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1.  Overexpression of parkin in rat nigrostriatal dopamine system protects against methamphetamine neurotoxicity 
Experimental neurology  2013;247:359-372.
Methamphetamine (METH) is a central nervous system psychostimulant with a high potential for abuse. At high doses, METH causes a selective degeneration of dopaminergic terminals in the striatum, sparing other striatal terminals and cell bodies. We previously detected a deficit in parkin after binge METH in rat striatal synaptosomes. Parkin is an ubiquitin-protein E3 ligase capable of protecting dopamine neurons from diverse cellular insults. Whether the deficit in parkin mediates the toxicity of METH and whether parkin can protect from toxicity of the drug is unknown. The present study investigated whether overexpression of parkin attenuates degeneration of striatal dopaminergic terminals exposed to binge METH. Parkin overexpression in rat nigrostriatal dopamine system was achieved by microinjection of adeno-associated viral transfer vector 2/6 encoding rat parkin (AAV2/6-parkin) into the substantia nigra pars compacta. The microinjections of AAV2/6-parkin dose-dependently increased parkin levels in both the substantia nigra pars compacta and striatum. The levels of dopamine synthesizing enzyme, tyrosine hydroxylase, remained at the control levels; therefore, tyrosine hydroxylase immunoreactivity was used as an index of dopaminergic terminal integrity. In METH-exposed rats, the increase in parkin levels attenuated METH-induced decreases in striatal tyrosine hydroxylase immunoreactivity in a dose-dependent manner, indicating that parkin can protect striatal dopaminergic terminals against METH neurotoxicity.
PMCID: PMC4321803  PMID: 23313192
methamphetamine; toxicity; parkin; neuroprotection; dopamine; striatum
2.  Altered neuronal activity relationships between the pedunculopontine nucleus and motor cortex in a rodent model of Parkinson's disease 
Experimental neurology  2008;213(2):268-280.
The pedunculopontine nucleus (PPN) is a new deep brain stimulation (DBS) target for Parkinson's disease (PD), but little is known about PPN firing pattern alterations in PD. The anesthetized rat is a useful model for investigating the effects of dopamine loss on the transmission of oscillatory cortical activity through basal ganglia structures. After dopamine loss, synchronous oscillatory activity emerges in the subthalamic nucleus and substantia nigra pars reticulata in phase with cortical slow oscillations. To investigate the impact of dopamine cell lesion-induced changes in basal ganglia output on activity in the PPN, this study examines PPN spike timing with reference to motor cortex (MCx) local field potential (LFP) activity in urethane- and ketamine-anesthetized rats. Seven – ten days after unilateral 6-hydroxydopamine lesion of the medial forebrain bundle, spectral power in PPN spike trains and coherence between PPN spiking and PPN LFP activity increased in the ∼1 Hz range in urethane-anesthetized rats. PPN spike timing also changed from firing predominantly in-phase with MCx slow oscillations in the intact urethane-anesthetized rat to firing predominantly antiphase to MCx oscillations in the hemi-parkinsonian rat. These changes were not observed in the ketamine-anesthetized preparation. These observations suggest that dopamine loss alters PPN spike timing by increasing inhibitory oscillatory input to the PPN from basal ganglia output nuclei, a phenomenon that may be relevant to motor dysfunction and PPN DBS efficacy in PD patients.
PMCID: PMC4318559  PMID: 18601924
pedunculopontine nucleus; Parkinson's disease; motor cortex; oscillations; local field potential; dopamine; deep brain stimulation; basal ganglia; urethane; ketamine
3.  [No title available] 
PMCID: PMC3946993  PMID: 24275526
4.  [No title available] 
PMCID: PMC3947015  PMID: 24246279
5.  [No title available] 
PMCID: PMC3970269  PMID: 24316193
6.  Morphine inhibits Purkinje cell survival and dendritic differentiation in organotypic cultures of the mouse cerebellum 
Experimental neurology  1994;130(1):95-105.
