Search

Rats with lesions of the hippocampus or sham lesions were required in four experiments to escape from a square swimming pool by finding a submerged platform. Experiments 1 and 2 commenced with passive training in which rats were repeatedly placed on the platform in one corner-the correct corner-of a pool with distinctive walls. A test trial then revealed a strong preference for the correct corner in the sham but not the hippocampal group. Subsequent active training of being required to swim to the platform resulted in both groups acquiring a preference for the correct corner in the two experiments. In Experiments 3 and 4, rats were required to solve a discrimination between different panels pasted to the walls of the pool, by swimming to the middle of a correct panel. Hippocampal lesions prevented a discrimination being formed between panels of different lengths (Experiment 3), but not between panels showing lines of different orientations (Experiment 4); rats with sham lesions mastered both problems. It is suggested that an intact hippocampus is necessary for the formation of stimulus-goal associations that permit successful passive spatial leaning. It is further suggested that an intact hippocampus is not necessary for the formation of stimulus-response associations, except when they involve information about length or distance., (© 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.)

Sensorimotor gating is the state-dependent transfer of sensory information into a motor system. When this occurs at an early stage of the processing stream it enables stimuli to be filtered out or partially ignored, thereby reducing the demands placed on advanced systems. Prepulse inhibition (PPI) of the acoustic startle reflex (ASR) is the standard measure of sensorimotor gating. A brainstem-midbrain circuitry is widely viewed as mediating both PPI and ASR. In this circuitry, the pedunculopontine tegmental nucleus (PPTg) integrates sensory input and cortico-basal ganglia output and, via presumed cholinergic signaling, inhibits ASR-generating neurons within the reticular formation. Non-selective damage to all neuronal types within PPTg reduces PPI. We assessed whether this effect originates in the loss of cholinergic signaling by examining ASR and PPI in rats bearing non-selective (excitotoxic) or selective cholinergic (Dtx-UII) lesions of PPTg. Excitotoxic lesions had no effect on ASR but reduced PPI at all prepulse levels tested. In contrast, selective depletion of cholinergic neurons reduced ASR to the extent that PPI was not measurable with standard (10-20 s) inter-trial intervals. Subsequent testing revealed appreciable ASRs could be generated when the inter-trial interval was increased (180 s). Under these conditions, PPI was assessed and no deficits were found after lesions of cholinergic PPTg neurons. These results show that cholinergic output from PPTg is essential for rapidly regenerating the ASR, but has no influence on PPI. Results are discussed in terms of sensorimotor integration circuitry and psychiatric disorders that feature disrupted ASR and PPI., (© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Premature birth represents a clinical situation of risk for brain injury. The diversity of pathophysiological processes complicates efforts to find effective therapeutic strategies. Excitotoxicity is one important factor in the pathogenesis of preterm brain injury. The observation that sigma-1 receptor agonists possess neuroprotective potential, at least partly mediated by a variety of anti-excitotoxic mechanisms, has generated great interest in targeting those receptors to counteract brain injury. The objective of this study was to evaluate the effect of the highly specific sigma-1 receptor agonist, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) to protect against excitotoxic developmental brain injury in vivo and in vitro. Primary hippocampal neurons were pre-treated with PPBP before glutamate was applied and subsequently analyzed for cell death (PI/calcein AM), mitochondrial activity (TMRM) and morphology of the neuronal network (WGA) using confocal microscopy. Using an established neonatal mouse model we also determined whether systemic injection of PPBP significantly attenuates excitotoxic brain injury. PPBP significantly reduced neuronal cell death in primary hippocampal neurons exposed to glutamate. Neurons treated with PPBP showed a less pronounced loss of mitochondrial membrane potential and fewer morphological changes after glutamate exposure. A single intraperitoneal injection of PPBP given one hour after the excitotoxic insult significantly reduced microglial cell activation and lesion size in cortical gray and white matter. The present study provides strong support for the consideration of sigma-1 receptor agonists as a candidate therapy for the reduction of neonatal excitotoxic brain lesions and might offer a novel target to counteract developmental brain injury., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Basic fibroblast growth factor (bFGF/FGF-2) is known to possess neuroprotective and neurite outgrowth activity properties. In this study, the effects of a novel synthetic compound that mimics the neuroprotective properties of bFGF - SUN11602 - were examined in vitro and in vivo. SUN11602 promoted neurite outgrowth of primarily cultured rat hippocampal neurons. For the in vivo study, an Alzheimer's disease (AD) model with severe damage to the hippocampal tissue was constructed by injecting the hippocampi of rats with aggregated Aβ1-40, followed 48 h later by an injection of ibotenate [an agonist for N-methyl-d-aspartate (NMDA) receptor]. Oral administration of SUN11602 at the midpoint of Aβ1-40 and ibotenate injections attenuated short-term memory impairment in the Y-maze test, as well as spatial learning deficits in the water maze task. In addition, the SUN11602 treatment inhibited the increase of peripheral-type benzodiazepine-binding sites (PTBBS), which are a marker for gliosis. A negative correlation was found between PTBBS numbers and learning capacity in the water maze task. These results suggest that SUN111602 improved memory and learning deficits in the hippocampally lesioned rats by preventing neuronal death and/or promotion of neurite outgrowth. Taken together, these results indicate that SUN11602, a bFGF-like compound with neuroprotective and neurite outgrowth activity, may be beneficial for the treatment of progressive neurodegenerative diseases such as AD., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Anatomically and functionally located between basal ganglia and brainstem circuitry, the pedunculopontine tegmental nucleus (PPTg) is in a pivotal position to contribute to motor behavior. Studies in primates have reported akinesia and postural instability following destruction of the PPTg. In humans, the PPTg partially degenerates in Parkinson's disease and stimulation of this region is under investigation as a possible therapeutic. Studies in rats report no crude motor impairment following PPTg lesion, although a detailed assessment of the role of the PPTg in rat motor function has not been reported. Our studies applied motor tests generally used in rodent models of Parkinson's disease to rats bearing either excitotoxic damage to all neuronal populations within PPTg, or selective destruction of the cholinergic subpopulation created with the toxin Dtx-UII. Neither lesion type altered baseline locomotion. On the rotarod, excitotoxic lesions produced a persistent impairment on the accelerating, but not fixed speed, conditions. In the vermicelli handling task (a quantitative measure of fine motor control and effective behavioral sequencing) excitotoxic lesions produced no single impairment, but globally increased the number of normal and abnormal behaviors. In contrast, depletion of cholinergic PPTg neurons produced impairment on the accelerating rotarod but no changes in vermicelli handling. Together, these results show that while PPTg lesions produce no impairment in the execution of individual motor actions, impairments emerge when the demands of the task increase. Results are discussed in terms of PPTg acting as part of a rapid action selection system, which integrates sensory information into motor output., (© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The aim of this study was to demonstrate that two REM clusters, which emerge following bilateral pedunculopontine tegmental nucleus (PPT) lesions in rats, are two functionally distinct REM states. We performed the experiments in Wistar rats, chronically instrumented for sleep recording. Bilateral PPT lesions were produced by the microinfusion of 100 nl of 0.1M ibotenic acid (IBO). Following a recovery period of 2 weeks, we recorded their sleep for 6h. Bilateral PPT lesions were identified by NADPH - diaphorase histochemistry. We applied Fourier analysis to the signals acquired throughout the 6h recordings, and each 10s epoch was differentiated as a Wake, NREM or REM state. We analyzed the topography of the sleep/wake states architecture and their transition structure, their all state-related EEG microstructures, and the sensorimotor (SMCx) and motor (MCx) cortex REM related cortico-muscular coherences (CMCs). Bilateral PPT lesion in rats increased the likelihood of the emergence of two distinct REM sleep states, specifically expressed within the MCx: REM1 and REM2. Bilateral PPT lesion did not change the sleep/wake states architecture of the SMCx, but pathologically increased the duration of REM1 within the MCx, alongside increasing Wake/REM1/Wake and NREM/REM2/NREM transitions within both cortices. In addition, the augmented total REM SMCx EEG beta amplitude and REM1 MCx EEG theta amplitude was the underlying EEG microstructure pathology. PPT lesion induced REM1 and REM2 are differential states with regard to total EMG power, topographically distinct EEG microstructures, and locomotor drives to nuchal musculature., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Aim: Although periaqueductal grey matter activation is known to elicit respiratory and cardiovascular responses, the role of this midbrain area in the compensatory responses to hypoxia is still unknown. To test the participation of the periaqueductal grey matter in cardiorespiratory and thermal responses to hypoxia in adult male Wistar rats, we performed a chemical lesion of the dorsolateral/dorsomedial or the ventrolateral/lateral periaqueductal grey matter using ibotenic acid., Methods: Pulmonary ventilation, mean arterial pressure, heart rate and body temperature were measured in unanaesthetized rats during normoxic and hypoxic exposure (5, 15, 30 min, 7% O2)., Results: An ibotenic acid lesion of the dorsolateral/dorsomedial periaqueductal grey matter caused a higher increase in pulmonary ventilation (67.1%, 1730±282.5 mL kg(-1) min(-1)) compared to the Sham group (991.4±194 mL kg(-1) min(-1)) after 15 min in hypoxia, whereas for the ventrolateral/Lateral periaqueductal grey matter lesion, no differences were observed between groups. Mean arterial pressure, heart rate and body temperature were not affected by a dorsolateral/dorsomedial or ventrolateral/lateral periaqueductal grey matter lesion., Conclusion: Middle to caudal portions of the dorsolateral/dorsomedial periaqueductal grey matter neurones modulate the hypoxic ventilatory response, exerting an inhibitory modulation during low O2 situations. In addition, the middle to caudal portions of the dorsolateral/dorsomedial or ventrolateral/lateral periaqueductal grey matter do not appear to exert a tonic role on cardiovascular or thermal parameters during normoxic and hypoxic conditions., (© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

