Lateral habenula lesions impair the association of a conditioned stimulus with the absence of an unconditioned stimulus: Retardation task.

Recent studies have indicated that the lateral habenula (LHb) mediates the association of a conditioned stimulus (CS) with the absence of an unconditioned stimulus (US). We generated a CS-no US association using an explicit unpaired training procedure and evaluated the conditioned inhibitory properties using the modified version of the retardation-of-acquisition procedure, one of the procedures for assessing conditioned inhibition. First, rats in the unpaired group received explicit unpaired light (CS) and food (US) presentations, followed by light-food pairings. Rats in the comparison group received paired training alone. The rats in the two groups showed increased food-cup responses to light over paired training. However, rats in the unpaired group showed a slower acquisition of light and food excitatory conditioning than those in the comparison group. Light acquired conditioned inhibitory properties through explicitly unpaired training, as evidenced by its slowness. Second, we examined the effects of the LHb lesions on the decremental effects of unpaired learning on subsequent excitatory learning. Sham-operated rats exhibited decremental effects of unpaired learning on subsequent excitatory learning, while rats with LHb neurotoxic lesions did not. Third, we tested whether preexposure to the same number of lights presented in the unpaired training retarded the acquisition of subsequent excitatory conditioning. Preexposure to light did not significantly retard the acquisition of subsequent excitatory associations, with no LHb lesion effects. These findings indicate that LHb is critically involved in the association between CS and the absence of US.

Capsaicin attenuates excitotoxic-induced neonatal brain injury and brain mast cell-mediated neuroinflammation in newborn rats.

Excitotoxicity and neuroinflammation are key contributors to perinatal brain injuries. Capsaicin, an active ingredient of chili peppers, is a potent exogenous agonist for transient receptor potential vanilloid 1 receptors. Although the neuroprotective and anti-inflammatory effects of capsaicin are well-documented, its effects on excitotoxic-induced neonatal brain injury and neuroinflammation have not previously been investigated. The aim of this study was to investigate the effects of capsaicin on brain damage, brain mast cells, and inflammatory mediators in a model of ibotenate-induced excitotoxic brain injury in neonatal rats. P5 rat-pups were intraperitoneally injected with vehicle, 0.2-, 1-, and 5-mg/kg doses of capsaicin, or the NMDA (N-methyl-d-aspartate) receptor antagonist MK-801 (dizocilpine), 30 min before intracerebral injection of 10 µg ibotenate. The naive-control group received no substance administration. The rat pups were sacrificed one or five days after ibotenate injection. Levels of activin A and interleukin (IL)-1ß, IL-6, and IL-10 in brain tissue were measured using the enzyme-linked immunosorbent assay method. Cortex and white matter thicknesses, white matter lesion size, and mast cells were evaluated in brain sections stained with cresyl-violet or toluidine-blue. Capsaicin improved ibotenate-induced white matter lesions and cerebral white and gray matter thicknesses in a dose-dependent manner. In addition, it suppressed the degranulation and increased number of brain mast cells induced by ibotenate. Capsaicin also reduced the excitotoxic-induced production of neuronal survival factor activin A and of the pro-inflammatory cytokines IL-1ß, and IL-6 in brain tissue. However, IL-10 levels were not altered by the treatments. MK-801, as a positive control, reversed all these ibotenate-induced changes, further confirming the success of the model. Our findings provide, for the first time, evidence for the therapeutic effects of capsaicin against excitotoxic-induced neonatal brain injury and brain mast cell-mediated neuroinflammation. Capsaicin may therefore be a promising candidate in the prevention and/or reduction of neonatal brain damage.

Behavioural effects in mice orally exposed to domoic acid or ibotenic acid are influenced by developmental stages and sex differences.

The structure of the brain is dramatically altered during the critical period. Physiological substances (neurotransmitters, hormones, etc.) in the body fluctuate significantly before and after sexual maturation. Therefore, the effect of chemical exposure on the central nervous system often differs depending on the developmental stage and sex. We aimed to compare the behavioural effects that emerged from the administration of chemicals to mice of different life stages (immature or mature) and different sex (male or female). We administered mice with domoic acid (DA), a marine poison, and ibotenic acid (IA), found in poisonous mushrooms. These excitatory amino acids act as agonists for glutamate and are potent neurotoxins. Interestingly, the behavioural effects of these chemicals were completely different. Following DA administration, we observed memory deficits only in groups of male mice treated at maturity. Following IA administration, we observed deviations in emotional behaviour in groups of male mice treated at both immaturity and maturity. In contrast, few characteristic changes were detected in all groups of females. Our results support the theory that the behavioural effects of chemical administration vary considerably with developmental stages and sex. In conclusion, our findings promote better understanding of individual differences in excitatory chemical-induced neurotoxicity and provide evidence for future risk strategies and treatments.

