Lesions within the head direction system reduce retrosplenial c-fos expression but do not impair performance on a radial-arm maze task.

The lateral mammillary nuclei are a central structure within the head direction system yet there is still relatively little known about how these nuclei contribute to spatial performance. In the present study, rats with selective neurotoxic lesions of the lateral mammillary nuclei were tested on a working memory task in a radial-arm maze. This task requires animals to distinguish between eight radially-oriented arms and remember which arms they have entered within a session. Even though it might have been predicted that this task would heavily tax the head direction system, the lesion rats performed equivalently to their surgical controls on this task; no deficit emerged even when the task was made more difficult by rotating the maze mid-way through testing in order to reduce reliance on intramaze cues. Rats were subsequently tested in the dark to increase the use of internally generated direction cues but the lesion rats remained unimpaired. In contrast, the lateral mammillary nuclei lesions were found to decrease retrosplenial c-Fos levels. These results would suggest that the head direction system is not required for the acquisition of the standard radial-arm maze task. It would also suggest that small decreases in retrosplenial c-Fos are not sufficient to produce behavioural impairments.

Glial response to 17ß-estradiol in neonatal rats with excitotoxic brain injury.

White-matter injury is the most common cause of the adverse neurodevelopmental outcomes observed in preterm infants. Only few options exist to prevent perinatal brain injury associated to preterm delivery. 17ß-estradiol (E2) is the predominant estrogen in circulation and has been shown to be neuroprotective in vitro and in vivo. However, while E2 has been found to modulate inflammation in adult models of brain damage, how estrogens influence glial cells response in the developing brain needs further investigations. Using a model of ibotenate-induced brain injury, we have refined the effects of E2 in the developing brain. E2 provides significant neuroprotection both in the cortical plate and the white matter in neonatal rats subjected to excitotoxic insult mimicking white matter and cortical damages frequently observed in very preterm infants. E2 promotes significant changes in microglial phenotypes balance in response to brain injury and the acceleration of oligodendrocyte maturation. Maturational effects of E2 on myelination process were observed both in vivo and in vitro. Altogether, these data demonstrate that response of glial cells to E2 could be responsible for its neuroprotective properties in neonatal excitotoxic brain injury.

Neurodegeneration with inflammation is accompanied by accumulation of iron and ferritin in microglia and neurons.

Chronic inflammation in the substantia nigra (SN) accompanies conditions with progressive neurodegeneration. This inflammatory process contributes to gradual iron deposition that may catalyze formation of free-radical mediated damage, hence exacerbating the neurodegeneration. This study examined proteins related to iron-storage (ferritin) and iron-export (ferroportin) (aka metal transporter protein 1, MTP1) in a model of neurodegeneration. Ibotenic acid injected stereotactically into the striatum leads to loss of GABAergic neurons projecting to SN pars reticulata (SNpr), which subsequently leads to excitotoxicity in the SNpr as neurons here become vulnerable to their additional glutamatergic projections from the subthalamic nucleus. This imbalance between glutamate and GABA eventually led to progressive shrinkage of the SNpr and neuronal loss. Neuronal cell death was accompanied by chronic inflammation as revealed by the presence of cells expressing ED1 and CD11b in the SNpr and the adjacent white matter mainly denoted by the crus cerebri. The SNpr also exhibited changes in iron metabolism seen as a marked accumulation of inflammatory cells containing ferric iron and ferritin with morphology corresponding to macrophages and microglia. Ferritin was detected in neurons of the lesioned SNpr in contrast to the non-injected side. Compared to non-injected rats, surviving neurons of the SNpr expressed ferroportin at unchanged level. Analyses of dissected SNpr using RT-qPCR showed a rise in ferritin-H and -L transcripts with increasing age but no change was observed in the lesioned side compared to the non-lesioned side, indicating that the increased expression of ferritin in the lesioned side occurred at the post-transcriptional level. Hepcidin transcripts were higher in the lesioned side in contrast to ferroportin mRNA that remained unaltered. The continuous entry of iron-containing inflammatory cells into the degenerating SNpr and their subsequent demise is probably responsible for iron donation in neurodegeneration. This is accompanied by only a slight increase in neuronal ferritin and not ferroportin, which suggests that the iron-containing debris of dying inflammatory cells and degenerating neurons gets scavenged by invading macrophages and activated microglia to prevent an increase in neuronal iron.