The amygdala has been implicated in a variety of motivational and attentional functions related to appetitive learning. Some studies showed that electrolytic lesions of the amygdaloid complex disrupted reinforcement omission effects (ROEs). However, recent studies that investigated ROEs employing neurotoxic lesions in specific amygdala areas - the central nucleus (CeA) or basolateral complex (BLA) of the amygdala - showed that CeA lesions or BLA lesions can interfere with, but do not eliminate ROEs. Although the effects of neurotoxic lesions in particular areas of the amygdala differed from those of a large gross lesion, these studies have indicated that it is possible that the amygdala is involved in ROE modulation. Furthermore, the effect that a neurotoxic lesion involving both areas (CeA and BLA) has on ROEs remains unexplored. Thus, the present study aimed to clarify whether the functional impairment related to large amygdala activation affects ROEs, in a neurotoxic lesion procedure. If this is the case, the underlying process may contribute to a better understanding of the involvement of the amygdala in ROEs modulation. After acquisition of stable performance during pre-lesion training in which rats were trained to respond on a fixed-interval 6 s with limited hold 6 s schedules (FI 6 s LH 6 s), lesions were made including both the CeA and BLA areas. In test sessions, the partial omission of reinforcement was introduced. The results showed that bilateral lesion of both CeA and BLA impaired ROEs, suggesting that amygdala is part of ROEs' modulation circuitry., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Affections are thought to regulate pain perception through the descending pain inhibitory system in the central nervous system. In this study, we examined in mice the affective change by inhalation of the lemon oil, which is well used for aromatherapy, and the effect of lemon odor on pain sensation. We also examined the anterior cingulate cortex (ACC) and descending pain inhibitory system to such regulation of pain., Results: In the elevated plus maze, the time spent in the open arms was increased by inhalation of lemon oil. The pain behavior induced by injection of formalin into the hind paw was decreased. By inhalation of lemon oil, the number of c-Fos expression by formalin injection was significantly increased in the ACC, periaqueductal grey (PAG), nucleu raphe magnus (NRM) and locus ceruleus, and decreased in the spinal dorsal horn (SDH). The destruction of the ACC with ibotenic acid led to prevent the decrease of formalin-evoked nocifensive behavior in mice exposed to lemon oil. In these mice, the change of formalin-induced c-Fos expression in the ACC, lateral PAG, NRM and SDH by lemon odor was also prevented. Antagonize of dopamine D1 receptor in the ACC prevented to the analgesic effect of lemon oil., Conclusions: These results suggest that the analgesic effect of lemon oil is induced by dopamine-related activation of ACC and the descending pain inhibitory system.

