Excitatory amino acid receptors in the prefrontal cortex of aging mice

The zones of the prefrontal cortex of Balb/c mice were tested for age-related changes of the ionotropic excitatory amino acid receptors density, together with zones of the dorsal cortex. Kainate, N-methyl-D-aspartate, and amino-3-hydroxy-5-methyloxazole-4-propionate sites were measured by slice receptor binding techniques in cortical zones from animals at the age of 6, 12, 18, and 24 months. An increase of the N-methyl-D-aspartate sites was detected in the medial prefrontal zone of mid-aged animals and was followed by a decrease at old age; a decrease of the N-methyl-D-aspartate and kainate sites was found for the medial dorsal (cingulate) cortex at old age. The age-related changes of receptor densities in the different cortical areas seem unrelated in origin. The sites decrease in the cingulate cortex could affect the transfer of the prefrontal cortex activity toward limbic structures.     

Role of the medial prefrontal cortex in N-methyl-D-aspartate receptor antagonist induced sensorimotor gating deficit in rats

The medial prefrontal cortex (mPFC) regulates sensorimotor gating measured as prepulse inhibition (PPI) of startle. We here tested the effect of lesions of the mPFC on the PPI-disruptive effect of the non-competitive NMDA receptor antagonist dizocilpine in rats. Neurotoxic lesions of the mPFC were induced by ibotenic acid. Rats were tested for PPI after systemic injection of dizocilpine (0.15 mg/kg) and after injection of the dopamine receptor agonist apomorphine (2 mg/kg). Dizocilpine failed to disrupt PPI in rats with mPFC lesions while the PPI-disruptive effect of apomorphine was not affected. Startle response magnitude in the absence of prepulses was not affected by mPFC lesions or drugs. These data suggest that the mPFC is an important brain region within the neuronal circuit responsible for NMDA receptor antagonist induced PPI-deficits.     

Neuronal activity in dorsomedial frontal cortex and prefrontal cortex reflecting irrelevant stimulus dimensions

Previous studies of the dorsomedial frontal cortex (DMF) and the prefrontal cortex (PF) have shown that, when monkeys respond to nonspatial features of a discriminative stimulus (e.g., color) and the stimulus appears at a place unrelated to the movement target, neurons nevertheless encode stimulus location. This observation could support the idea that these neurons always encode stimulus location, regardless of its relevance to an instrumentally conditioned behavior. Past studies, however, leave open the possibility that activity observed during one operant task might reflect the contingencies of a different task, performed at different times. To test these alternatives, we examined the activity of DMF and PF neurons in two rhesus monkeys conditioned to perform an operant eye-movement task in which only the color and shape of visual stimuli served as salient discriminative features. Each of eight stimuli was associated with a response to a different eye-movement target. The location of these stimuli varied from trial to trial but was of no behavioral relevance, and the monkeys did not perform any operant task in which stimulus location controlled behavior. A substantial minority of neurons in both DMF and PF nevertheless encoded stimulus location, which indicates that this property does not depend on its relevance in an instrumentally conditioned behavior. Electronic Publication     

PSA-NCAM expression in the human prefrontal cortex

The prefrontal cortex (PFC) of adult rodents is capable of undergoing neuronal remodeling and neuroimaging studies in humans have revealed that the structure of this region also appears affected in different psychiatric disorders. However, the cellular mechanisms underlying this plasticity are still unclear. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) may mediate these structural changes through its anti-adhesive properties. PSA-NCAM participates in neurite outgrowth and synaptogenesis and changes in its expression occur parallel to neuronal remodeling in certain regions of the adult brain. PSA-NCAM is expressed in the hippocampus and temporal cortex of adult humans, but it has not been studied in the PFC. Employing immunohistochemistry on sections from the rostromedial superior frontal gyrus we have found that PSA-NCAM is expressed in the human PFC neuropil following a laminated pattern and in a subpopulation of mature neurons, which lack doublecortin expression. Most of these cells have been identified as interneurons expressing calbindin. The expression of PSA-NCAM in the human PFC is similar to that of rodents. Since this molecule has been linked to the neuronal remodeling found in experimental models of depression, it may also participate in the structural plasticity described in the PFC of depressed patients.     