Parabrachial Nucleus Contributions to Glucagon-Like Peptide-1 Receptor Agonist-Induced Hypophagia.

Exendin-4 (Ex4), a glucagon-like peptide-1 receptor (GLP-1R) agonist approved to treat type 2 diabetes mellitus, is well known to induce hypophagia in human and animal models. We evaluated the contributions of the hindbrain parabrachial nucleus (PBN) to systemic Ex4-induced hypophagia, as the PBN receives gustatory and visceral afferent relays and descending input from several brain nuclei associated with feeding. Rats with ibotenic-acid lesions targeted to the lateral PBN (PBNx) and sham controls received Ex4 (1 µg/kg) before 24 h home cage chow or 90 min 0.3 M sucrose access tests, and licking microstructure was analyzed to identify components of feeding behavior affected by Ex4. PBN lesion efficacy was confirmed using conditioned taste aversion (CTA) tests. As expected, sham control but not PBNx rats developed a CTA. In sham-lesioned rats, Ex4 reduced chow intake within 4 h of injection and sucrose intake within 90 min. PBNx rats did not show reduced chow or sucrose intake after Ex4 treatment, indicating that the PBN is necessary for Ex4 effects under the conditions tested. In sham-treated rats, Ex4 affected licking microstructure measures associated with hedonic taste evaluation, appetitive behavior, oromotor coordination, and inhibitory postingestive feedback. Licking microstructure responses in PBNx rats after Ex4 treatment were similar to sham-treated rats with the exception of inhibitory postingestive feedback measures. Together, the results suggest that the PBN critically contributes to the hypophagic effects of systemically delivered GLP-1R agonists by enhancing visceral feedback.

Lesions of the laterodorsal tegmental nucleus alter the cholinergic innervation and neuropeptide Y expression in the medial prefrontal cortex and nucleus accumbens.

The effects of the ibotenic acid infused into the area of the laterodorsal tegmental nucleus (LDT) of rats on the expression of cortical and accumbal neuropeptides were assessed. The effects of this manipulation were determined in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) by estimating the numerical density of varicosities immunoreactive for vesicular acetylcholine transporter and the total number of NAc neurons immunoreactive for choline acetyltransferase (ChAT) and neuropeptide Y (NPY) as well as the total number of mPFC neurons immunoreactive for NPY and vasoactive intestinal polypeptide (VIP). In LDT-lesioned rats, the density of the cholinergic varicosities was reduced in the ventral divisions of the mPFC and in all divisions of the NAc. In addition, in these rats, the total number of NPY-immunoreactive neurons was reduced in all subregions of the mPFC and in the NAc. Conversely, the total number of VIP-immunoreactive neurons in the mPFC and of ChAT-immunoreactive neurons in the NAc did not differ between LDT- and sham-lesioned rats. These data provide the first direct evidence for a relationship between selective damage of LDT cholinergic neurons and decreased expression of NPY in the mPFC and NAc. They also reveal that different types of cortical and accumbal interneurons respond differently to the cholinergic denervation induced by LDT lesions.

3,4-dihydroxyphenylethanol attenuates spatio-cognitive deficits in an Alzheimer's disease mouse model: modulation of the molecular signals in neuronal survival-apoptotic programs.