Background: The progressive development of Alzheimer's disease (AD) pathology follows a spatiotemporal pattern in the human brain. In a transgenic (Tg) mouse model of AD expressing amyloid precursor protein (APP) with the arctic (E693G) mutation, pathology spreads along anatomically connected structures. Amyloid-β (Aβ) pathology first appears in the subiculum and is later detected in interconnected brain regions, including the retrosplenial cortex. We investigated whether the spatiotemporal pattern of Aβ pathology in the Tg APP arctic mice to interconnected brain structures can be interrupted by destroying neurons using a neurotoxin and thereby disconnecting the neural circuitry., Results: We performed partial unilateral ibotenic acid lesions of the subiculum (first structure affected by Aβ pathology) in young Tg APParc mice, prior to the onset of pathology. We assessed Aβ/C99 pathology in mice aged up to 6 months after injecting ibotenate into the subiculum. Compared to the brains of intact Tg APP arctic mice, we observed significantly decreased Aβ/C99 pathology in the ipsilateral dorsal subiculum, CA1 region of the hippocampus and the retrosplenial cortex; regions connecting to and from the dorsal subiculum. By contrast, Aβ/C99 pathology was unchanged in the contralateral hippocampus in the mice with lesions., Conclusion: These results, obtained in an animal model of AD, support the notion that Aβ/C99 pathology is transmitted between interconnected neurons in AD.

We investigated in three groups of awake and sleeping goats whether there are differences in ventilatory responses after injections of Ibotenic acid (IA, glutamate receptor agonist and neurotoxin) into the pre-Bötzinger complex (preBötC), lateral parabrachial (LPBN), medial (MPBN) parabrachial, or Kölliker-Fuse nuclei (KFN). In one group, within minutes after bilateral injection of 10μl IA (50mM) into the preBötC, there was a 10-fold increase in breathing frequency, but 1.5h later, the goats succumbed to terminal apnea. These data are consistent with findings in reduced preparations that the preBötC is critical to sustaining normal breathing. In a second group, increasing volumes (0.5-10μl) of IA injected at weekly intervals into the preBötC elicited a near-dose-dependent tachypnea and irregular breathing that lasted at least 5h. There were apneas restricted to wakefulness, but none were terminal. Postmortem histology revealed that the preBötC was 90% destroyed, but there was a 25-40% above normal number of neurons in the presumed parafacial respiratory group that may have contributed to maintenance of arterial blood gas homeostasis. In a third group, bilateral injections (1 and 10μl) of IA into the LPBN, MPBN, or KFN did not significantly increase breathing in any group, and there were no terminal apneas. However, 3-5h after the injections into the KFN, breathing frequency was decreased and the three-phase eupneic breathing pattern was eliminated. Between 10 and 15h after the injections, the eupneic breathing pattern was not consistently restored to normal, breathing frequency remained attenuated, and there were apneas during wakefulness. Our findings during wakefulness and NREM sleep warrant concluding that (a) the preBötC is a primary site of respiratory rhythm generation; (b) the preBötC and the KFN are determinants of respiratory pattern generation; (c) after IA-induced lesions, there is time-dependent plasticity within the respiratory control network; and (d) ventilatory control mechanisms are state dependent., (© 2014 Elsevier B.V. All rights reserved.)

Rats were administered 3 versions of an object recognition task: In the spontaneous object recognition task (SOR) animals discriminated between a familiar object and a novel object; in the temporal order task they discriminated between 2 familiar objects, 1 of which had been presented more recently than the other; and, in the object-in-place task, they discriminated among 4 previously presented objects, 2 of which were presented in the same locations as in preexposure and 2 in different but familiar locations. In each task animals were tested at 2 delays (5 min and 2 hr) between the sample and test phases in the SOR and object-in-place task, and between the 2 sample phases in the temporal order task. Performance in the SOR was poorer with the longer delay, whereas in the temporal order task performance improved with delay. There was no effect of delay on object-in-place performance. In addition the performance of animals with neurotoxic lesions of the dorsal hippocampus was selectively impaired in the object-in-place task at the longer delay. These findings are interpreted within the framework of Wagner's (1981) model of memory.

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., (Published by Elsevier Inc.)

The executive function processes of set-shifting and reversal learning in rodents are mediated by the medial prefrontal cortex and the orbitofrontal cortex, respectively. Here, we investigated both set-shifting and reversal learning in a developmental animal model of schizophrenia, the neonatal ventral hippocampal lesion (NVHL) model. The NVHL manipulation is known to disrupt development of the medial prefrontal cortex, and to impair behaviors dependent on this area, but potential orbitofrontal abnormalities and reversal learning deficits are less well studied. Animals received excitotoxic lesions of the ventral hippocampus (NVHL) or a sham treatment during the first postnatal week, and all animals were subsequently tested in adulthood on either an operant set-shifting or an operant reversal task. Results indicated that NVHL animals were able to acquire a simple discrimination rule and exhibited normal reversal learning, but were impaired on a prefrontal-dependent set-shifting task. Furthermore, this set-shifting deficit was due to an increase in perseverative errors, which indicate difficulty suppressing a previously learned strategy and result from medial prefrontal insult. Together, these results confirm and extend the idea that cognitive impairments in the NVHL animal are primarily driven by medial prefrontal abnormalities, while the orbitofrontal cortex may remain relatively unaffected., (Copyright © 2013 Elsevier B.V. All rights reserved.)