Dopamine D4 receptors in the lateral habenula regulate depression-related behaviors via a pre-synaptic mechanism in experimental Parkinson's disease.

Although multiple studies report that unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induce depressive-like behaviors and hyperactivity of the lateral habenula (LHb), effects of dopamine (DA) D4 receptors in the LHb on depressive-like behaviors are unclear. Here we found that intra-LHb injection of the different doses of D4 receptor agonist A412997 and antagonist L741742 produced the different behavioral responses in SNc sham-lesioned rats, and only the high doses of A412997 and L741742 increased the expression of depressive-like behaviors or produced antidepressant-like effects in SNc-lesioned rats. The low doses of A412997 and L741742 altered the firing rate of LHb neurons and release of DA, GABA and glutamate in the LHb via the GABAergic rostromedial tegmental nucleus (RMTg) in SNc sham-lesioned rats, but not in SNc-lesioned rats. The high doses of A412997 and L741742 also altered the firing rate and release of the transmitters in both SNc sham-lesioned and SNc-lesioned rats, whereas these effects were not involved in the RMTg. Lesions of the SNc shortened the duration of significant effects on the firing rate and release of the transmitters induced by the high doses of A412997 and L741742. These findings suggest that D4 receptors in the LHb are involved in depression-like behaviors via the pre- and post-synaptic mechanisms and depletion of DA decreases the function and/or the expression of both pre- and post-synaptic D4 receptors. This study also points to the importance of the pre-synaptic D4 receptors in the regulation of Parkinson's disease-related depression.

Ablation of olfactory bulb glutamatergic neurons induces depressive-like behaviors and sleep disturbances in mice.

RATIONALE: Major depression is a serious, but common, psychological disorder, which consists of a long-lasting depressive mood, feelings of helplessness, anhedonia, and sleep disturbances. It has been reported that rats with bilateral olfactory bulbectomies (OBXs) exhibit depressive-like behaviors which indicates that the olfactory bulb (OB) plays an important role in the formation of depression. However, which type of OB neurons plays an important role in the formation of depression remains unclear. OBJECTIVE: To determine the role of OB neuronal types in depression and related sleep-wake dysfunction. METHODS: Firstly, we established and evaluated a conventional physical bilateral OBX depression model. Secondly, we used chemical methods to ablate OB neurons, while maintaining the original shape, and evaluated depressive-like behaviors. Thirdly, we utilized AAV-flex-taCasp3-TEVp and transgenetic mice to specifically ablate the OB GABAergic or glutamatergic neurons, then evaluated depressive-like behaviors. RESULTS: Compared with measured parameters in sham mice, mice with OBXs or ibotenic acid-induced OB lesions exhibited depressive-like behaviors and sleep disturbances, as demonstrated by results of depressive-like behavior tests and sleep recordings. Selective lesioning of OB glutamatergic neurons, but not GABAergic neurons induced depressive-like behaviors and increased rapid eye movement sleep during the light phase of the circadian cycle. CONCLUSIONS: These results indicate that OB glutamatergic neurons play a key role in olfactory-related depression and sleep disturbance.

Reduced Sensitivity to Anesthetic Agents upon Lesioning the Mesopontine Tegmental Anesthesia Area in Rats Depends on Anesthetic Type.