The effects of morphine on the morphogenesis and survival of calbindin-D28kimmunoreactive Purkinje cells was studied in organotypic explant cultures isolated from 1- or 7-day-old mouse cerebella. To reduce experimental variability, bilaterally matched pairs of organotypic cultures were used to compare the effects of opiate drug treatment. One explant within each pair was untreated, while the remaining explant was continuously treated for 7 to 10 days with morphine, morphine plus naloxone, or naloxone alone. In explants derived from 1-day-old mice, morphine treatment significantly reduced Purkinje cell dendritic length compared to symmetrically-matched untreated control explants. The concentration of morphine estimated to cause a half-maximal reduction (EC50) in dendritic length was 4.9 × 10−8 M. At higher concentrations (EC50 = 3.6 × 10−6 M), morphine also significantly decreased the number of Purkinje cells in explants from 1-day-old mice compared to untreated explants. Electron microscopy identified increased numbers of degenerating Purkinje cells in explants derived from 1-day-old mice. This showed that high concentrations (10−5 M) of morphine reduced Purkinje cell numbers by decreasing their rate of survival. In explants derived from 7-day-old mice, morphine (10−5 M) neither affected Purkinje cell dendritic length nor cell numbers compared to symmetrically-matched untreated (control) explants. Collectively, these findings suggest that morphine per se, through a direct action on the cerebellum, can affect Purkinje cell differentiation and survival. The results additionally suggest there is a critical period during development when Purkinje cells are especially vulnerable to the effects of morphine.
PMCID: PMC4306355  PMID: 7821399
Endogenous opioid systems; Calbindin-D28k; Cerebellar development; Cell death; Drug abuse; Critical period; Neurotoxicity
7.  Commentary: Dopaminergic dysfunction in DYT1 dystonia 
Experimental neurology  2008;212(2):242-246.
A three-base-pair deletion in the torsinA gene leads to generalized torsion dystonia (DYT1) in humans, an often devastating movement disorder in which voluntary movements are disrupted by sustained muscle spasms and abnormal limb posturing. In a recent issue of Experimental Neurology, Zhao et al. (2008) have provided a thorough behavioral, anatomic, and biochemical characterization of a mouse line that over-expresses human mutant torsinA, with particular emphasis on the possible role of dopaminergic dysfunction in these animals. This commentary provides an overview of the clinical and genetic features of the human disease and of the available transgenic mouse models for DYT1 dystonia, and discusses the evidence favoring the role of dopamine in the clinical manifestations of the disease.
PMCID: PMC4305330  PMID: 18513716
8.  Fractalkine signaling and Tau hyper-phosphorylation are associated with autophagic alterations in lentiviral Tau and Aβ1–42 gene transfer models 
Experimental neurology  2013;251:10.1016/j.expneurol.2013.01.009.
Tau hyper-phosphorylation (p-Tau) and neuro-inflammation are hallmarks of neurodegeneration. Previous findings suggest that microglial activation via CX3CL1 promotes p-Tau. We examined inflammation and autophagic p-Tau clearance in lentiviral Tau and mutant P301L expressing rats and used lentiviral Aβ1–42 to induce p-Tau. Lentiviral Tau or P301L expression significantly increased caspase-3 activity and TNF-α, but CX3CL1 was significantly higher in animals expressing Tau compared to P301L. Lentiviral Aβ1–42 induced p-Tau 4 weeks post-injection, and increased caspase-3 activation (8-fold) and TNF-α levels. Increased levels of ADAM-10/17 were also detected with p-Tau. IL-6 levels were increased but CX3CL1 did not change in the absence of p-Tau (2 weeks); however, p- Tau reversed these effects, which were associated with increased microglial activity. We observed changes in autophagic markers, including accumulation of autophagic vacuoles (AVs) and p-Tau accumulation in autophagosomes but not lysosomes, suggesting alteration of autophagy. Taken together, microglial activation may promote p-Tau independent of total Tau levels via CX3CL1 signaling, which seems to depend on interaction with inflammatory markers, mainly IL-6. The simultaneous change in autophagy and CX3CL1 signaling suggests communication between microglia and neurons, raising the possibility that accumulation of intraneuronal amyloid, due to lack of autophagic clearance, may lead microglia activation to promote p-Tau as a tag for phagocytic degradation.
PMCID: PMC3644355  PMID: 23333589
Tau phosphorylation; CX3CL1; inflammation; autophagosome; autophagy
9.  Intraspinal transplantation and modulation of donor neuron electrophysiological activity 
Experimental neurology  2013;251:47-57.