In order to identify the differences for the onset and progression of functionally distinct cholinergic innervation disorders, we investigated the effect of bilateral nucleus basalis (NB) and pedunculopontine tegmental nucleus (PPT) lesions on sleep/wake states and electroencephalographic (EEG) microstructure in rats, chronically implanted for sleep recording. Bilateral NB lesion transiently altered Wake/NREM duration within the sensorimotor cortex, and Wake/REM duration within the motor cortex, while there was no change in the sleep/wake states distributions following the bilateral PPT lesion. Bilateral PPT lesion sustainably increased the Wake/REM and REM/Wake transitions followed by inconsistent dysregulation of the NREM/REM and REM/NREM transitions in sensorimotor cortex, but oppositely by their increment throughout four weeks in motor cortex. Bilateral NB lesion sustainably decreased the NREM/REM and REM/NREM transitions during four weeks in the sensorimotor cortex, but oppositely increased them in the motor cortex. We have shown that the sustained beta and gamma augmentation within the sensorimotor and motor cortex, and across all sleep/wake states, simultaneously with Wake delta amplitude attenuation only within the sensorimotor cortex, were the underlying EEG microstructure for the sleep/wake states transitions structure disturbance following bilateral PPT lesion. In contrast, the bilateral NB lesion only augmented REM theta in sensorimotor cortex during three weeks. We have shown that the NB and PPT lesions induced differing, structure-related EEG microstructure and transition structure disturbances particularly expressed in motor cortex during NREM and REM sleep. We evidenced for the first time the different topographical expression of the functionally distinct cholinergic neuronal innervation impairment in rat., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The pedunculopontine tegmental nucleus (PPT) represents a major aggregation of cholinergic neurons in the mammalian brainstem, which is important in the generation and maintenance of REM sleep. We investigated the effects of unilateral and bilateral PPT lesions on sleep and all the conventional sleep-state related EEG frequency bands amplitudes, in an attempt to find the EEG markers for the onset and progression of PPT cholinergic neuronal degeneration. The experiments were performed on 35 adult male Wistar rats, chronically implanted for sleep recording. During the surgical procedure for EEG and EMG electrodes implantation, the unilateral or bilateral PPT lesion was produced under ketamine/diazepam anesthesia, by the stereotaxically guided microinfusion of 100 nl 0.1M ibotenic acid (IBO) into PPT. We applied Fourier analysis to signals acquired throughout 6h of recordings, and each 10s epoch was differentiated as a Wake, NREM or REM state. We also calculated the group probability density estimates (PDE) of all Wake, NREM and REM conventional EEG frequency amplitudes, and the number of all the transition states using MATLAB 6.5. Our results show that the unilateral or bilateral PPT lesions did not change the sleep/wake architecture, but did change the sleep/wake state transitions structure and the sleep/state related "EEG microstructure". Unilateral or bilateral PPT lesions sustainably increased Wake/REM and REM/Wake transitions from 14 to 35 days after lesions. This was followed by decreased NREM/REM and REM/NREM transitions from 28 days only in the case of the bilateral PPT lesion. The unilateral PPT lesion augmented both Wake theta and REM beta while it also attenuated the relative amplitude of the Wake delta frequency, with a delay of one week. Following a bilateral PPT lesion there was augmentation of the relative amplitude of the Wake, NREM, and REM beta and REM gamma frequency which occurred simultaneously to NREM and Wake delta attenuation. We have shown that the PPT cholinergic neuronal loss sustainably increased the number of the Wake/REM and REM/Wake transitions and augmented sleep-states related cortical activation that was simultaneously expressed by the high frequency amplitude augmentation, as well as Wake and NREM delta frequency attenuation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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., (Copyright © 2013 Wiley Periodicals, Inc.)

The current study examined the long-term effects of neonatal amygdala lesions on emotional and hypothalamic-pituitary-adrenal (HPA) axis reactivity to an acute stressor in rhesus monkeys. Rhesus monkeys received either bilateral MRI-guided ibotenic acid amygdala (Neo-Aibo; n=6) or sham (Neo-C; n=7) lesions between 7 and 14 days of age. Emotional reactivity was assessed using the Human Intruder paradigm at 2 months, 4.5 months, and 6-8 years of age, whereas stress neuroendocrine response was only assessed in adulthood (6-8 years). The modulation of defensive and emotional behaviors based on the gaze direction of the intruder emerged between 2 and 4 months of age in surrogate-peer reared sham-operated infant monkeys, as already shown for mother-reared infants. Although neonatal amygdala lesions did not impair the ability to exhibit defensive and emotional behaviors, it altered the modulation of these responses based on the intruder's gaze direction. The changes in emotional reactivity after neonatal amygdala lesions emerged in infancy and persisted throughout adulthood when they were associated with a reduction of basal cortisol levels and a blunted cortisol response to the stressor. These changes are reminiscent of those found after adult-onset amygdala lesions, demonstrating little functional compensation following early amygdala damage., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The medullary raphé is an important component of the central respiratory network, playing a key role in CO2 central chemoreception. However, its participation in hypoxic ventilatory responses is less understood. In the present study, we assessed the role of nucleus raphé obscurus (ROb), and specifically 5-HT neurons confined in the ROb, on ventilatory and thermoregulatory responses to hypoxia. Chemical lesions of the ROb were performed using either ibotenic acid (non-specific lesion; control animals received PBS) or anti-SERT-SAP (5-HT specific lesion; control animals received IgG-SAP). Ventilation (V˙E; whole body plethysmograph) and body temperature (Tb; data loggers) were measured during normoxia (21% O2, N2 balance) and hypoxia exposure (7% O2, N2 balance, 1h) in conscious adult rats. Ibotenic acid or anti-SERT-SAP-induced lesions did not affect baseline values of V˙E and Tb. Similarly, both lesion procedures did not alter the ventilatory or thermoregulatory responses to hypoxia. Although evidence in the literature suggests a role of the rostral medullary raphé in hypoxic ventilatory responses, under the present experimental conditions our data indicate that caudal medullary raphé (ROb) and its 5-HT neurons neither participate in the tonic maintenance of breathing nor in the ventilatory and thermal responses to hypoxia., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Brain-derived neurotrophic factor (BDNF) plays a prominent role in neuroprotection against perinatal brain injury. Dexmedetomidine, a selective agonist of α2-adrenergic receptors, also provides neuroprotection against glutamate-induced damage. Because adrenergic receptor agonists can modulate BDNF expression, our goal was to examine whether dexmedetomidine's neuroprotective effects are mediated by BDNF modulation in mouse perinatal brain injury., Methods: The protective effects against glutamate-induced injury of BDNF and dexmedetomidine alone or in combination with either a neutralizing BDNF antibody or an inhibitor of the extracellular signal-regulated kinase pathway (PD098059) were compared in perinatal ibotenate-induced cortical lesions (n = 10-20 pups/groups) and in mouse neuronal cultures (300 μM of ibotenate for 6 h). The effect of dexmedetomidine on BDNF expression was examined in vivo and in vitro with cortical neuronal and astrocyte isolated cultures., Results: Both BDNF and dexmedetomidine produced a significant neuroprotective effect in vivo and in vitro. Dexmedetomidine enhanced Bdnf4 and Bdnf5 transcription and BDNF protein cortical expression in vivo. Dexmedetomidine also enhanced Bdnf4 and Bdnf5 transcription and increased BDNF media concentration in isolated astrocyte cultures but not in neuronal cultures. Dexmedetomidine's protective effect was inhibited with BDNF antibody (mean lesion size ± SD: 577 ± 148 μm vs. 1028 ± 213 μm, n = 14-20, P < 0.001) and PD098059 in vivo but not in isolated neuron cultures. Finally, PD098059 inhibited the increased release of BDNF induced by dexmedetomidine in astrocyte cultures., Conclusion: These results suggest that dexmedetomidine increased astrocyte expression of BDNF through an extracellular signal-regulated kinase-dependent pathway, inducing subsequent neuroprotective effects.