BACKGROUND: The brainstem mesopontine tegmental anesthesia area is a key node in circuitry responsible for anesthetic induction and maintenance. Microinjecting the γ-aminobutyric acid-mediated (GABAergic) anesthetic pentobarbital in this nucleus rapidly and reversibly induces general anesthesia, whereas lesioning it renders the animal relatively insensitive to pentobarbital administered systemically. This study investigated whether effects of lesioning the mesopontine tegmental anesthesia area generalize to other anesthetic agents. METHODS: Cell-selective lesions were made using ibotenic acid, and rats were later tested for changes in the dose-response relation to etomidate, propofol, alfaxalone/alfadolone, ketamine, and medetomidine delivered intravenously using a programmable infusion pump. Anesthetic induction for each agent was tracked using five behavioral endpoints: loss of righting reflex, criterion for anesthesia (score of 11 or higher), criterion for surgical anesthesia (score of 14 or higher), antinociception (loss of pinch response), and deep surgical anesthesia (score of 16). RESULTS: As reported previously for pentobarbital, on-target mesopontine tegmental anesthesia area lesions reduced sensitivity to the GABAergic anesthetics etomidate and propofol. The dose to achieve a score of 16 increased to 147 ± 50% of baseline in control animals ± SD (P = 0.0007; 7 lesioned rats and 18 controls) and 136 ± 58% of baseline (P = 0.010; 6 lesioned rats and 21 controls), respectively. In contrast, responsiveness to the neurosteroids alfaxalone and alfadolone remained unchanged compared with baseline (94 ± 24%; P = 0.519; 6 lesioned rats and 18 controls) and with ketamine increased slightly (90 ± 11%; P = 0.039; 6 lesioned rats and 19 controls). The non-GABAergic anesthetic medetomidine did not induce criterion anesthesia even at the maximal dose tested. The dose to reach the maximal anesthesia score actually obtained was unaffected by the lesion (112 ± 8%; P = 0.063; 5 lesioned rats and 18 controls). CONCLUSIONS: Inability to induce anesthesia in lesioned animals using normally effective doses of etomidate, propofol, and pentobarbital suggests that the mesopontine tegmental anesthesia area is the effective target of these, but not necessarily all, GABAergic anesthetics upon systemic administration. Cortical and spinal functions are likely suppressed by recruitment of dedicated ascending and descending pathways rather than by direct, distributed drug action.

Premotor Cortical-Cerebellar Reorganization in a Macaque Model of Primary Motor Cortical Lesion and Recovery.

Neuromotor systems have the capacity for functional recovery following local damage. The literature suggests a possible role for the premotor cortex and cerebellum in motor recovery. However, the specific changes to interactions between these areas following damage remain unclear. Here, we demonstrate potential rewiring of connections from the ipsilesional ventral premotor cortex (ip-PMv) to cerebellar structures in a nonhuman primate model of primary motor cortex (M1) lesion and motor recovery. Cerebellar connections arising from the ip-PMv were investigated by comparing biotinylated dextran amine (BDA) between two groups of male Macaca mulatta: M1-lesion/motor recovery group and intact group. There were more BDA-labeled boutons and axons in all ipsilesional deep cerebellar nuclei (fastigial, interposed, and dentate) in the M1-lesion/recovery group than in the intact group. The difference was evident in the ipsilesional fastigial nucleus (ip-FN), and particularly observed in its middle, a putative somatosensory region of the ip-FN, which was characterized by absent or little expression of aldolase C. Some of the altered projections from the ip-PMv to ip-FN neurons were confirmed as functional because the synaptic markers, synaptophysin and vesicular glutamate transporter 1, were colocalized with BDA-labeled boutons. These results suggest that the adult primate brain after motor lesions can reorganize large-scale networks to enable motor recovery by enhancing sensorimotor coupling and motor commands via rewired fronto-cerebellar connections.SIGNIFICANCE STATEMENT Damaging the motor cortex causes motor deficits, which can be recovered over time. Such motor recovery may result from functional compensation in remaining neuromotor areas, including the ventral premotor cortex. We investigated compensatory changes in neural axonal outputs from ventral premotor to deep cerebellar nuclei in a monkey model of primary motor cortical lesion and motor recovery. The results showed an increase in premotor projections and synaptic formations in deep cerebellar nuclei, especially the sensorimotor region of the fastigial nucleus. Our results provide the first evidence that large-scale reorganization of fronto-cerebellar circuits may underlie functional recovery after motor cortical lesions.

Excitotoxicity Alters Endogenous Secretoneurin Plasma Levels, but Supplementation with Secretoneurin Does Not Protect Against Excitotoxic Neonatal Brain Injury.