Rat fetal spinal cord (FSC) tissue, naturally enriched with interneuronal progenitors, was introduced into high cervical, hemi-resection (Hx) lesions. Electrophysiological analyses were conducted to determine if such grafts exhibit physiologically-patterned neuronal activity and if stimuli which increase respiratory motor output also alter donor neuron bursting. Three months following transplantation, the bursting activity of FSC neurons and the contralateral phrenic nerve were recorded in anesthetized rats during a normoxic baseline period and brief respiratory challenges. Spontaneous neuronal activity was detected in 80 % of the FSC transplants, and autocorrelation of action potential spikes revealed distinct correlogram peaks in 87% of neurons. At baseline, the average discharge frequency of graft neurons was 13.0 ± 1.7 Hz, and discharge frequency increased during a hypoxic respiratory challenge (p < 0.001). Parallel studies in unanesthetized rats showed that FSC tissue recipients had larger inspiratory tidal volumes during brief hypoxic exposures (p < 0.05 vs. C2Hx rats). Anatomical connectivity was explored in additional graft recipients by injecting a transynaptic retrograde viral tracer (pseudorabies virus, PRV) directly into matured transplants. Neuronal labeling occurred throughout graft tissues and also in the host spinal cord and brainstem nuclei, including those associated with respiratory control. These results underscore the neuroplastic potential of host-graft interactions and training approaches to enhance functional integration within targeted spinal circuitry.
PMCID: PMC3893055  PMID: 24192152
fetal spinal cord; transplantation; spinal cord repair; cervical spinal cord injury; hypoxia; respiratory recovery
10.  Nitro-oleic acid desensitizes TRPA1 and TRPV1 agonist responses in adult rat DRG neurons 
Experimental neurology  2013;251:12-21.
Nitro-oleic acid (OA-NO2), an electrophilic fatty acid nitroalkene byproduct of redox reactions, activates transient receptor potential ion channels (TRPA1 and TRPV1) in primary sensory neurons. To test the possibility that signaling actions of OA-NO2 might modulate TRP channels, we examined: (1) interactions between OA-NO2 and other agonists for TRPA1 (allyl-isothiocyanate, AITC) and TRPV1 (capsaicin) in rat dissociated dorsal root ganglion cells using Ca2+ imaging and patch clamp techniques and (2) interactions between these agents on sensory nerves in the rat hindpaw. Ca2+ imaging revealed that brief application (15-30 sec) of each of the three agonists induced homologous desensitization. Heterologous desensitization also occurred when one agonist was applied prior to another agonist. OA-NO2 was more effective in desensitizing the response to AITC than the response to capsaicin. Prolonged exposure to OA-NO2 (20 min) had a similar desensitizing effect on AITC or capsaicin. Homologous and heterologous desensitization were also demonstrated with patch clamp recording. Deltamethrin, a phosphatase inhibitor, reduced the capsaicin or AITC induced desensitization of OA-NO2 but did not suppress the OA-NO2 induced desensitization of AITC or capsaicin, indicating that heterologous desensitization induced by either capsaicin or AITC occurs by a different mechanism than the desensitization produced by OA-NO2. Subcutaneous injection of OA-NO2 (2.5 mM, 35 μL) into a rat hindpaw induced delayed and prolonged nociceptive behavior. Homologous desensitization occurred with AITC and capsaicin when applied at 15 minute intervals, but did not occur with OA-NO2 when applied at a 30 min interval. Pretreatment with OA-NO2 reduced AITC-evoked nociceptive behaviors but did not alter capsaicin responses. These results raise the possibility that OA-NO2 might be useful clinically to reduce neurogenic inflammation and certain types of painful sensations by desensitizing TRPA1 expressing nociceptive afferents.
PMCID: PMC3897192  PMID: 24212047
desensitization; nociception; nitro-oleic acid; primary sensory neuron; TRP channels
11.  Mechanism of Highly Synchronized Bilateral Hippocampal Activity 
Experimental neurology  2013;251:101-111.
