Acclimatization to middle altitude hypoxia protects against developmental and cognitive deficits caused by acute fetal hypoxia in mice.

Acute fetal hypoxia (AFH) can elicit postnatal motor deficits and cognitive impairments. To test whether lifelong acclimatization to middle altitude (MA) hypoxia has protective effects on the impairments caused by AFH, ICR mice bred at 1 900 m altitude for 6-7 generations were evaluated under AFH. On gestation day 9 (GD 9), 13 (GD 13) or 17 (GD 17), pregnant mice received a single exposure to acute hypoxia (7% O2, 6 h). Physiological and neurodevelopmental behaviors, motor function (open field), spatial learning and memory (Morris water maze), and anxiety level (elevated plus maze) were examined in the offspring from neonate to adulthood. In the neonatal age, among all the physiological and behavioral landmarks, almost no differences were found in the hypoxia groups. In the juvenile period, no obvious impairments of motor function and anxiety level were found in the hypoxia groups. In the adult period, no obvious impairment of motor function was found in hypoxia groups; Interestingly, AFH groups' offspring showed normal or enhanced long-term spatial memory ability after AFH. These data suggest that AFH cause little abnormalities in the offspring of MA-adapted mice. To further investigate the underlying mechanisms, the neuronal numbers in behavior-related brain areas (accumbens nucleus, basal amygdala and hippocampus) were counted, and the physiological parameters of the blood were measured. The morphological data showed that no obvious neuronal necrosis was found in all hypoxia groups. In addition, blood tests showed that red blood corpuscle count, hemoglobin concentration and hematocrit levels in mice raised at MA were markedly higher in both males and females, compared with controls raised at the sea level. These data suggest that lifelong acclimatization to MA hypoxia has protective effects against development delay, motor deficits and spatial learning and memory impairments induced by AFH, and the protective effects may be due to higher hemoglobin concentration and hematocrit levels in the blood. The findings may provide a better understanding of fetal hypoxia and potential intervention treatments.

Rhesus monkey brain development during late infancy and the effect of phencyclidine: a longitudinal MRI and DTI study.

Early brain development is a complex and rapid process, the disturbance of which may cause the onset of brain disorders. Based on longitudinal imaging data acquired from 6 to 16 months postnatal, we describe a systematic trajectory of monkey brain development during late infancy, and demonstrate the influence of phencyclidine (PCP) on this trajectory. Although the general developmental trajectory of the monkey brain was close to that of the human brain, the development in monkeys was faster and regionally specific. Gray matter volume began to decrease during late infancy in monkeys, much earlier than in humans in whom it occurs in adolescence. Additionally, the decrease of gray matter volume in higher-order association regions (the frontal, parietal and temporal lobes) occurred later than in regions for primary functions (the occipital lobe and cerebellum). White matter volume displayed an increasing trend in most brain regions, but not in the occipital lobe, which had a stable volume. In addition, based on diffusion tensor imaging, we found an increase in fractional anisotropy and a decrease in diffusivity, which may be associated with myelination and axonal changes in white matter tracts. Meanwhile, we tested the influence of 14-day PCP treatment on the developmental trajectories. Such treatment tended to accelerated brain maturation during late infancy, although not statistically significant. These findings provide comparative information for the understanding of primate brain maturation and neurodevelopmental disorders.

Parameter comparison of white matter diffusion tensor imaging (DTI) in rhesus macaques (Macaca mulatta).

In this study, we analyzed diffusion tensor imaging (DTI) results of brain white matter in rhesus macaques (Macaca mulatta) with four different parameter settings and found that the sequence A (b=1 000 s/mm(2), spatial resolution=1.25 mm×1.25 mm× 1.25 mm, numbers of direction=33, NSA=3) and B (b=800 s/mm(2), spatial resolution=1.25 mm×1.25 mm×1.25 mm, numbers of direction=33, NSA=3) could accurately track coarse fibers. The fractional anisotropy (FA) derived from sequence C (b=1 000s/mm(2), spatial resolution=0.55 mm×0.55 mm×2.5 mm, direction number=33, NSA=3) was too fuzzy to be used in tracking white matter fibers. By comparison, the high resolution and the FA with high contrast of gray matter and white matter derived from sequence D (b=800 s/mm(2), spatial resolution=1.0 mm×1.0 mm ×1.0 mm, numbers of direction=33, NSA=3) qualified in its application in tracking both thick and thin fibers, making it an optimal DTI setting for rhesus macaques.

