching test) could be significantly improved by both the subthalamic nucleus and levodopa administration, which reproduced the results of our previous study. The finger fine motor ability (measured by the gripping test) could be significantly improved by levodopa administration, but not by the subthalamic nucleus. Our results verified the utility and reliability of the gripping test, which is a simple, convenient, and objective task for evaluating the finger fine motor skill in Parkinson's disease monkeys. Mechanisms of the efficacy of deep brain stimulation on fine motor ability require further investigation.

Toxicological and behavioral study of two potential antibacterial agents:4-chloromercuribenzoic acid and quercetin on Swiss-albino mice.

Global dissemination of carbapenem resistant-Gram negative bacteria (CR-GNB) is supposed to be clinically alarming because it extremely delimits the treatment options against serious infections. 4-Chloromercuribenzoic acid (pCMB) is an efficient metallo-enzyme inhibitor, and quercetin is known for antioxidant, antiviral, anticancer, antimicrobial, and anti-inflammatory activities. These two compounds could be considered as potential candidates for the treatment of CR-GNB mediated infections. Hence, in this study, antibacterial activity of pCMB and quercetin was evaluated against CR-GNB through minimum inhibitory concentration (MIC) determination. Toxicity of pCMB and quercetin was evaluated by LC50 calculation through brine shrimp test (BST) and by investigating hematological, serum biochemical, and histopathological parameters in Swiss-albino mice. Moreover, aggressive-depressive-cognitive behavioral effects of pCMB and quercetin on murine model were evaluated. All the carbapenem resistant isolates (CR-GNB) exhibited MIC values in the range of 4-256 µg/ml, 16-256 µg/ml, and 64-1024 µg/ml for pCMB, quercetin, and meropenem, respectively. BST determined LC50 of pCMB and quercetin at 91.57 ± 0.35 mg/L and 448.45 ± 0.46 mg/L, respectively. Oral administration of low dose of pCMB and quercetin did not induce any significant changes in morphological, behavioral, hematological, serum biochemical, and histopathological parameters among Swiss-albino mice. But, a high dose of pCMB and quercetin exhibited slight toxicity. However, no death was reported for any dosage of pCMB and quercetin. Therefore, pCMB and quercetin might be considered for further investigations on alternative therapeutics to combat against CR-GNB.

Low dose γ radiation enhances antidepressant effect of resveratrol: Behavioral and neurochemical studies.

The low dose of radiation (LDR) has received growing attention for its beneficial neuroprotective effect. This study was designed to investigate the enhancing effect of LDR on the antidepressant potential of resveratrol against diazepam-induced depression in mice. Female mice divided into five groups; control, diazepam (2 mg/kg), LDR (0.5Gy) + diazepam, resveratrol (20 mg/kg) + diazepam, LDR + resveratrol+diazepam. Mice received diazepam showed depressive symptoms as evidenced by decreased locomotor activity in the open field and increased immobility time in the forced swimming and tail suspension tests integrated with a marked decline in biogenic amines (serotonin, norepinephrine, and dopamine) in brain tissues. These effects were ameliorated by LDR or resveratrol administration demonstrating an antidepressant activity. Interestingly, LDR triggered the antidepressant effect of resveratrol as it restored the changes in behavioral tests, neurotransmitters, and neuro-histoarchitecture. In conclusion, these findings suggested that LDR could be considered as a novel adjuvant that augmented the resveratrol antidepressant effect and might serve as a potential therapeutic approach for depression.

Propranolol prevents cerebral blood flow changes and pain-related behaviors in migraine model mice.

Propranolol, a ß-adrenergic receptor blocker, is one of the most commonly used prophylactic drugs for migraines. Cortical spreading depression (CSD) is the propagation wave of neuronal excitation along with cerebral blood flow (CBF) changes over the cerebral cortex and has been implicated in the pathological process of migraine auras and its pain response. However, the effect of propranolol on CSD-related CBF changes and behavioral responses remains poorly understood. In this study, we measured CSD-related CBF responses using a micro-device with a green light emitting diode (LED) and micro-complementary-metal-oxide-semiconductor (CMOS) image sensor and evaluated pain-related reduced locomotor activity in mice. An injection of KCl into the visual cortex led to CSD-related CBF changes; however, propranolol prevented the increase in CBF as well as delayed the propagation velocity in KCl-induced CSD. Furthermore, an injection of KCl reduced locomotor activity and induced freezing behavior in awake and freely moving mice, which were prevented by propranolol treatment. These results suggest that the modulation of CSD-related CBF responses by the blockade of ß-adrenergic receptor contributes to its prophylactic effects on migraines.

Attenuation of neuro-inflammation improves survival and neurodegeneration in a mouse model of severe neonatal hyperbilirubinemia.