Objective: The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease, and multiple sclerosis. However, mechanisms underpinning this process remain unidentified., Methods: We combined in vivo systemic lipopolysaccharide-induced or interleukin (IL)-1β-induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL-1β sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models, we assessed metabotropic glutamate receptors (mGluR) signaling and regulation., Results: We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation-induced G protein-coupled receptor kinase 2 (GRK2) downregulation and genetic deletion of GRK2 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization., Interpretation: Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders., (Copyright © 2013 American Neurological Association.)

It has been suggested that the role of the hippocampus for episodic memory is to selectively bind together item and contextual information. One such model, the Binding of Items and Context (BIC) model, proposed that the perirhinal cortex provides item and the postrhinal/parahippocampal cortex provides context to the hippocampus via the medial (MEC) and lateral entorhinal cortices (LEC) to be bound into an episodic representation. This model proposes that item and context information are stored and processed independently and in parallel before hippocampal processing. To evaluate this model, the present experiment evaluated the role of the MEC and LEC for item and contextual novelty detection. The present results suggest that excitotoxic lesions to the LEC primarily disrupt item novelty detection, whereas lesions to the MEC primarily disrupt contextual novelty detection. These data provide a functional double dissociation between the MEC and LEC across item and contextual processing. Despite this dissociation, the present results suggest that item and contextual information are not represented independently before hippocampal processing. These data support the basic assumptions of the BIC model, but suggest that item and context information may interact in the entorhinal cortex., (Copyright © 2013 Wiley Periodicals, Inc.)

Previous studies have demonstrated that bilateral lesions of the gustatory (medial) zone of the parabrachial nucleus (PBN) in the pons eliminate the salt (sodium chloride; NaCl) appetite induced in rats by treatment with the diuretic drug, furosemide. The present studies reexamined NaCl intake of rats with PBN lesions induced by ibotenic acid, using multiple models of salt appetite. The impairment of a conditioned taste aversion, an established consequence of PBN damage, was used as an initial screen with which to assess the effectiveness of the lesions. Rats with PBN lesions did not drink either 0.3 of a molar (M) solution of NaCl or 0.5 M NaCl in response to daily treatment with desoxycorticosterone acetate. These findings suggest that the excitatory stimulus of salt appetite mediated by mineralocorticoids is abolished by PBN lesions. In contrast, rats with PBN lesions drank some 0.5 M NaCl and more 0.3 M NaCl, in addition to water, in response to hypovolemia induced by subcutaneous injection of 30% polyethylene glycol solution. Those findings suggest that an excitatory stimulus of salt appetite, presumably mediated by Angiotensin II, is not abolished by PBN lesions. These and other observations indicate that lesions of the gustatory PBN in rats may or may not eliminate salt appetite, depending on which model is used and which concentration of NaCl solution is available.

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., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Our study investigates the impact of different volume sham control and excitotoxin microinfusions in vivo on local reactive astroglial response within rat nucleus basalis (NB). We followed the effects of unilateral 200, 100, and 50 nL of sham-control (phosphate buffer PBS) versus ibotenic acid (IBO) microinfusions, mechanical NB lesion (10 µL Hamylton syringe needle positioned into NB for 5 min), or physiological control (intact brain), on the local reactive astroglial response within the NB site, by immunoreactivity against glial fibrillary acidic protein (GFAP). NB lesions were identified by NADPHdiaphorase histochemistry. Local astrocytes responses within NB were suppressed by both high volume microinfusions, PBS and IBO (200 and 100 nL) versus mechanical lesion. Our study has proved, for the first time, the volume of microinfusion as critical for any selective pharmacological stimulation or lesion in vivo, and suggest the microinfusion volume less than 50nL as protective for physiological astroglial reactivity.

The orbitofrontal cortex (OFC) and basolateral amygdala (BLA) constitute part of a neural circuit important for adaptive, goal-directed learning. One task measuring flexibility of response to changes in reward is discrimination reversal learning. Damage to OFC produces well documented impairments on various forms of reversal learning in rodents, monkeys, and humans. Recent reports show that BLA, though highly interconnected with OFC, may be differentially involved in reversal learning. In the present experiment, we compared the effects of bilateral, ibotenic acid lesions of OFC or BLA (or SHAM) on visual discrimination and reversal learning. Specifically, we used pairwise visual discrimination methods, as is commonly administered in non-human primate studies, and analyzed how animals use positive and negative trial-by-trial feedback, domains not previously explored in a rat study. As expected, OFC lesions displayed significantly slower reversal learning than SHAM and BLA rats across sessions. Rats with BLA lesions, conversely, showed facilitated reversal learning relative to SHAM and OFC groups. Furthermore, a trial-by-trial analysis of the errors committed showed the BLA group benefited more from incorrectly performed trials (or negative feedback) on future choices than either SHAM or OFC rats. This provides evidence that BLA and OFC are involved in updating responses to changes in reward contingency and that the roles are distinct. Our results are discussed in relation to a competitive framework model for OFC and BLA in reward processing.

This study describes a novel spatial memory paradigm for monkeys and reports the effects of neonatal damage to the hippocampus on performance in adulthood. Monkeys were trained to forage in eight boxes hung on the walls of a large enclosure. Each box contained a different food item that varied in its intrinsic reward value, as determined from food preference testing. Monkeys were trained on a spatial and a cued version of the task. In the spatial task, the boxes looked identical and remained fixed in location whereas in the cued task, the boxes were individuated with colored plaques and changed location on each trial. Ten adult Rhesus macaques (5 neonatal sham-operated and 5 with neonatal neurotoxic hippocampal lesions) were allowed to forage once daily until they preferentially visited boxes containing preferred foods. The data suggest that all monkeys learned to discriminate preferred from nonpreferred food locations, but that monkeys with neonatal hippocampal damage committed significantly more working memory errors than controls in both tasks. Furthermore, following selective satiation, controls altered their foraging pattern to avoid the satiated food, whereas lesioned animals did not, suggesting that neonatal hippocampal lesions prohibit learning of specific food-place associations. We conclude that whereas an intact hippocampus is necessary to form specific item-in-place associations, in its absence, cortical areas may support more broad distinctions between food types that allow monkeys to discriminate places containing highly preferred foods., ((PsycINFO Database Record (c) 2013 APA, all rights reserved).)