Evidence for involvement of N-methyl-D-aspartate receptor in tonic inhibitory control of dopaminergic transmission in rat medial frontal cortex

Bilateral infusion of DL-2-amino-5-phosphonovalerate (DL-APV) (which is a competitive antagonist for N-methyl-D-aspartate (NMDA) receptor) into the medial frontal cortex of conscious rats increased the amount of 3,4-dihydroxyphenylacetic acid (DOPAC) and the DOPAC/dopamine (DA) ratio in the cortical area. Moreover, intra-prefrontal injection of DL-APV, D-APV, DL-2-amino-7-phosphonoheptanoate and 3-[(+/-])-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (which are selective NMDA receptor antagonists), but not the L-isomer of APV and gamma-glutamyl-aminomethyl sulphonate (a relative antagonist for non-NMDA receptors), facilitated prefrontal DA utilization in a NMDA-reversible manner. These findings suggest that NMDA-type excitatory amino acid receptors may be involved in a tonic inhibitory regulation of dopaminergic transmission in the medial frontal cortex in vivo.     

Synapses are lost during aging in the primate prefrontal cortex

An electron microscopic analysis has been carried out on the effects of age on the numerical density of both excitatory (asymmetric) and inhibitory (symmetric) synapses in the neuropil of layers 2/3 and of layer 5 in area 46 from the frontal cortex of behaviorally tested rhesus monkeys. There is no change in the lengths of synaptic junctions with age or in the percentage distribution of synapses relative to the postsynaptic spines and dendritic shafts. However, in layers 2/3 there is an overall loss of about 30% of synapses from 5 to 30 years of age, and both asymmetric and symmetric synapses are lost at the same rate. In layer 5 the situation is different; the overall loss of synapses is only 20% and this is almost entirely due to a loss of asymmetric synapses, since there is no significant loss of symmetric synapses from this layer with age. When the synapse data are correlated with the overall cognitive impairment shown by the monkeys, it is found that there is a strong correlation between the numerical density of asymmetric synapses in layers 2/3 and cognitive impairment, with a weaker correlation between symmetric synapse loss and cognitive impairment. In layer 5 on the other hand there is no correlation between synapse loss and cognitive impairment. However synapse loss is not the only factor causing cognitive impairment, since in previous studies of area 46 we have found that age-related alteration in myelin in this frontal area also significantly contributes to cognitive decline. The synapse loss is also considered in light of earlier studies, which show that the frequency of spontaneous excitatory synaptic responses is reduced with age in layers 2/3 neurons.     

The expression of growth hormone receptor gene transcript in the prefrontal cortex is affected in male mice with diabetes-induced learning impairments

Stress plays a role in the development and severity of psychotic symptoms and there may be a genetic component to stress vulnerability in schizophrenia. Using an established mouse model for schizophrenia, we investigated the behavioural and endocrine response of Nrg1 transmembrane domain mutant mice (Nrg1 HET) and wild type-like (WT) littermates to acute restraint stress. Animals were screened at 3-4 months and 6-7 months of age (before and after onset of hyperlocomotion) for open field behaviour and serum corticosterone levels. In younger mice, stress reduced locomotive and explorative measures and increased anxiety-like behaviour regardless of genotype. Older Nrg1 mutants were less susceptible to the effects of stress on anxiety-related behaviours. All mice responded to restraint stress with robust increases in serum corticosterone. Importantly, the stress-induced increase in corticosterone was more pronounced in Nrg1 mutant than WT mice at the younger but not the older age. Our results suggest that transmembrane domain Nrg1 has only a moderate effect on the acute stress response of mice. The behavioural differences detected between WT and Nrg1 HET mice at the older age were evident without parallel modifications to the glucocorticoid system.     