Excitotoxicity plays an important role in the pathogenesis of developing brain injury. The neuropeptide secretoneurin (SN) has neuroprotective potential. The aim of this study was to investigate SN plasma concentrations following excitotoxicity and to evaluate the effect of SN as therapeutic strategy in excitotoxic newborn brain injury. Baseline SN plasma concentrations were established in healthy animals. To evaluate the effect of an excitotoxic insult on SN levels, mice pups were subjected to an intracranial injection of ibotenic acid and SN plasma concentrations were measured thereafter. To assess SN's neuroprotective potential, a subgroup of animals was randomly assigned to the following groups: i) "single treatment": vehicle 1× phosphate-buffered saline (PBS), SN 0.25 µg/g body weight (bw), SN 2.5 µg/g bw or SN 12.5 µg/g bw in a single dose 1 h after insult; ii) "acute repetitive treatment": vehicle 1× PBS or SN 0.25 µg/g bw every 24 h starting 1 h after insult; iii) "delayed repetitive treatment": vehicle 1× PBS or SN 0.25 µg/g bw every 24 h starting 60 h after insult. Animals subjected to excitotoxic injury showed significantly lower SN plasma concentrations 6 and 120 h after insult in comparison to healthy controls. Administration of SN did not positively affect lesion size, apoptotic cell death, microglial cell activation or cell proliferation. To conclude, endogenous SN plasma levels are lower in newborn mice subjected to an excitotoxic insult than in healthy controls. Supplementation with SN in various treatment regimens is not neuroprotective in the experimental animal model of excitotoxic newborn brain injury.

Basolateral amygdalar inactivation blocks chronic stress-induced lamina-specific reduction in prefrontal cortex volume and associated anxiety-like behavior.

Chronic exposure to stress causes cognitive deficits, anxiety and depression. Earlier studies have suggested that the prefrontal cortex (PFC) and basolateral amygdala (BLA) can differentially modulate the stress-induced alterations either by their action on HPA axis or via direct reciprocal connections between them. The PFC dysfunction and BLA hypertrophy following stress are known to cause anxiety and affective symptoms. Recent studies indicate that inactivation of BLA projections to PFC remarkably decreases anxiety. However, the effect of BLA inactivation on stress-induced anxiety and associated volume loss in prelimbic (PrL) and anterior cingulate (ACC) subregions of PFC is not known. Accordingly, we evaluated the effect of BLA lesion or inactivation during chronic immobilization stress (CIS) on an approach-avoidance task and associated volume loss in the PFC. The stressed rats showed a significant volumetric reduction in layer I and II of the PrL and ACC. Interestingly, BLA lesion prior to stress prevented the volume loss in PrL and ACC. Further, BLA lesion blocked the anxiety-like behavior in stressed rats. However, in the absence of stress, BLA lesion increased the number of shocks as compared to controls. As BLA lesion produced an anticonflict effect, we performed temporary inactivation of BLA specifically during stress. Similar to BLA lesion, lidocaine-induced inactivation prevented the stress-induced volume loss and anxiety-like behavior. We demonstrate that inactivation of BLA during stress prevents CIS-induced anxiety and associated structural correlates in the PFC. The present study extends the hypothesis of amygdalar silencing as a possible management strategy for stress and associated disorders.

Toxicity of muscimol and ibotenic acid containing mushrooms reported to a regional poison control center from 2002-2016.

BACKGROUND: Amanita muscaria (AM) and A. pantherina (AP) contain ibotenic acid and muscimol and may cause both excitatory and sedating symptoms. Gastrointestinal (GI) symptoms are not classically described but have been reported. There are relatively few reported cases of poisoning with these mushrooms in North America. METHODS: This is a retrospective review of ingestions of ibotenic acid and muscimol containing mushrooms reported to a United States regional poison center from 2002-2016. Cases were included if identification was made by a mycologist or if AM was clearly described. RESULTS: Thirty-four cases met inclusion criteria. There were 23 cases of AM, 10 AP, and 1 A. aprica. Reason for ingestion included foraging (12), recreational (6), accidental (12), therapeutic (1), self-harm (1), and unknown (2). Of the accidental pediatric ingestions 4 (25%) were symptomatic. None of the children with a symptomatic ingestion of AM required admission. A 3-year-old male who ingested AP had vomiting, agitation, and lethargy and received benzodiazepines. He was intubated and had a 3-day ICU stay. There were 25 symptomatic patients. All but one patient developed symptoms within 6 h. Six patients had symptoms for less than 6 h while 15 had symptoms lasting less than 24 h. Ingestions of AP were more symptomatic than AM with regard to the presence of any GI symptoms (80% vs. 35%), central nervous system (CNS) depression (70% vs. 35%), and CNS excitation (70% vs. 35%) respectively. Five patients were intubated. No patients experienced hypotension, seizures, acute kidney injury, or hepatotoxicity. No deaths were reported. DISCUSSION: Ingestion of ibotenic acid/muscimol containing mushrooms often produces a syndrome with GI upset, CNS excitation, and CNS depression either alone or in combination. Ingestion of AP was associated with a higher rate of symptoms compared to AM.