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.

Aims: To investigate the therapeutic effects and acting mechanism of a combination of Chinese herb active components, i.e., a combination of baicalin, jasminoidin and cholic acid (CBJC) on Alzheimer's disease (AD)., Methods: Male rats were intracerebroventricularly injected with ibotenic acid (IBO), and CBJC was orally administered. Therapeutic effect was evaluated with the Morris water maze test, FDG-PET examination, and histological examination, and the acting mechanism was studied with DNA microarrays and western blotting., Results: CBJC treatment significantly attenuated IBO-induced abnormalities in cognition, brain functional images, and brain histological morphology. Additionally, the expression levels of 19 genes in the forebrain were significantly influenced by CBJC; approximately 60% of these genes were related to neuroprotection and neurogenesis, whereas others were related to anti-oxidation, protein degradation, cholesterol metabolism, stress response, angiogenesis, and apoptosis. Expression of these genes was increased, except for the gene related to apoptosis. Changes in expression for 5 of these genes were confirmed by western blotting., Conclusion: CBJC can ameliorate the IBO-induced dementia in rats and may be significant in the treatment of AD. The therapeutic mechanism may be related to CBJC's modulation of a number of processes, mainly through promotion of neuroprotection and neurogenesis, with additional promotion of anti-oxidation, protein degradation, etc.

This study examined the firing rate and pattern of electrophysiologically and chemically identified GABA interneurons in the dorsal raphe nucleus (DRN), and role of 5-HT(1A) receptor agonist 8-OH-DPAT and the medial prefrontal cortex (mPFC) in the firing activity in rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc). The interneurons in rats with lesions of the SNc showed a more burst-firing, while having no change in the firing rate; the mPFC and combined mPFC and SNc lesions in rats decreased the firing rate of the interneurons and firing pattern shifted towards a more burst-firing compared to rats with sham lesions of the SNc, respectively. In rats with sham lesions of the SNc, administration of 8-OH-DPAT (1-243 μg/kg, i.v.) produced excitatory-inhibitory, excitatory and inhibitory effects in the firing rate of individual interneurons. However, when these effects were averaged over the group, 8-OH-DPAT had no significant effect on firing rate. In rats with lesions of the SNc, mPFC and the paired lesions, 8-OH-DPAT, at the same doses, inhibited all interneurons tested, respectively. Cumulative doses producing inhibition in rats with the paired lesions were higher than that of rats with lesions of the mPFC. In contrast to rats with sham lesions of the SNc, SNc lesion reduced expression of 5-HT(1A) receptor on parvalbumin positive neurons in the DRN, a subpopulation of GABA interneurons. Our results indicate that the SNc and mPFC regulate the firing activity of GABA interneurons in the DRN. Furthermore, response of likely GABA interneurons to systemic administration of 8-OH-DPAT is altered by lesion of the SNc and mPFC., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Effects of basic fibroblast growth factor (bFGF), a potent neurotrophin, on neuronal damage induced by sequential treatment of amyloid β (Aβ) peptide and excitatory amino acid were examined in vitro and in vivo. Treatment of rat primary cortical neurons with glutamate (10μM, 30μM) resulted in neuronal damage, and pretreatment of the neurons with Aβ(25-35) (1.0μM) at 48h before glutamate stimulation augmented the susceptibility of the cells to the glutamate-induced neurotoxicity. Application of bFGF (0.3, 1, 3ng/ml) and MK-801 (1, 3, 10, 30nM) to the culture at 24h before glutamate stimulation markedly decreased the neuronal damage elicited by Aβ(25-35) and glutamate. In a rat model of Alzheimer's disease, in which aggregated Aβ(1-40) (4μg/1μl) was injected into the hippocampus, followed by an injection of ibotenate (an NMDA receptor agonist, 0.3μg/0.5μl) into the same sites at 48h later, significant neuronal damage and learning deficit was induced. Administration of bFGF (25ng/1μl) into the hippocampus at 24h before ibotenate inhibited the neuronal damage and demonstrated a trend of attenuating spatial learning deficits. These results suggest that bFGF might be a useful agent for treatment of Alzheimer's disease in which Aβ peptide and glutamate would be involved as causative substances., (Copyright © 2012 Elsevier B.V. All rights reserved.)

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., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The α2 adrenergic receptor antagonist yohimbine (YO) is a sympathomimetic drug that crosses the blood-brain barrier after systemic administration. YO promotes increased transmitter release from noradrenergic (NA) axon terminals in the central nucleus of the amygdala (CEA), bed nucleus of the stria terminalis (BST), hypothalamus, and other brain regions implicated in physiological and behavioral responses to stressful and threatening stimuli. YO is potently anxiogenic in humans and experimental animals, including rats. To determine whether direct connections between the CEA and anterolateral group of BST nuclei (algBST) are necessary for YO anxiogenesis in rats, neurotoxic ibotenate lesions of the CEA in one hemisphere and the ipsi- or contralateral algBST were conducted to disrupt CEA-algBST communication uni- or bilaterally. Sham-lesioned controls received microinjections of vehicle into the CEA and algBST. Two weeks later, behavior was assessed in the elevated plus maze (EPMZ) in rats after i.p. saline or YO (1.0mg/kg). Central ibotenate lesion placement and extent was assessed post-mortem in NeuN-immunolabeled tissue sections. The ability of YO to increase anxiety-like behavior in the EPMZ was similarly robust in rats with sham lesions or ipsilateral CEA-algBST lesions. Conversely, YO anxiogenesis in the EPMZ was disrupted in rats with asymmetric lesions designed to bilaterally disconnect the CEA and algBST, whereas neither unilateral nor bilateral disconnecting lesions altered EPMZ behavior in rats after i.p. saline. We conclude that the anxiogenic effects of increased NA signaling in rats after YO require direct CEA-algBST interactions that do not shape EPMZ behavior under baseline conditions., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