In vivo studies of epileptiform discharges in the hippocampi of rodents have shown that bilateral seizure activity can sometimes be synchronized with very small delays (< 2 ms). This observed small time delay of epileptiform activity between the left and right CA3 regions is unexpected given the physiological propagation time across the hemispheres (> 6 ms). The goal of this study is to determine the mechanisms of this tight synchronization with in-vitro electrophysiology techniques and computer simulations. The hypothesis of a common source was first eliminated by using an in-vitro preparation containing both hippocampi with a functional ventral hippocampal commissure (VHC) and no other tissue. Next, the hypothesis that a noisy baseline could mask the underlying synchronous activity between the two hemispheres was ruled out by low noise in-vivo recordings and computer simulation of the noisy environment. Then we built a novel bilateral CA3 model to test the hypothesis that the phenomenon of very small left-to-right propagation delay of seizure activity is a product of epileptic cell network dynamics. We found that the commissural tract connectivity could decrease the delay between seizure events recorded from two sides while the activity propagated longitudinally along the CA3 layer thereby yielding delays much smaller than the propagation time between the two sides. The modeling results indicate that both recurrent and feedforward inhibition were required for shortening the bilateral propagation delay and depended critically on the length of the commissural fiber tract as well as the number of cells involved in seizure generation. These combined modeling/experimental studies indicate that it is possible to explain near perfect synchronization between the two hemispheres by taking into account the structure of the hippocampal network.
PMCID: PMC3902113  PMID: 24262205
Epilepsy; Synchronization; in vivo; in vitro; in silico
12.  Targeting deficiencies in mitochondrial respiratory complex I and functional uncoupling exerts anti-seizure effects in a genetic model of temporal lobe epilepsy and in a model of acute temporal lobe seizures 
Experimental neurology  2013;251:84-90.
Mitochondria actively participate in neurotransmission by providing energy (ATP) and maintaining normative concentrations of reactive oxygen species (ROS) in both presynaptic and postsynaptic elements. In human and animal epilepsies, ATP-producing respiratory rates driven by mitochondrial respiratory complex (MRC) I are reduced, antioxidant systems are attenuated and oxidative damage is increased. We report that MRCI-driven respiration and functional uncoupling (an inducible antioxidant mechanism) are reduced and levels of H2O2 are elevated in mitochondria isolated from KO mice. Experimental impairment of MRCI in WT hippocampal slices via rotenone reduces paired-pulse ratios (PPRs) at mossy fiber-CA3 synapses (resembling KO PPRs), and exacerbates seizure-like events in vitro. Daily treatment with AATP [a combination therapy composed of ascorbic acid (AA), alpha-tocopherol (T), sodium pyruvate (P) designed to synergistically target mitochondrial impairments] improved mitochondrial functions, mossy fiber PPRs, and reduced seizure burden index (SBI) scores and seizure incidence in KO mice. AATP pretreatment reduced severity of KA-induced seizures resulting in 100% protection from the severe tonic-clonic seizures in WT mice. These data suggest that restoration of bioenergetic homeostasis in the brain may represent a viable anti-seizure target for temporal lobe epilepsy.
PMCID: PMC3990438  PMID: 24270080
Mitochondria; seizures; epilepsy; kainic acid; Kv1.1 knockout mice; Kcna1-null mice; ascorbic acid; pyruvate; alpha-tocopherol; mitochondrial uncoupling; mitochondrial complex I; paired-pulse ratios; seizure-like events; ROS; antioxidant; field potentials
13.  Neuronal Circuits In Epilepsy: Do They Matter? 
Experimental neurology  2012;244:67-74.
Seizures occur in groups of neurons and involve complex interactions across several regions. The focus of much epilepsy research has been on changes in single neuronal populations but the interpretation of the implications these changes is often limited by not being able to place those observed changes appropriately overall function of the brain. Understanding regional interactions at the beginning and during the evolution of a seizure may help place the changes in the appropriate context of the pathophysiology of epilepsy and guide us in identifying more effective therapies. In this paper we will focus on the circuits that support the different stages of seizures. Although we are far from knowing how the system works to initiate and spread seizures, we hope to provide a framework upon which we can place cellular changes. The concepts of seizure focus, initiating seizure circuits, paths of spread and neuromodulatory centers will be used to develop a systems view of epilepsy.