Microglia in the developing prefrontal cortex of rats show dynamic changes following neonatal disconnection of the ventral hippocampus.

Impaired ventral hippocampal (VH)-prefrontal cortex (PFC) connectivity is implicated in many cognitive and behavioral disorders. Excitotoxic neonatal VH (nVH) lesion in rat pups has been shown to induce synaptic pruning in the PFC as well as behavioral changes of relevance to developmental neuropsychiatric disorders. In the current study, we hypothesized that microglia, immune cells required for proper brain development and plasticity, may play a role in the development of abnormal behaviors in the nVH-lesioned animals. Ibotenic acid-induced nVH lesion was induced in postnatal day (P)7 male rats. Developmental changes in microglial density, morphology, ultrastructure and gene expression were analyzed in the PFC at P20 and P60. Our results revealed increased microglial reactivity and phagocytic activity in the lesioned rats at P20. Increased mRNA levels of C3 and C1q, complement molecules involved in synaptic pruning, were concomitantly observed. Diminished, but maintained, microglial reactivity and reduced antioxidative defenses were identified in lesioned rats at P60. Behavioral deficits were significantly reduced in the post-pubertal rats by suppressing microglial reactivity by a one-week minocycline treatment immediately after the lesion, These results suggest that early-life disconnection of the VH has long-lasting consequences for microglial functions in the connected structures. Alterations in microglia may underlie synaptic reorganization and behavioral deficits observed following neonatal VH disconnection.

Adult Neurogenesis Conserves Hippocampal Memory Capacity.

The hippocampus is crucial for declarative memories in humans and encodes episodic and spatial memories in animals. Memory coding strengthens synaptic efficacy via an LTP-like mechanism. Given that animals store memories of everyday experiences, the hippocampal circuit must have a mechanism that prevents saturation of overall synaptic weight for the preservation of learning capacity. LTD works to balance plasticity and prevent saturation. In addition, adult neurogenesis in the hippocampus is proposed to be involved in the down-scaling of synaptic efficacy. Here, we show that adult neurogenesis in male rats plays a crucial role in the maintenance of hippocampal capacity for memory (learning and/or memory formation). Neurogenesis regulated the maintenance of LTP, with decreases and increases in neurogenesis prolonging or shortening LTP persistence, respectively. Artificial saturation of hippocampal LTP impaired memory capacity in contextual fear conditioning, which completely recovered after 14 d, which was the time required for LTP to decay to the basal level. Memory capacity gradually recovered in parallel with neurogenesis-mediated gradual decay of LTP. Ablation of neurogenesis by x-ray irradiation delayed the recovery of memory capacity, whereas enhancement of neurogenesis using a running wheel sped up recovery. Therefore, one benefit of ongoing adult neurogenesis is the maintenance of hippocampal memory capacity through homeostatic renewing of hippocampal memory circuits. Decreased neurogenesis in aged animals may be responsible for the decline in cognitive function with age.SIGNIFICANCE STATEMENT Learning many events each day increases synaptic efficacy via LTP, which can prevent the storage of new memories in the hippocampal circuit. In this study, we demonstrate that hippocampal capacity for the storage of new memories is maintained by ongoing adult neurogenesis through homoeostatic renewing of hippocampal circuits in rats. A decrease or an increase in neurogenesis, respectively, delayed or sped up the recovery of memory capacity, suggesting that hippocampal adult neurogenesis plays a critical role in reducing LTP saturation and keeps the gate open for new memories by clearing out the old memories from the hippocampal memory circuit.

Neurotoxic lesions of the pedunculopontine tegmental nucleus impair the elaboration of postictal antinociception.