Alzheimer's disease (AD), the most common type of dementia, is a devastating neurodegenerative disease characterized by progressive neuro-cognitive dysfunction. In our study, we investigated the potential of 3,4-dihydroxyphenylethanol (DOPET), a dopamine metabolite, and also a polyphenol from olive oil, in ameliorating soluble oligomeric amyloid ß1-42 plus ibotenic acid (oA42i)-induced neuro-behavioral dysfunction in C57BL/6 mice. The results depicted that intracerebroventricular injection of oA42i negatively altered the spatial reference and working memories in mice, whereas DOPET treatment significantly augmented the spatio-cognitive abilities against oA42i. Upon investigation of the underlying mechanisms, oA42i-intoxicated mice displayed significantly activated death kinases including JNK- and p38-MAPKs with concomitantly inhibited ERK-MAPK/RSK2, PI3K/Akt1, and JAK2/STAT3 survival signaling pathways in the hippocampal neurons. Conversely, DOPET treatment reversed these dysregulated signaling mechanisms comparable to the sham-operated mice. Notably, oA42i administration altered the Bcl-2/Bad levels and activated the caspase-dependent mitochondria-mediated apoptotic pathway involving cytochrome c, apoptotic protease activating factor-1, and caspase-9/3. In contrary, DOPET administration stabilized the dysregulated activities of these apoptotic/anti-apoptotic markers and preserved the mitochondrial ultra-architecture. Besides, we observed that oA42i intoxication substantially down-regulated the expression of genes involved in the regulation of survival and memory functions including sirtuin-1, cyclic AMP response element-binding protein (CREB), CREB-target genes (BDNF, c-Fos, Nurr1, and Egr1) and a disintegrin and metalloprotease 10. Fascinatingly, DOPET treatment significantly diminished these aberrations when compared to the oA42i group. Taken together, these results accentuate that DOPET may be a multipotent agent to combat AD.

Cognitive control and the anterior cingulate cortex: how conflicting stimuli affect attentional control in the rat.

Converging evidence supports the hypothesis that the prefrontal cortex is critical for cognitive control. One prefrontal subregion, the anterior cingulate cortex, is hypothesized to be necessary to resolve response conflicts, disregard salient distractors and alter behavior in response to the generation of an error. These situations all involve goal-oriented monitoring of performance in order to effectively adjust cognitive processes. Several neuropsychological disorders, e.g., schizophrenia, attention deficit hyperactivity and obsessive compulsive disorder, are accompanied by morphological changes in the anterior cingulate cortex. These changes are hypothesized to underlie the impairments on tasks that require cognitive control found in these subjects. A novel conflict monitoring task was used to assess the effects on cognitive control of excitotoxic lesions to anterior cingulate cortex in rats. Prior to surgery all subjects showed improved accuracy on the second of two consecutive, incongruent trials. Lesions to the anterior cingulate cortex abolished this. Lesioned animals had difficulty in adjusting cognitive control on a trial-by-trial basis regardless of whether cognitive changes were increased or decreased. These results support a role for the anterior cingulate cortex in adjustments in cognitive control.

Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia.

Abnormal development can lead to deficits in adult brain function, a trajectory likely underlying adolescent-onset psychiatric conditions such as schizophrenia. Developmental manipulations yielding adult deficits in rodents provide an opportunity to explore mechanisms involved in a delayed emergence of anomalies driven by developmental alterations. Here we assessed whether oxidative stress during presymptomatic stages causes adult anomalies in rats with a neonatal ventral hippocampal lesion, a developmental rodent model useful for schizophrenia research. Juvenile and adolescent treatment with the antioxidant N-acetyl cysteine prevented the reduction of prefrontal parvalbumin interneuron activity observed in this model, as well as electrophysiological and behavioral deficits relevant to schizophrenia. Adolescent treatment with the glutathione peroxidase mimic ebselen also reversed behavioral deficits in this animal model. These findings suggest that presymptomatic oxidative stress yields abnormal adult brain function in a developmentally compromised brain, and highlight redox modulation as a potential target for early intervention.

Remote context fear conditioning remains hippocampus-dependent irrespective of training protocol, training-surgery interval, lesion size, and lesion method.