PMCID: PMC4266595  PMID: 22342991
Epilepsy; Seizure; Functional anatomy; Brain circuit; Cortical-subcortical interaction; Neuromodulation
14.  Sox10-MCS5 enhancer dynamically tracks human oligodendrocyte progenitor fate 
Experimental neurology  2013;247:694-702.
In this study, we sought to establish a novel method to prospectively and dynamically identify live human oligodendrocyte precursor cells (OPCs) and oligodendrocyte lineage cells from brain dissociates and pluripotent stem cell culture. We selected a highly conserved enhancer element of the Sox10 gene, known as MCS5, which directs reporter expression to oligodendrocyte lineage cells in mouse and zebrafish. We demonstrate that lentiviral Sox10-MCS5 induced expression of GFP at high levels in a subpopulation of human CD140a/PDGFαR-sorted OPCs as well as their immature oligodendrocyte progeny. Furthermore, we show that almost all Sox10-MCS5:GFPhigh cells expressed OPC antigen CD140a and human OPCs expressing SOX10, OLIG2, and PDGFRA mRNAs could be prospectively identified using GFP based fluorescence activated cells sorting alone. Additionally, we established a human induced pluripotent cell (iPSC) line transduced with the Sox10-MCS5:GFP reporter using a Rex-Neo cassette. Similar to human primary cells, GFP expression was restricted to embryoid bodies containing both oligodendrocyte progenitor and oligodendrocyte cells and co-localized with NG2 and O4-positive cells respectively. As such, we have established a novel reporter system that can track oligodendrocyte commitment in human cells, establishing a valuable tool to improve our understanding and efficiency of human oligodendrocyte derivation.
PMCID: PMC4254711  PMID: 23507034
SOX10; enhancer; pluripotent; lentivirus
15.  Presenilins regulate the cellular activity of ryanodine receptors differentially through isotype-specific N-terminal cysteines 
Experimental neurology  2013;0:10.1016/j.expneurol.2013.09.001.
Presenilins (PS), endoplasmic reticulum (ER) transmembrane proteins, form the catalytic core of γ-secretase, an amyloid precursor protein processing enzyme. Mutations in PS lead to Alzheimer's disease (AD) by altering γ-secretase activity to generate pathologic amyloid beta and amyloid plaques in the brain. Here, we identified a novel mechanism where binding of the soluble, cytosolic N-terminal domain (NTF) of PS to intracellular Ca2+ release channels, ryanodine receptors (RyR), controls Ca2+ release from the ER. While PS1NTF decreased total RyR-mediated Ca2+ release, PS2NTF had no effect at physiological Ca2+ concentrations. This differential function and isotype-specificity is due to four cysteines absent in PS1NTF, present, however, in PS2NTF. Site-directed mutagenesis targeting these cysteines converted PS1NTF to PS2NTF function and vice versa, indicating differential RyR binding. This novel mechanism of intracellular Ca2+ regulation through the PS-RyR interaction represents a novel target for AD drug development and the treatment of other neurodegenerative disorders that critically depend on ryanodine receptor and presenilin signaling.
PMCID: PMC3843983  PMID: 24029002
neuroprotection; oxidative stress; endoplasmic reticulum; Alzheimer's disease; intracellular calcium
16.  Repeated intravenous doxapram induces phrenic motor facilitation 
Experimental neurology  2013;0:10.1016/j.expneurol.2013.08.016.
Doxapram is a respiratory stimulant used to treat hypoventilation. Here we investigated whether doxapram could also trigger respiratory neuroplasticity. Specifically, we hypothesized that intermittent delivery of doxapram at low doses would lead to long-lasting increases (i.e., facilitation) of phrenic motor output in anesthetized, vagotomized, and mechanically-ventilated rats. Doxapram was delivered intravenously in a single bolus (2 or 6 mg/kg) or as a series of 3 injections (2 mg/kg) at 5 min intervals. Control groups received pH-matched saline injections (vehicle) or no treatment (anesthesia time control). Doxapram evoked an immediate increase in phrenic output in all groups, but a persistent increase in burst amplitude only occurred after repeated dosing with 2 mg/kg. At 60 min following the last injection, phrenic burst amplitude was 168±24% of baseline (%BL) in the group receiving 3 injections (P < 0.05 vs. controls), but was 103±8%BL and 112±4%BL in the groups receiving a single dose of 2 or 6 mg/kg, respectively. Following bilateral section of the carotid sinus nerves, the acute phrenic response to doxapram (2 mg/kg) was reduced by 68% suggesting that at low doses the drug was acting primarily via the carotid chemoreceptors. We conclude that intermittent application of doxapram can trigger phrenic neuroplasticity, and this approach might be of use in the context of respiratory rehabilitation following neurologic injury.