Objective: Activated microglia play a central role in the inflammatory and excitotoxic component of various acute and chronic neurological disorders. However, the mechanisms leading to their activation in the latter context are poorly understood, particularly the involvement of N-methyl-D-aspartate receptors (NMDARs), which are critical for excitotoxicity in neurons. We hypothesized that microglia express functional NMDARs and that their activation would trigger neuronal cell death in the brain by modulating inflammation., Methods and Results: We demonstrate that microglia express NMDARs in the murine and human central nervous system and that these receptors are functional in vitro. We show that NMDAR stimulation triggers microglia activation in vitro and secretion of factors that induce cell death of cortical neurons. These damaged neurons are further shown to activate microglial NMDARs and trigger a release of neurotoxic factors from microglia in vitro, indicating that microglia can signal back to neurons and possibly induce, aggravate, and/or maintain neurologic disease. Neuronal cell death was significantly reduced through pharmacological inhibition or genetically induced loss of function of the microglial NMDARs. We generated Nr1 LoxP(+/+) LysM Cre(+/-) mice lacking the NMDAR subunit NR1 in cells of the myeloid lineage. In this model, we further demonstrate that a loss of function of the essential NMDAR subunit NR1 protects from excitotoxic neuronal cell death in vivo and from traumatic brain injury., Interpretation: Our findings link inflammation and excitotoxicity in a potential vicious circle and indicate that an activation of the microglial NMDARs plays a pivotal role in neuronal cell death in the perinatal and adult brain., (Copyright © 2012 American Neurological Association.)

The dorsal striatum, which contains the dorsolateral striatum (DLS) and dorsomedial striatum (DMS), integrates the acquisition and implementation of instrumental learning in cooperation with the nucleus accumbens (NAc). The dorsal striatum regulates the basal ganglia circuitry through direct and indirect pathways. The mechanism by which these pathways mediate the learning processes of instrumental actions remains unclear. We investigated how the striatal indirect (striatopallidal) pathway arising from the DLS contributes to the performance of conditional discrimination. Immunotoxin targeting of the striatal neuronal type containing dopamine D(2) receptor in the DLS of transgenic rats resulted in selective, efficient elimination of the striatopallidal pathway. This elimination impaired the accuracy of response selection in a two-choice reaction time task dependent on different auditory stimuli. The impaired response selection was elicited early in the test sessions and was gradually restored as the sessions continued. The restoration from the deficits in auditory discrimination was prevented by excitotoxic lesion of the NAc but not by that of the DMS. In addition, lesion of the DLS mimicked the behavioral consequence of the striatopallidal removal at the early stage of test sessions of discriminative performance. Our results demonstrate that the DLS-derived striatopallidal pathway plays an essential role in the execution of conditional discrimination, showing its contribution to the control of selection accuracy of learned motor responses. The results also suggest the presence of a mechanism that compensates for the learning deficits during the repetitive sessions, at least partly, demanding accumbal function.

Brain abnormalities acquired early in life may cause schizophrenia, characterized by adulthood onset of psychosis, affective flattening, and cognitive impairments. Cognitive symptoms, like impaired cognitive control, are now recognized to be important treatment targets but cognition-promoting treatments are ineffective. We hypothesized that cognitive training during the adolescent period of neuroplastic development can tune compromised neural circuits to develop in the service of adult cognition and attenuate schizophrenia-related cognitive impairments that manifest in adulthood. We report, using neonatal ventral hippocampus lesion rats (NVHL), an established neurodevelopmental model of schizophrenia, that adolescent cognitive training prevented the adult cognitive control impairment in NVHL rats. The early intervention also normalized brain function, enhancing cognition-associated synchrony of neural oscillations between the hippocampi, a measure of brain function that indexed cognitive ability. Adolescence appears to be a critical window during which prophylactic cognitive therapy may benefit people at risk of schizophrenia., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: The neonatal ventral hippocampal lesion (NVHL) rat model has been proposed as an experimental model for schizophrenia. NVHL rats display impaired central nervous system (CNS) inhibition, which may lead to a phenomenon similar to P50 sensory gating deficits observed in schizophrenic patients. In this study, we investigated whether sensory gating deficits occurred in the NVHL rat as a model for schizophrenia., Methods: We created the NVHL rat model using ibotenate. The P20 and N40 were measured to assess sensory response and gating in NVHL and sham rats. Epidural electrodes recorded evoked potentials (EPs), from which latencies, amplitudes, difference scores (S1-S2), and gating ratios (S2/S1) were assessed., Results: Compared with sham controls, prolonged S1 N40 latency and decreased S2 N40 amplitude were detected in the NVHL group. In neither difference scores nor gating ratios, a significant difference was found between NVHL group and sham controls., Conclusions: NVHL rats may be a valid animal model for schizophrenia. This strategy will be useful in future neurobiological studies investigating the etiology of schizophrenia.

Substance abuse and addiction are associated with an apparent devaluation of, and inattention to, natural rewards. This consequence of addiction can be modeled using a reward comparison paradigm where rats avoid intake of a palatable taste cue that comes to predict access to a drug of abuse. Evidence suggests rats avoid intake following such pairings, at least in part, because the taste cue pales in comparison to the highly rewarding drug expected in the near future. In accordance, lesions of the gustatory thalamus or cortex eliminate avoidance of a taste cue when paired with either a drug of abuse or a rewarding sucrose solution, but not when paired with the aversive agent, LiCl. The present study used bilateral ibotenic acid lesions to evaluate the role of a neighboring thalamic structure, the trigeminal orosensory area (TOA), in avoidance of a gustatory cue when paired with sucrose (experiment 1), morphine (experiment 2), cocaine (experiment 3), or LiCl (experiment 4). The results show that the TOA lesion disrupts, but does not eliminate avoidance of a taste cue that predicts access to a preferred sucrose solution and leaves intact the development of a LiCl-induced conditioned taste aversion. The lesion does, however, eliminate the suppression of intake of a taste cue when paired with experimenter-administered morphine or cocaine using our standard parameters. As such, this is the first manipulation found to dissociate avoidance of a taste cue when mediated by a sweet or by a drug of abuse.

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.