Systems consolidation involves the reorganization of brain circuits that support long-term memory. It is a prolonged process that can take days, weeks, or longer. An animal model of systems consolidation was established in the early 1990s and provided compelling support for the initial observations in humans, that hippocampal damage disproportionally impairs recent memory compared to remote memory. Context fear conditioning was the most frequently and successfully used task to study systems consolidation and demonstrate temporally graded retrograde amnesia. However, recent studies have failed to support these early findings of temporal gradients and instead reported that both recent and remote memories are equally impaired. Thus, the status of context fear conditioning as method to study the process of systems consolidation is at present uncertain. Accordingly, we evaluated classically conditioned fear memory in large groups of rats with hippocampal damage by manipulating several procedural variables including the training protocol, the training-surgery interval, the extent of hippocampal damage, and the method of damaging the hippocampus. The results indicate that hippocampal damage profoundly impairs context fear conditioning. These findings are unambiguous and independent of any particular procedural manipulation we evaluated. We suggest that the preponderance of currently available evidence indicates that context fear memory remains hippocampus-dependent indefinitely.

Cyclin D1 is required for proliferation of Olig2-expressing progenitor cells in the injured cerebral cortex.

Little is known about the molecular mechanisms driving proliferation of glial cells after an insult to the central nervous system (CNS). To test the hypothesis that the G1 regulator cyclin D1 is critical for injury-induced cell division of glial cells, we applied an injury model that causes brain damage within a well-defined region. For this, we injected the neurotoxin ibotenic acid into the prefrontal cortex of adult mice, which leads to a local nerve cell loss but does not affect the survival of glial cells. Here, we show that cyclin D1 immunoreativity increases drastically after neurotoxin injection. We find that the cyclin D1-immunopositive (cyclin D1+) cell population within the lesioned area consists to a large extent of Olig2+ oligodendrocyte progenitor cells. Analysis of cyclin D1-deficient mice demonstrates that the proliferation rate of Olig2+ cells diminishes upon loss of cyclin D1. Further, we show that cyclin-dependent kinase (cdk) 4, but not cdk6 or cdk2, is essential for driving cell division of Olig2-expressing cells in our injury model. These data suggest that distinct cell cycle proteins regulate proliferation of Olig2+ progenitor cells following a CNS insult.

Chronic administration of risperidone in a rat model of schizophrenia: a behavioural, morphological and molecular study.

In the present work we analyzed the effect of the chronic administration of risperidone (2mg/kg over 65 days) on behavioural, morphological and molecular aspects in an experimental model of schizophrenia obtained by bilateral injection of ibotenic acid into the ventral hippocampus of new-born rats. Our results show that during their adult lives the animals with hippocampal lesions exhibit different alterations, mainly at behavioural level and in the gene expression of dopamine D(2) and 5-HT(2A) receptors. However, at morphological level the study performed on the prefrontal cortex did not reveal any alterations in either the thickness or the number of cells immunoreactive for c-Fos, GFAP, CBP or PV. Overall, risperidone administration elicited a trend towards the recovery of the values previously altered by the hippocampal lesion, approaching the values seen in the animals without lesions. It may be concluded that the administration of risperidone in the schizophrenia model employed helps to improve the altered functions, with no significant negative effects.

Potentiation of response to low doses of levodopa in MPTP-injected monkeys by chemical unilateral subthalamotomy.

OBJECT: Subthalamotomy is a stereotactic surgery performed in patients with disabling dyskinesias due to Parkinson disease. The authors set out to model this human condition in MPTP monkeys and determine if subthalamotomy allowed a reduction of levodopa for similar benefit. METHODS: The authors performed unilateral subthalamotomy in 4 parkinsonian dyskinetic monkeys by stereotactic injection of ibotenic acid. An optimal dose, defined as the highest dose of levodopa improving parkinsonian motor symptoms while inducing low or no dyskinesias, was established in these animals. Each monkey was scored for the antiparkinsonian and dyskinetic effects of the optimal dose of levodopa, as well as suboptimal and dyskinesia-inducing doses (60% and 140% of the optimal dose, respectively), and these scores were compared with those obtained at baseline before and after subthalamotomy. Bradykinesia was assessed by a prehension task. RESULTS: Unilateral subthalamotomy had a positive effect on the antiparkinsonian response for all doses of levodopa as well as the baseline. There were no differences in the antiparkinsonian response between the suboptimal dose postsurgery and the optimal dose presurgery. Dyskinesias were increased at the suboptimal and the optimal doses. After surgery, the duration of response to levodopa increased between 20% and 25% in the suboptimal dose, whereas it remained unchanged with higher doses. Bradykinesia was significantly reduced after surgery only at the suboptimal dose. CONCLUSIONS: Subthalamotomy potentiated the response to suboptimal doses of levodopa. Thus, levodopa can be reduced by 40% after surgery for similar beneficial antiparkinsonian response and less dyskinesia than with an optimal dose before surgery.