PSA-NCAM expression in the rat medial prefrontal cortex

Modulation of soluble guanylate cyclase (sGC) by nitric oxide (NO) is altered in brain from cirrhotic patients. The aim of this work was to assess whether an animal model of cirrhosis, bile duct ligation, alone or combined with diet-induced hyperammonemia for 7-10 days reproduces the alterations in NO modulation of sGC found in brains from cirrhotic patients. sGC activity was measured under basal conditions and in the presence of NO in cerebellum and cerebral cortex of the following groups of rats: controls, bile duct ligation without or with hyperammonemia and hyperammonemia without bile duct ligation. In cerebellum activation of sGC by NO was significantly lower in bile duct ligated rats with (12 +/- five-fold) or without (14 +/- six-fold) hyperammonemia than in control rats (23 +/- seven-fold). In cerebral cortex activation of sGC by NO was higher in rats with bile duct ligation with hyperammonemia (124 +/- 30-fold) but not without hyperammonemia (59 +/- 15-fold) than in control rats (66 +/- 11-fold). The combination of bile duct ligation and hyperammonemia reproduces the alterations in the modulation of soluble guanylate cyclase by NO found in cerebral cortex and cerebellum of cirrhotic patients while bile duct ligation or hyperammonemia alone reproduces the effects in cerebellum but not in cerebral cortex.     

A decrease in interleukin-1 receptor antagonist expression in the prefrontal cortex of schizophrenic patients

Interleukin-1 (IL-1) mediates psychological stress responses by regulating monoamine metabolism and secretion of corticotropin-releasing factor, and is therefore, implicated in various psychiatric diseases. To evaluate the contribution of IL-1 signaling to the brain pathology of schizophrenia, we measured protein and/or mRNA levels for IL-1beta and endogenous IL-1 receptor antagonist (IL-1RA) in the postmortem brain tissues of prefrontal and parietal cortex, putamen, and hypothalamus. Both protein and mRNA levels of IL-1RA were specifically decreased in the prefrontal cortex of schizophrenic patients, whereas IL-1beta levels were not significantly altered in all the regions examined. The IL-1RA decrease was not correlated with the dose of antipsychotics given to patients. There was no influence of this illness on protein levels for IL-1 receptor type 1 in the prefrontal cortex, either. In contrast, IL-1RA serum levels were increased in schizophrenic patients, especially in drug-free patients, as reported previously. These findings suggest that chronic schizophrenia down-regulates IL-1RA production the prefrontal cortex, irrespective of its impact on the periphery. IL-1RA reduction might reflect an immunopathologic trait of the prefrontal region in schizophrenic patients.     

解偶联蛋白在肝性脑病小鼠黑质和前额叶皮层中表达变化

目的:观察不同时间内肝性脑病(Hepatic encephalopathy,HE)小鼠黑质和大脑前额叶皮层中线粒体解偶联蛋白2/4(Uncoupling Protein 2/4,UCP2/4)的变化及可能的关系。方法:取C57/BL小鼠,随机分为sham组、HE 1 d、4 d、7 d四组。HE组小鼠腹膜腔内注射硫代乙酰胺(TAA),sham组注射同等剂量的Na Cl。用Elisa检测小鼠血清中血清氨水平;随后分别运用Western Blot和RT-q PCR测定UCP2/4在黑质和前额叶皮层全组织蛋白和线粒体蛋白水平变化以及mRNA水平中的表达差异。结果:(1)肝性脑病组小鼠血氨水平较对照组小鼠明显升高(P0.01);在蛋白水平检测发现,(2)肝性脑病黑质中UCP2在总组织和线粒体水平表达均明显增加(P0.001),而UCP4却无明显变化(P0.05);(3)在肝性脑病前额叶皮层中UCP2和UCP4在总蛋白水平和线粒体提纯蛋白水平中均明显增加(P0.05);在RT-q PCR水平检测,(4)肝性脑病小鼠黑质中UCP2水平显著增加(P0.01),而UCP4未见明显变化(P0.05);(5)肝性脑病小鼠前额叶皮层发现UCP2(P0.001)和(P0.01)UCP4在mRNA水平均显著升高。结论:肝性脑病小鼠黑质和前额叶皮层中线粒体解偶联蛋白2和4发挥着重要的作用。     

Insulin receptors in the brain cortex of aging mice

The aim of the present study was to analyze whether aging also affects central insulin receptors in brain cortex as it does in whole brain of BALB/c-nu mice. Results showed statistically significant decrease of number and increase of affinity of insulin high affinity binding sites in old animals. As a consequence, central insulin actions, among which neuromodulation of monoaminergic system, can result altered during aging.     