All pre-term newborns and a high proportion of term newborns develop neonatal jaundice. Neonatal jaundice is usually a benign condition and self-resolves within few days after birth. However, a combination of unfavorable complications may lead to acute hyperbilirubinemia. Excessive hyperbilirubinemia may be toxic for the developing nervous system leading to severe neurological damage and death by kernicterus. Survivors show irreversible neurological deficits such as motor, sensitive and cognitive abnormalities. Current therapies rely on the use of phototherapy and, in unresponsive cases, exchange transfusion, which is performed only in specialized centers. During bilirubin-induced neurotoxicity different molecular pathways are activated, ranging from oxidative stress to endoplasmic reticulum (ER) stress response and inflammation, but the contribution of each pathway in the development of the disease still requires further investigation. Thus, to increase our understanding of the pathophysiology of bilirubin neurotoxicity, encephalopathy and kernicterus, we pharmacologically modulated neurodegeneration and neuroinflammation in a lethal mouse model of neonatal hyperbilirubinemia. Treatment of mutant mice with minocycline, a second-generation tetracycline with anti-inflammatory and neuroprotective properties, resulted in a dose-dependent rescue of lethality, due to reduction of neurodegeneration and neuroinflammation, without affecting plasma bilirubin levels. In particular, rescued mice showed normal motor-coordination capabilities and behavior, as determined by the accelerating rotarod and open field tests, respectively. From the molecular point of view, rescued mice showed a dose-dependent reduction in apoptosis of cerebellar neurons and improvement of dendritic arborization of Purkinje cells. Moreover, we observed a decrease of bilirubin-induced M1 microglia activation at the sites of damage with a reduction in oxidative and ER stress markers in these cells. Collectively, these data indicate that neurodegeneration and neuro-inflammation are key factors of bilirubin-induced neonatal lethality and neuro-behavioral abnormalities. We propose that the application of pharmacological treatments having anti-inflammatory and neuroprotective effects, to be used in combination with the current treatments, may significantly improve the management of acute neonatal hyperbilirubinemia, protecting from bilirubin-induced neurological damage and death.

Dorsal Forebrain-Specific Deficiency of Reelin-Dab1 Signal Causes Behavioral Abnormalities Related to Psychiatric Disorders.

Reelin-Dab1 signaling is involved in brain development and neuronal functions. The abnormalities in the signaling through either reduction of Reelin and Dab1 gene expressions or the genomic mutations in the brain have been reported to be associated with psychiatric disorders. However, it has not been clear if the deficiency in Reelin-Dab1 signaling is responsible for symptoms of the disorders. Here, to examine the function of Reelin-Dab1 signaling in the forebrain, we generated dorsal forebrain-specific Dab1 conditional knockout mouse (Dab1 cKO) and performed a behavioral test battery on the Dab1 cKO mice. Although conventional Dab1 null mutant mice exhibit cerebellar atrophy and cerebellar ataxia, the Dab1 cKO mice had normal cerebellum and showed no motor dysfunction. Dab1 cKO mice exhibited behavioral abnormalities, including hyperactivity, decreased anxiety-like behavior, and impairment of working memory, which are reminiscent of symptoms observed in patients with psychiatric disorders such as schizophrenia and bipolar disorder. These results suggest that deficiency of Reelin-Dab1 signal in the dorsal forebrain is involved in the pathogenesis of some symptoms of human psychiatric disorders.

Effects of stress on behavior and resting-state fMRI in rats and evaluation of Telmisartan therapy in a stress-induced depression model.

BACKGROUND: The etiology of depression and its effective therapeutic treatment have not been clearly identified. Using behavioral phenotyping and resting-state functional magnetic resonance imaging (r-fMRI), we investigated the behavioral impact and cerebral alterations of chronic unpredictable mild stress (CUMS) in the rat. We also evaluated the efficacy of telmisartan therapy in this rodent model of depression. METHODS: Thirty-two rats were divided into 4 groups: a control group(C group), a stress group(S group), a stress + telmisartan(0.5 mg/kg)group (T-0.5 mg/kg group) and a stress + telmisartan(1 mg/kg) group (T-1 mg/kg group). A behavioral battery, including an open field test (OFT), a sucrose preference test (SPT), and an object recognition test (ORT), as well as r-fMRI were conducted after 4 weeks of CUMS and telmisartan therapy. The r-fMRI data were analyzed using the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) approach. The group differences in the behavior and r-fMRI test results as well as the correlations between these 2 approaches were examined. RESULTS: CUMS reduced the number of rearings and the total moved distance in OFT, the sucrose preference in SPT, and novel object recognition ability in ORT. The telmisartan treatment (1 mg/kg) significantly improved B-A/B + A in the ORT and improved latency scores in the OFT and SPT. The S group exhibited a decreased ReHo in the motor cortex and pons, but increased ReHo in the thalamus, visual cortex, midbrain, cerebellum, hippocampus, hypothalamus, and olfactory cortex compared to the C group. Telmisartan (1 mg/kg)reversed or attenuated the stress-induced changes in the motor cortex, midbrain, thalamus, hippocampus, hypothalamus, visual cortex, and olfactory cortex. A negative correlation was found between OFT rearing and ReHo values in the thalamus. Two positive correlations were found between ORT B-A and the ReHo values in the olfactory cortexand pons. CONCLUSIONS: Telmisartan may be an effective complementary drug for individuals with depression who also exhibit memory impairments. Stress induced widespread regional alterations in the cerebrum in ReHo measures while telmissartan can reverse part of theses alterations. These data lend support for future research on the pathology of depression and provide a new insight into the effects of telmisartan on brain function in depression.