Generalised tonic-clonic seizures, generated by abnormal neuronal hyper-activity, cause a significant and long-lasting increase in the nociceptive threshold. The pedunculopontine tegmental nucleus (PPTN) plays a crucial role in the regulation of seizures as well as the modulation of pain, but its role in postictal antinociceptive processes remains unclear. In the present study, we aimed to investigate the involvement of PPTN neurons in the postictal antinociception. Wistar rats had their tail-flick baseline recorded and were injected with ibotenic acid (1.0 µg/0.2 µL) into the PPTN, aiming to promote a local neurotoxic lesion. Five days after the neuronal damage, pentylenetetrazole (PTZ; 64 mg/kg) was intraperitoneally administered to induce tonic-clonic seizures. The tail-withdrawal latency was measured immediately after the seizures (0 min) and subsequently at 10-min intervals until 130 min after the seizures were induced pharmacologically. Ibotenic acid microinjected into the PPTN did not reduce the PTZ-induced seizure duration and severity, but it diminished the postictal antinociception from 0 to 130 min after the end of the PTZ-induced tonic-clonic seizures. These results suggest that the postictal antinociception depends on the PPTN neuronal cells integrity.

The rostromedial tegmental nucleus is essential for non-rapid eye movement sleep.

The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep-wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep-wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation.

Icariside II ameliorates ibotenic acid-induced cognitive impairment and apoptotic response via modulation of MAPK pathway in rats.

BACKGROUND: Excitotoxicity is extensively recognized as a major pathological process of neuronal death and has been proved to play a key role in Alzheimer's disease (AD). ICS II, a flavonoid compound from Herba Epimedii Maxim, is attracting great interests due to its neuroprotective properties. PURPOSE: The present study was aimed to explore the effects of ICS II on cognitive dysfunction and apoptotic response induced by excitatory neurotoxin ibotenic acid (IBO) injection in rats. METHODS: Rats subjected to bilateral hippocampal injection of IBO were intragastrically administered with 4, 8 and 16 mg/kg ICS II or 0.6 mg/kg donepezil once a day for continuous 20 days. Learning and memory functions were tested by Morris water maze. The neuronal morphology in hippocampus was examined by HE staining and Nissl staining, respectively. Neuronal apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. The expression of apoptosis-related proteins and the activation of mitogen-activated protein kinase (MAPK) pathway were detected by Western blot. RESULTS: It was uncovered that hippocampal injection of IBO caused learning and memory impairment, neuronal damage and loss, as well as pro-apoptotic response. ICS II administrated at doses of 8 and 16 mg/kg not only rescued behavioral performance, but also protected hippocampal neurons against neurotoxicity via suppressing the elevation of Bax/Bcl-2 ratio and the activation of caspase-3. Meanwhile, ICS II repressed the down-regulation of calbindin protein induced by IBO. Additionally, ICS II exerted an inhibitory effect on MAPK (p38, ERK1/2 and JNK) pathway phosphorylation. CONCLUSION: These results suggest that ICS II attenuates IBO-induced cognitive deficits, possibly via the regulation of calbindin expression and the inhibition of apoptotic response. In addition, the MAPK signaling pathway is implicated in the potential mechanisms of ICS II against IBO-induced excitotoxicity, indicating that ICS II is a promising compound for treatment of excitotoxicity-related diseases, including AD.

Effects of neonatal excitotoxic lesions in ventral thalamus on social interaction in the rat.

The role of the thalamus in schizophrenia has increasingly been studied in recent years. Deficits in the ventral thalamus have been described in only few postmortem and neuroimaging studies. We utilised our previously introduced neurodevelopmental animal model, the neonatal excitotoxic lesion of the ventral thalamus of Sprague-Dawley rats (Wolf et al., Pharmacopsychiatry 43:99-109, 22). At postnatal day (PD7), male pubs received bilateral thalamic infusions with ibotenic acid (IBA) or artificial cerebrospinal fluid (control). In adulthood, social interaction of two animals not familiar to each other was studied by a computerised video tracking system. This study displays clear lesion effects on social interaction of adult male rats. The significant reduction of total contact time and the significant increase in distance between the animals in the IBA group compared to controls can be interpreted as social withdrawal modelling a negative symptom of schizophrenia. The significant increase of total distance travelled in the IBA group can be hypothesised as agitation modelling a positive symptom of schizophrenia. Using a triple concept of social interaction, the percentage of no social interaction (Non-SI%) was significantly larger, and inversely, the percentage of passive social interaction (SI-passive%) was significantly smaller in the IBA group when compared to controls. In conclusion, on the background of findings in schizophrenic patients, the effects of neonatal ventral thalamic IBA lesions in adult male rats support the hypothesis of face and construct validity as animal model of schizophrenia.

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.