Decreased expression of NEFH and PCP4/PEP19 in the prefrontal cortex of alcoholics

Patients with alcoholism exhibit behavioral adaptations to ethanol such as tolerance, dependence, and addiction. Molecular mechanisms that underlie these altered behavioral responses to ethanol are largely unclear. We have performed oligonucleotide microarray analysis in postmortem prefrontal cortices of alcoholics. Among about 12,000 genes represented on microarray, a total of 79 genes showed differential expression changes in alcoholics compared with control subjects, consisting of 54 up- and 25 down-regulated genes. Altered expressions in alcoholics were observed in genes having a wide range of biological functions. The remarkable findings were up-regulation of myelin-related genes and molecular chaperones in alcoholics. Among the genes identified, decreased expressions of NEFH and PCP4/PEP19 were further examined. NEFH encodes a component of neurofilament protein in neurons. PCP4/PEP19 encodes protein involved in calcium signaling and neuronal apoptosis. Observation of their down-regulations in alcoholics in microarray analysis was confirmed by real-time quantitative RT-PCR, and was also confirmed in the independent set of postmortem brains of alcoholics. The present results may provide some insights into understanding the mechanism of ethanol-induced altered behavioral responses at the molecular level.     

Impact of expected reward on neuronal activity in prefrontal cortex,frontal and supplementary eye fields and premotor cortex

In several regions of the macaque brain, neurons fire during delayed response tasks at a rate determined by the value of the reward expected at the end of the trial. The activity of these neurons might be related either to the internal representation of the appetitive value of the expected reward or to motivation-dependent variations in the monkey's level of motor preparation or motor output. According to the first interpretation, reward-related activity should be most prominent in areas affiliated with the limbic system. According to the second interpretation, it should be most prominent in areas affiliated with the motor system. To distinguish between these alternatives, we carried out single-neuron recording while monkeys performed a memory-guided saccade task in which a visual cue presented early in each trial indicated whether the reward would be large or small. Neuronal activity accompanying task performance was monitored in the dorsolateral prefrontal cortex (PFC), the frontal eye field (FEF), a transitional zone caudal to the frontal eye field (FEF/PM), premotor cortex (PM), the supplementary eye field (SEF), and the rostral part of the supplementary motor area (SMAr). The tendency for neuronal activity to increase after cues that predicted a large reward became progressively stronger in progressively more posterior areas both in the lateral sector of the frontal lobe (PFC < FEF < FEF/PM < PM) and in the medial sector (SEF < SMAr). The very strong reward-related activity of premotor neurons was presumably attributable to the monkey's motivation-dependent level of motor preparation or motor output. This finding points to the need to determine whether reward-related activity in other nonlimbic brain areas, including dorsolateral prefrontal cortex and the dorsal striatum, genuinely represents the value of the expected reward or, alternatively, is related to motivational modulation of motor signals.     

Cocaine alters catalase activity in prefrontal cortex and striatum of mice

Catalase is one of the enzymes that convert hydrogen peroxide (H2O2) to H2O presenting a protective role against free radicals. In this study, catalase activity was determined in homogenates of striatum (ST) and prefrontal cortex (PFC) in order to examine the participation of oxidative stress (OS) on cocaine actions in mice brain. Male Swiss mice were injected (i.p.) with cocaine at low (10 and 30 mg/kg) and high doses (90 mg/kg), and observed for 1 h. After cocaine overdose (90 mg/kg) some animals presented only status epilepticus (SE) while others died after seizures. These animals were dissected and divided in two groups, SE and death. Catalase activity was also determined after pretreatment with the anticonvulsant drug, diazepam, alone or injected before cocaine 90 mg/kg, and after seizures induced by a high dose of bupropion, a known inhibitor of NE and DA reuptake used for comparison. Results showed a decrease in catalase activity of the PFC and ST after SE and death induced by cocaine and bupropion overdoses. Cocaine at low doses decreased the enzyme activity only in ST. Diazepam treatment alone and before cocaine overdose did not interfere with catalase activity. This reduction in catalase activity may reflect an increase in H2O2 content in PFC and ST. Previous data reports that H2O2 inhibits dopamine transporter activity, suggesting that the decrease in catalase activity may potentiate the toxic mechanism of drugs that inhibit monoamines reuptake. As far as we know, this is the first report showing an involvement of OS in the cocaine's central mechanism of action.     