Altered distribution of inhibitory interneurons in polymicrogyria.

There is a high incidence of epilepsy in patients with polymicrogyria; however, the epileptogenic mechanisms are largely unknown. The density of parvalbumin-immunoreactive interneurons was evaluated in an experimental model of polymicrogyria, in order to assess the potential changes in the development of one population of inhibitory interneurons. Newborn hamsters received an intracerebral injection of ibotenate, and all injected animals showed abnormal cortical layers characterized by one or two microgyrus in the fronto-parietal cortex. A quantitative analysis revealed that the ratios of parvalbumin-immunoreactive neurons in total neurons were significantly reduced in the medial paramicrogyral area, and in the medial and central parts of microgyrus in comparison to that in the lateral part of microgyrus (P<0.01). The lateral paramicrogyral area had the greatest number of parvalbumin-immunoreactive neurons, which was increased significantly in comparison to that in the control cortex (P<0.01). We suggest that the callosal, thalamic and intracortical afferents to the microgyrus and paramicrogyral area may induce a remarkable imbalance between the excitatory and inhibitory activities of the cortical structures, associated with the epileptogenic mechanism in polymicrogyria.

Periaqueductal gray matter modulates the hypercapnic ventilatory response.

The periaqueductal gray (PAG) is a midbrain structure directly involved in the modulation of defensive behaviors. It has direct projections to several central nuclei that are involved in cardiorespiratory control. Although PAG stimulation is known to elicit respiratory responses, the role of the PAG in the CO(2)-drive to breathe is still unknown. The present study assessed the effect of chemical lesion of the dorsolateral and dorsomedial and ventrolateral/lateral PAG (dlPAG, dmPAG, and vPAG, respectively) on cardiorespiratory and thermal responses to hypercapnia. Ibotenic acid (IBO) or vehicle (PBS, Sham group) was injected into the dlPAG, dmPAG, or vPAG of male Wistar rats. Rats with lesions outside the dlPAG, dmPAG, or vPAG were considered as negative controls (NC). Pulmonary ventilation (VE: ), mean arterial pressure (MAP), heart rate (HR), and body temperature (Tb) were measured in unanesthetized rats during normocapnia and hypercapnic exposure (5, 15, 30 min, 7 % CO(2)). IBO lesioning of the dlPAG/dmPAG caused 31 % and 26.5 % reductions of the respiratory response to CO(2) (1,094.3 ± 115 mL/kg/min) compared with Sham (1,589.5 ± 88.1 mL/kg/min) and NC groups (1,488.2 ± 47.7 mL/kg/min), respectively. IBO lesioning of the vPAG caused 26.6 % and 21 % reductions of CO(2) hyperpnea (1,215.3 ± 108.6 mL/kg/min) compared with Sham (1,657.3 ± 173.9 mL/kg/min) and NC groups (1,537.6 ± 59.3). Basal VE: , MAP, HR, and Tb were not affected by dlPAG, dmPAG, or vPAG lesioning. The results suggest that dlPAG, dmPAG, and vPAG modulate hypercapnic ventilatory responses in rats but do not affect MAP, HR, or Tb regulation in resting conditions or during hypercapnia.

Human neural stem cells genetically modified to express human nerve growth factor (NGF) gene restore cognition in the mouse with ibotenic acid-induced cognitive dysfunction.