Magnesium Sulfate Prevents Neurochemical and Long-Term Behavioral Consequences of Neonatal Excitotoxic Lesions: Comparison Between Male and Female Mice.

Magnesium sulfate (MgSO4) administration to mothers at risk of preterm delivery is proposed as a neuroprotective strategy against neurological alterations such as cerebral palsy in newborns. However, long-term beneficial or adverse effects of MgSO4 and sex-specific sensitivity remain to be investigated. We conducted behavioral and neurochemical studies of MgSO4 effects in males and females, from the perinatal period to adolescence in a mouse model of cerebral neonatal lesion. The lesion was produced in 5-day-old (P5) pups by ibotenate intracortical injection. MgSO4 (600 mg/kg, i.p.) prior to ibotenate prevented lesion-induced sensorimotor alterations in both sexes at P6 and P7. The lesion increased glutamate level at P10 in the prefrontal cortex, which was prevented by MgSO4 in males. In neonatally lesioned adolescent mice, males exhibited more sequelae than females in motor and cognitive functions. In the perirhinal cortex of adolescent mice, the neonatal lesion induced an increase in vesicular glutamate transporter 1 density in males only, which was negatively correlated with cognitive scores. Long-term sequelae were prevented by neonatal MgSO4 administration. MgSO4 never induced short- or long-term deleterious effect on its own. These results also strongly suggest that sex-specific neuroprotection should be foreseen in preterm infants.

Persistently Altered Metabolic Phenotype following Perinatal Excitotoxic Brain Injury.

Excitotoxicity plays a key role during insults to the developing brain such as neonatal encephalopathy, stroke, and encephalopathy of prematurity. Such insults affect many thousands of infants each year. Excitotoxicity causes frank lesions due to cell death and gliosis and disturbs normal developmental process, leading to deficits in learning, memory, and social integration that persist into adulthood. Understanding the underlying processes of the acute effects of excitotoxicity and its persistence during brain maturation provides an opportunity to identify mechanistic or diagnostic biomarkers, thus enabling and designing possible therapies. We applied mass spectrometry to provide metabolic profiles of brain tissue and plasma over time following an excitotoxic lesion (intracerebral ibotenate) to the neonatal (postnatal day 5) mouse brain. We found no differences between the plasma from the control (PBS-injected) and excitotoxic (ibotenate-injected) groups over time (on postnatal days 8, 9, 10, and 30). In the brain, we found that variations in amino acids (arginine, glutamine, phenylananine, and proline) and glycerophospholipids were sustaining acute and delayed (tertiary) responses to injury. In particular, the effect of the excitotoxic lesion on the normal profile of development was linked to alterations in a fingerprint of glycerophospolipids and amino acids. Specifically, we identified increases in the amino acids glutamine, proline, serine, threonine, tryptophan, valine, and the sphingolipid SM C26:1, and decreases in the glycerophospholipids, i.e., the arachidonic acid-containing phosphatidylcholine (PC aa) C30:2 and the PC aa C32:3. This study demonstrates that metabolic profiling is a useful approach to identify acute and tertiary effects in an excitotoxic lesion model, and generating a short list of targets with future potential in the hunt for identification, stratification, and possibly therapy.

Neural Reorganization Due to Neonatal Amygdala Lesions in the Rhesus Monkey: Changes in Morphology and Network Structure.

It is generally believed that neural damage that occurs early in development is associated with greater adaptive capacity relative to similar damage in an older individual. However, few studies have surveyed whole brain changes following early focal damage. In this report, we employed multimodal magnetic resonance imaging analyses of adult rhesus macaque monkeys who had previously undergone bilateral, neurotoxic lesions of the amygdala at about 2 weeks of age. A deformation-based morphometric approach demonstrated reduction of the volumes of the anterior temporal lobe, anterior commissure, basal ganglia, and pulvinar in animals with early amygdala lesions compared to controls. In contrast, animals with early amygdala lesions had an enlarged cingulate cortex, medial superior frontal gyrus, and medial parietal cortex. Diffusion-weighted imaging tractography and network analysis were also used to compare connectivity patterns and higher-level measures of communication across the brain. Using the communicability metric, which integrates direct and indirect paths between regions, lesioned animals showed extensive degradation of network integrity in the temporal and orbitofrontal cortices. This work demonstrates both degenerative as well as progressive large-scale neural changes following long-term recovery from neonatal focal brain damage.