Age- and gender-related metabonomic alterations in striatum and cerebellar cortex in rats.

In order to identify the neurochemical alterations in motor associated subcortical nuclei, and enhance our understanding of neurophysiology of progressive reduction in fine motor control with aging, the metabolic changes in striatum and cerebellar cortex in SD rats along with aging were investigated using a metabonomic approach based on high resolution "magic angle spinning" 1H-NMR spectroscopy and partial least squares-discriminant analysis. It was found that there were increased myo-inositol and lactate, and decreased taurine in these two brain regions of old rats. The above changes may be a marker for alterations of neuronal cells, which reduce fine motor control. Besides, some of the metabolites are gender-related and region-specific. Old female rats had decreased glutamate and increased creatine in striatum, while old male rats had increased choline in striatum, and increased GABA in cerebellar cortex, respectively. However, further analyses showed that most of the metabolites in male rats were not distinctively different with those of female ones except choline, which was in a relative lower level in striatum of male rats. All this results suggest that energy metabolism is an important indication of age-related change, which is not only in male, but also in female rats.

Metabonomic alterations in hippocampus, temporal and prefrontal cortex with age in rats.

The metabolic changes in hippocampus, temporal cortex and prefrontal cortex in SD rats along with aging were explored using a metabonomic approach, which based on high resolution "magic angle spinning"(1)H NMR spectroscopy. The metabolite profiles were analyzed by partial least squares-discriminant analysis, and the results showed that the metabolites of the above three brain regions in old rats were dramatically different from that in the adult and young rats. The old rats showed increased myo-inositol and lactate in all of the three brain regions, and decreased N-acetylaspartate in temporal and frontal cortex, Glutamate-GABA level became imbalance in temporal cortex of old rats. In addition, compared with the adult female rats, male rats had higher levels of N-acetylaspartate, taurine, and creatine in temporal or frontal cortex. The age-related metabolic changes may indicate the early functional alterations of neural cells in these brain regions, especially the temporal cortex. The gender-related metabolic changes suggest the significance of the hormonal regulation in brain metabolism. Our work highlights the potential of metabolic profiling to enhance our understanding of biological mechanisms of brain aging.

Metabolic changes in temporal lobe structures measured by HR-MAS NMR at early stage of electrogenic rat epilepsy.

The purpose of this study was to determine cerebral metabolic profile changes in response to electric stimulation to the right dorsal hippocampus (HPC) for the establishment of an epileptic rat model. Electroencephalogram measurements and behavioral results indicated that the experimental rats were in an early stage of epilepsy. Metabolites were determined by high-resolution magic-angle-spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy of the following intact brain tissue: bilateral hippocampi, entorhinal cortices (ECs), and temporal lobes (TLs). The NMR data was statistically analyzed using principal component analysis (PCA). Results demonstrated that metabolic profiles were significantly different between the experimental and sham rats in the bilateral hippocampi and the ipsilateral EC. Significant increases in total creatine in the ipsilateral HPC and alanine in the ipsilateral TL were measured (p<0.05). Some metabolite levels were disturbed in the bilateral HPC-EC loops. In the sham group, glutamate and choline concentrations were significantly higher or lower in the ipsilateral EC than bilateral hippocampi, respectively (p<0.01). However, such differences were not observed in the experimental group. In addition, N-acetylaspartate levels in the experimental group were significantly less in the ipsilateral HPC than in bilateral ECs (p<0.05). The level of myo-inositol in the ipsilateral EC significantly increased in the experimental group, compared to the contralateral EC (p<0.05). These results may provide metabolic information about temporal lobe structures to provide more knowledge about epileptic abnormalities at the early stage.

[Characteristics of neural information encoding in epileptic networks involved in rat caudate putamen-hippocampi].