Alzheimer's disease (AD) is characterized by degeneration and loss of neurons and synapses throughout the brain, causing the progressive decline in cognitive function leading to dementia. No effective treatment is currently available. Nerve growth factor (NGF) therapy has been proposed as a potential treatment of preventing degeneration of basal forebrain cholinergic neurons in AD. In a previous study, AD patient's own fibroblasts genetically modified to produce NGF were transplanted directly into the brain and protected cholinergic neurons from degeneration and improved cognitive function in AD patients. In the present study, human neural stem cells (NSCs) are used in place of fibroblasts to deliver NGF in ibotenic acid-induced learning-deficit rats. Intrahippocampal injection of ibotenic acid caused severe neuronal loss, resulting in learning and memory deficit. NGF protein released by F3.NGF human NSCs in culture medium is 10-fold over the control F3 naive NSCs at 1.2 µg/10(6) cells/day. Overexpression of NGF in F3.NGF cells induced improved survival of NSCs from cytotoxic agents H2O2, Aß, or ibotenic acid in vitro. Intrahippocampal transplantation of F3.NGF cells was found to express NGF and fully improved the learning and memory function of ibotenic acid-challenged animals. Transplanted F3.NGF cells were found all over the brain and differentiated into neurons and astrocytes. The present study demonstrates that human NSCs overexpressing NGF improve cognitive function of learning-deficit model mice.

Effects of antenatal uteroplacental hypoperfusion on neonatal microvascularisation and excitotoxin sensitivity in mice.

Vascular intrauterine growth restriction (IUGR) occurs in about 5% of pregnancies and may reduce the incidence of periventricular leukomalacia in preterm newborns. We evaluated neonatal excitotoxicity in a murine model of vascular IUGR involving unilateral uterine ligation on embryonic day (E)13.5. Birth weight was significantly decreased in the ligation group compared with the sham group (p < 0.001). VEGFs, VEGF receptors (VEGFRs), and NMDA receptor subunit mRNAs in brain extracts were assayed using quantitative RT-PCR. Ligation was associated with increased mRNAs for the vascular marker PECAM-1 on postnatal day (PD)2 and VEGFR-3 on PD2 and PD10, contrasting with decreased VEGFA and VEGFC on PD10. Microvessel density was increased on PD7. Ligated and sham pups received intracerebral ibotenate (NMDA agonist) on PD2 or PD10. Cortical and white matter (WM) lesions after 5 d were reduced in ligated versus sham pups injected on PD2 (p < 0.001 and p < 0.01, respectively); this effect persisted on PD42 (p < 0.01 and p < 0.05, respectively). With ibotenate on PD10, lesions were exacerbated after 5 d in the ligated group in the cortex (p < 0.05) and WM (p < 0.05) and on PD42 in the cortex (p < 0.05). In conclusion, vascular IUGR offered only transient protection against neonatal excitotoxic lesions, possibly via angiogenesis.

Locus ceruleus and anterior cingulate cortex sustain wakefulness in a novel environment.

Locus ceruleus (LC) neuronal activity is correlated with the waking state, yet LC lesions produce only minor alterations in daily wakefulness. Here, we report that sustained elevations in neurobehavioral and EEG arousal in response to exposure to an environment with novel stimuli, including social interaction, are prevented by selective chemical lesions of the LC in rats. Similar results are seen when the anterior cingulate cortex (ACC), which receives especially dense LC innervation, is selectively denervated of LC input or is ablated by the cell-specific neurotoxin ibotenic acid. Anterograde tracing combined with tyrosine hydroxylase immunohistochemistry demonstrates ACC terminals in apposition with the distal dendrites of LC neurons. Our data implicate the ACC as both a source of input to the LC as well as one of its targets and suggests that the two structures engage in a dialog that may provide a critical neurobiological substrate for sustained attention.

Transplantation of magnetically labeled mesenchymal stem cells in a model of perinatal brain injury.