Voluntary facial expression and hemispheric asymmetry over the frontal cortex

Brain activity was monitored while 36 participants produced facial configurations denoting anger, disgust, fear, joy, and sadness. EEG alpha power was analyzed during each facial pose, with facial conditions grouped according to the approach/withdrawal motivational model of emotion. This model suggests that "approach" emotions are associated with relatively greater left frontal brain activity whereas "withdrawal" emotions are associated with relatively greater right frontal brain activity. In the context of a bilateral decrease in activation, facial poses of emotions in the withdrawal condition resulted in relatively less left frontal activation in the lateral-frontal, midfrontal and frontal-temporal-central region, but not in the parietal region, as predicted. Findings in the approach condition were less consistently supportive of predictions of the approach/withdrawal model. Implications for the approach/withdrawal model and for the emotion eliciting potential of voluntary facial movement are discussed.     

More is less: Emotion induced prefrontal cortex activity habituates in aging

Several recent studies have documented age-related changes in brain activity—less amygdala activity and higher prefrontal activity in response to emotional stimuli. Using functional magnetic resonance imaging (fMRI), we examined whether aging also affects the maintenance of activity to emotional stimuli and whether maintenance differs by the valence (negative, neutral and positive) of the pictures. Younger participants had a larger volume of activity in the amygdala but less in the prefrontal cortex than the old. The old showed more habituation to highly arousing negative but not positive or neutral stimuli in prefrontal cortex as compared to younger participants. Thus prefrontal cortex activity indexes emotion in the elderly, but not the young. Amplified prefrontal activity suggests elderly increase cognitive control for negative, highly arousing emotional stimuli, but it is not maintained. Taken together, age-related increases in prefrontal activity and reduced amygdala activity may underlie observed affective changes in aging.     

Involvement of neurotrophic factors in aging of noradrenergic innervations in hippocampus and frontal cortex

In the present study, we investigated the age-dependent changes in the axon terminals of the locus coeruleus (LC) neurons in the frontal cortex and hippocampus, in which a high degree of axonal branching in the middle-aged brain was suggested to occur in our previous electrophysiological study. We used 6-, 13- and 25-month-old male F344/N rats, and performed Western blot analysis of the norepinephrine transporter (NET), brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). NET expression level increased in the 13-month-old hippocampus, but was not altered by aging in the frontal cortex. BDNF expression level increased in the hippocampus, but did not change with age in the frontal cortex. On the other hand, GDNF expression level was increased with age in the frontal cortex, but was not in the hippocampus. These results suggest that the LC noradrenergic innervations may be locally regulated by different neurotrophic factors that exert their trophic actions at different target sites.     

糖尿病大鼠视网膜N-甲基-D-天门冬氨酸受体表达的变化

目的:观察糖尿病不同时期视网膜 N-甲基-D-天门冬氨酸(NMDA)受体各亚基的表达.方法:采用雄性 SD 大鼠腹腔内注射链脲佐菌素建立糖尿病大鼠模型,分别于4、8、12周灌注,取眼球、冷冻切片;免疫组织化学、原位杂交方法检测NMDA 受体 NRl、NR2A、NR2B 亚基表达的变化;用 RS IMAGE 软件进行图像分析.结果:NRl、NR2A、NR2B 基因及其蛋白表达在糖尿病第 4 周时开始升高,至12周升高具有统计学意义,特别是 NRl 的变化更为显著.结论:NMDA 受体各亚基的高表达参与了糖尿病视网膜病变.