AIM: To study the characteristics of neural information encoding of the epileptic networks involved caudate-putamen(CPu) and the hippocampi induced by tetanization of the right CPu in rats. METHODS: Experiments were performed on 59 SD rats. Acute or chronic tetanization of the right CPu (ATRC or CTRC) (60Hz,0.4-0.6 mA, 2 s) was used to induce rat epilepsy. RESULTS: (1) The bursting or primary unit afterdischarges of single neurons were asymmetric in dual hippocampi induced by the ATRC. (2) Continuous sharp waves were observed in ipsilateral or contralateral CPu induced by the CTRC. The oscillatory network seizures with phase shift appeared between two sharp waves in ipsilateral CPu. The frequency of oscillatory waves was negatively correlated with the time and fluctuated from 70 Hz to 110 Hz, then to 35 Hz, and finally to 30 Hz. (3) In the contralateral side primary network after discharges in the CPu were induced by the CTRC. Therefore, the characteristic primary network afterdischarges could be shifted from the CPu or to the HPC, but amplified. On the other hand, HPC sharp waves could be depressed when the CPu network seizures occurred. CONCLUSION: The reestablishment of CPu-hippocampal epileptic networks could be transhemispherically promoted by over-activation of the right CPu network, in which bilateral hippocampal neuronal network and CPu neural network were involved in some particular pathophysiological information encoding.

[Network interactions between caudate putamen and hippocampus contralateral to the right tetanized corpus callosum in rats].

AIM: To study the role of epileptic neural networks reestablished in contralateral caudate putamen (CPu)-hippocampus(HPC) by using chronic tetanization of the right corpus callosum (CTRCC). METHODS: Experiments were performed on 50 SD rats under anaesthesia. The left CPu (LCPu) and the left HPC(LHPC) electrographs were synchronously recorded after acute tetanization following CTRCC (60 Hz, 0.4-0.6 mA, 2 s). RESULTS: (1) In contralateralization to the side implanted interconvertible network inhibition between the CPu and the HPC were induced by combinedly using chronic and acute tetanization of the RCC. (2) Electrographic kindling in the LCPu or in the LHPC was recorded after CTRCC. (3) In case the LCPu or the LHPC electrographs were not kindled after CTRCC, hypsarrhythmia in the LCPu and reduced sharp waves in the HPC were induced b y repetitive tetanization of the RCC once again. Primary afterdischarges in the LCPu or in the LHPC electrographs were evoked by combinedly using chronic and acute tetanization of the RCC. CONCLUSION: Pathophysiological neural networks in the CPu and in the HPC might be reestablished in another side of hemispheres by chronic over-activation of the right CC, which is related to epileptogenesis. Abnormal interactions between the two functional neural networks might be involved in formation of secondary epileptic focus.

[Characteristics of electrographic and behavioral seizures induced by chronic tetanization of the right caudate-putamen in rats].

AIM: The electrographic and behavioral kindling effects were induced by chronic tetanization of the right caudate-putamen (CPu) to study the target-behavior expression involved in the CPu or hippocampus (HPC) network abnormalities. METHODS: Experiments were performed on 58 SD rats. Tetanization (60Hz,0.4 - 0.6mA, 2s) was delivered into the CPu or the HPC, once a day, for 7-12 days. Animal behaviors were observed every day and depth electrographs were recorded at the beginning or at the end of the experiments. RESULTS: Chronic tetanization of the CPu or of the HPC induced: (1) Rhythmic sharp waves in the CPu and paroxysmal epileptiform events in the HPC electrographs. (2) Primary behavioral seizures, secondary behavioral seizures, and kindling effects, including wet dog shakes (WEDS), rearing, face washing, immobility, chewing and head nodding. (3) Lower rate of primary WEDS (P < 0.01), and higher rate of secondary WEDS (P < 0.01) in the CPu-tetanized rats. (4) Longer silent period of behavioral seizures before kindling appeared in the CPu-tetanized rats. CONCLUSION: Kindling effects in the CPu-tetanized rats resembles those in the HPC-tetanized rats. The CPu might participate in the origin of epileptic focus and be involved in reestablishment of limbic epileptic networks, which may be responsible for the target-behavioral seizures.