Periventricular white matter injury (PVWMI) in preterm infants is a leading cause of cerebral palsy. Mesenchymal stem cell (MSC) transplantation in experimental models of adult demyelinating conditions is reported to reduce neurological deficits so we investigated their potential for treating developmental PVWMI. Neonatal rat MSCs, when cultured and labeled in vitro with fluorescent, micrometer-sized paramagnetic iron oxide particles (MPIO), retained their differentiation potential. Rats received bilateral intracerebral injections of ibotenic acid at postnatal day 5 causing PVWMI-like lesions with localized hypomyelination and sensorimotor deficits. MPIO-labeled MSCs were transplanted near the lesion in the right hemisphere 1 day postlesioning. Animals receiving cell transplants showed significantly increased antimyelin immunoreactivity in the corpus callosum, and improved reaching and retrieval skills, compared to animals receiving conditioned medium only. In separate experiments, in vivo MRI demonstrated that MPIO-labeled cells migrated away from the injection site toward lesioned areas in both hemispheres, confirmed by microscopy postmortem, but double-labeling studies found little evidence of differentiation into neural phenotypes. MSC transplantation led to significantly more forebrain cell proliferation, assayed by bromodeoxyuridine incorporation, than in controls. MSC transplants may have been neuroprotective and indirectly contributed to brain repair.

Interhemispheric regulation of the medial prefrontal cortical glutamate stress response in rats.

While stressors are known to increase medial prefrontal cortex (PFC) glutamate (GLU) levels, the mechanism(s) subserving this response remain to be elucidated. We used microdialysis and local drug applications to investigate, in male Long-Evans rats, whether the PFC GLU stress response might reflect increased interhemispheric communication by callosal projection neurons. We report here that tail-pinch stress (20 min) elicited comparable increases in GLU in the left and right PFC that were sodium and calcium dependent and insensitive to local glial cystine-GLU exchanger blockade. Unilateral ibotenate-induced PFC lesions abolished the GLU stress response in the opposite hemisphere, as did contralateral mGlu(2/3) receptor activation. Local dopamine (DA) D(1) receptor blockade in the left PFC potently enhanced the right PFC GLU stress response, whereas the same treatment applied to the right PFC had a much weaker effect on the left PFC GLU response. Finally, the PFC GLU stress response was attenuated and potentiated, respectively, following alpha(1)-adrenoreceptor blockade and GABA(B) receptor activation in the opposite hemisphere. These findings indicate that the PFC GLU stress response reflects, at least in part, activation of callosal neurons located in the opposite hemisphere and that stress-induced activation of these neurons is regulated by GLU-, DA-, norepinephrine-, and GABA-sensitive mechanisms. In the case of DA, this control is asymmetrical, with a marked regulatory bias of the left PFC DA input over the right PFC GLU stress response. Together, these findings suggest that callosal neurons and their afferentation play an important role in the hemispheric specialization of PFC-mediated responses to stressors.

Lovastatin improves neurological outcome after nucleus basalis magnocellularis lesion in rats.

Increasing evidence indicates that statins, specific inhibitors of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase, exerts neuroprotective actions rather than simply lowering cholesterol. However, the underlying mechanism has not been elucidated clearly. Here, the effect of lovastatin on the neurological outcomes of nucleus basalis magnocellularis (NBM)-lesioned rats and the pathophysiological mechanisms were investigated. Sprague-Dawley rats were divided into three groups: (i) a sham group; (ii) a model group: bilateral NBM of rats were injured by infusion of ibotenic acid; and (iii) a lovastatin-treated group: lovastatin was administrated orally for 4 weeks before treated by ibotenic acid. We show that lovastatin significantly improves the neurological outcomes as well as the choline acetyltransferase (ChAT) activity and muscarinic/NMDA receptor binding activity impaired by NBM lesion, and that lovastatin prevents neuron loss and induces Akt whereas inhibits p38 phosphorylation. Overall, the neuro-restorative and -protective effect of lovastatin may be attributed to the regulation of Akt- and p38-mediated signaling pathway together with improvement of muscarinic/NMDA receptor functions. Statins may be useful in the treatment of neurological disorders.