Rats with a neonatal ventral hippocampal lesion (NVHL) have been used to model certain features of schizophrenia because they display dopaminergic activity and behavioral alterations consistent with a dysfunctional prefrontal cortex after puberty. Microdialysis studies in normal rats demonstrated increased prefrontal dopamine release during the incentive phase of behavior in an experimental situation specifically designed to evidence this behavioral aspect: the so called "sensory-specific satiety" procedure. Our hypothesis is that if dopaminergic activity in the prefrontal cortex of NVHL rats differs from sham lesioned rats, the responsiveness to the aforementioned experimental situation should also be different. Extracellular medial prefrontal dopamine outflow increased in hungry control rats when they had access to food and decreased across satiety. It increased again when a new food was presented, even when the rats were satiated. NVHL rats also had increased dopamine prefrontal outflow in these conditions, but it remained high after the end of the consumption period. The food consumption behavior declined less rapidly and the reinstatement of food consumption, usually produced by new food, did not occur in NVHL rats, provided the lesions were large. These data were discussed in relation to several theoretical backgrounds developed about the incentive aspect of behavior and for understanding the pathophysiology of schizophrenia., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Cholinergic deficit is one of the most remarkable symptoms and plays an important role in Alzheimer's disease. In the present study, the protective effects of Akebia saponin D (ASD) on learning and memory impairments induced by excitatory neurotoxin ibotenic acid injection were examined in vivo. Our findings suggest that ASD (90 mg/kg, p.o.) would exert a rescue effect on rats both in behavioral performances in Morris water maze and Y maze and cholinergic functions detected by chemical methods. We further investigated in the hippocampus and found ASD could regulate apoptosis-related proteins expression following ibotenic acid injection. Additionally, mitogen-activated protein kinase (MAPK) family phosphorylations were inhibited after ASD treatment, implicating that the MAPK signaling pathway could be involved in the mechanism underlying neuroprotection of ASD against ibotenic acid-induced excitotoxicity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Neutral cues paired with rewards often appear to acquire motivational significance, as if the incentive motivational value of the reward is transferred to the cue. Such cues have been reported to modulate the performance of instrumental action (Pavlovian-instrumental transfer, PIT), serve as conditioned reinforcers in the establishment of new learning, and be the targets of approach and other cue-directed behaviors. Here we examined the effects of lesions of the amygdala central nucleus (CeA) on the acquisition of discriminative autoshaped lever-pressing. Insertion of one lever into the experimental chamber was reinforced by sucrose delivery, but insertion of another lever was not reinforced. Although sucrose delivery was not contingent on lever pressing, both CeA- and sham-lesioned rats rapidly came to press the reinforced but not the nonreinforced lever. Despite their showing little evidence of impairments in autoshaped lever pressing, these same CeA-lesioned rats showed significant deficits in the expression of PIT in a subsequent phase of the experiment. The lack of impaired autoshaping in CeA-lesioned rats contrasts with effects previously reported for conditioned orienting responses (ORs) and for other putative measures of incentive learning including PIT and conditioned approach to visual cues., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The role of the amygdala central nucleus (CeN) in habit learning was assessed in two experiments. First, we examined the effects of bilateral lesions of the anterior CeN on an overtraining-induced lever press habit evaluated using an outcome devaluation protocol. Overtraining generated habitual performance and rendered sham lesioned rats insensitive to outcome devaluation, an effect that was also found in rats given control lesions of the posterior CeN. In contrast, rats with lesions of the anterior CeN did not show normal habit acquisition and their performance remained goal-directed and sensitive to outcome devaluation. Nevertheless, lesions of either the posterior or the anterior CeN abolished the general excitatory influence of a Pavlovian conditioned stimulus on instrumental performance. Second, we assessed the functional interaction between the CeN and dorsolateral striatum (DLS), a region previously implicated in the acquisition of habits, using asymmetrical lesions to disconnect these structures. Rats were given a unilateral lesion of anterior CeN and a unilateral lesion of the DLS, made either ipsilateral (control) or contralateral (disconnection) to the CeN lesion, and given overtraining followed by outcome devaluation. Although the ipsilateral lesioned rats were insensitive to devaluation, the contralateral CeN-DLS lesion impaired habit acquisition, rendering performance sensitive to the devaluation treatment. These results are the first to implicate the CeN and its connection with a circuit involving DLS in habit learning. They imply that, in instrumental conditioning, regions of amygdala parse the instrumental outcome into the reward and reinforcement signals mediating goal-directed and habitual actions, respectively.

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, Aβ, 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.

The ability to react fast and efficiently in threatening situations is paramount for the survival of organisms and has been decisive in our evolutionary history. Defense mechanisms in primates rely on the fast recognition of potential predators and facial expressions of conspecifics. The neural circuitry responsible for the detection of threat is generally thought to be centered on the amygdala. Although it is a pivotal structure in the processing of emotional stimuli, the amygdala does not seem necessary for the early stages of this process. Here we show that bilateral neurotoxic lesions of the superior colliculus in infant capuchins monkeys impaired the recognition of a rubber-snake in a threat-reward conflict task. Lesioned monkeys were uninhibited by a snake in a food-reward retrieval task. Lack of inhibition in the task was observed over the course of 15 weeks. The long lasting recognition impairment of a natural predator observed here is similar to the tameness aspects of Kluver-Bucy syndrome, indicating an important role of this structure in threat recognition., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

In spite of over 30 years of research, the role of the Insular Cortex (IC) in taste memory still remains elusive. To study the role of the IC in taste memory, we used conditioned taste aversion (CTA) for two different concentrations of saccharin; 0.1% which is highly preferred, and 0.5% which is non-preferred. Rats that had been IC lesioned bilaterally with ibotenic acid (15 mg/ml) before CTA showed significant learning impairments for saccharin 0.1% but not for saccharin 0.5%. To test CTA memory retention, rats lesioned a week after CTA training became completely amnesic for saccharin 0.1% yet only mildly impaired for saccharin 0.5%. Interestingly, the resulting preference for either concentration matched that of IC lesioned animals when exposed to either saccharin solution for the first time, but not those of sham animals, implying that IC lesions after CTA for either saccharin solution rendered complete amnesia, irrespective of the original preference. Our data indicate that an intact IC is essential for CTA learning and retention, as well as for an early neophobic response, but not for taste preference itself. Our data supports a model where the IC is involved in general taste rejection., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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.

The formation of an integrated memory for a pattern of stimulation could be based on the elements of that pattern becoming directly linked to one another, or by each of the elements becoming linked to a shared separate configural representation. These 2 accounts have proven difficult to discriminate between. Here, rats received exposure to four patterns of stimulation, each consisting of an auditory stimulus, a visual context, and a time of day; and we examined whether pre-training lesions to the hippocampus influenced memory for the patterns. These lesions abolished pattern memory that required configural processes (Experiments 1A and 1B) but had no effect on pattern memory that could be supported by elemental processes (Experiment 2). This dissociation provides support for the views that elemental and configural processes ordinarily support pattern memory and that rats with lesions to the hippocampus are left reliant on elemental processes. (, (PsycINFO Database Record (c) 2011 APA, all rights reserved).)