PMCID: PMC3844021  PMID: 24013015
phrenic motor facilitation; doxapram; respiratory neuroplasticity
17.  Transient Impact of Spike on Theta Rhythm in Temporal Lobe Epilepsy 
Experimental neurology  2013;250:10.1016/j.expneurol.2013.09.023.
Epileptic spike is an indicator of hyper-excitability and hyper-synchrony of neural networks. While cognitive deficit in epilepsy is a common observation, how spikes transiently influence brain oscillations, especially those essential for cognitive functions, remains obscure. Here we aimed to quantify the transient impacts of sporadic spikes on theta oscillations and investigate how such impacts may evolve during epileptogenesis. Longitudinal depth EEG data were recorded in the CA1 area of pilocarpine temporal lobe epilepsy (TLE) rat models. Phase stability, a measure of synchrony, and theta power were estimated around spikes as well as in the protracted spike-free periods (FP) at least one hour after spike bursts. We found that the change in theta power did not correlate with the change in phase stability. More importantly, the impact of spikes on theta rhythm was highly time-dependent. While theta power decreased abruptly after spikes both in the latent and chronic stages, changes of theta phase stability demonstrated opposite trends in the latent and chronic stages, potentially due to the substantial reorganization of neural circuits along epileptogenesis. During FP, theta phase stability was significantly higher than the baseline level before injections, indicating that hyper-synchrony remained even hours after the spike bursts. We concluded that spikes have transient negative effects on theta rhythm, however, impacts are different during latent and chronic stages, implying that its influence on cognitive processes may also change over time during epileptogenesis.
PMCID: PMC3857724  PMID: 24100023
Theta Rhythm; Temporal Lobe Epilepsy; Hippocampus; Epileptogenesis
18.  Partial neuroprotection by nNOS inhibition during profound asphyxia in preterm fetal sheep 
Experimental neurology  2013;250:10.1016/j.expneurol.2013.10.003.
Preterm brain injury is partly associated with hypoxia-ischemia starting before birth. Excessive nitric oxide production during HI may cause nitrosative stress, leading to cell membrane and mitochondrial damage. We therefore tested the hypothesis that therapy with a new, selective neuronal nitric oxide synthase (nNOS) inhibitor, JI-10 (0.022 mg/kg bolus, n=8), given 30 min before 25 min of complete umbilical cord occlusion was protective in preterm fetal sheep at 101-104 d gestation (term is 147 d), compared to saline (n=8). JI-10 had no effect on fetal blood pressure, heart rate, carotid and femoral blood flow, total EEG power, nuchal activity, temperature or intracerebral oxygenation on near-infrared spectroscopy during or after occlusion. JI-10 was associated with later onset of post-asphyxial seizures compared with saline (p<0.05), and attenuation of the subsequent progressive loss of cytochrome oxidase (p<0.05). After 7 days recovery, JI-10 was associated with improved neuronal survival in the caudate nucleus (p<0.05), but not the putamen or hippocampus, and more CNPase positive oligodendrocytes in the periventricular white matter (p<0.05). In conclusion, prophylactic nNOS inhibition before profound asphyxia was associated with delayed onset of seizures, slower decline of cytochrome oxidase and partial white and grey matter protection, consistent with protection of mitochondrial function.
PMCID: PMC3867605  PMID: 24120436
Asphyxia; brain; nNOS; neuroprotection; preterm fetus
19.  Deletion in the N-terminal Half of Olfactomedin 1 Modifies Its Interaction with Synaptic Proteins and Causes Brain Dystrophy and Abnormal Behavior in Mice 
Experimental neurology  2013;250:10.1016/j.expneurol.2013.09.019.
Olfactomedin 1 (Olfm1) is a secreted glycoprotein that is preferentially expressed in neuronal tissues. Here we show that deletion of exons 4 and 5 from the Olfm1 gene, which encodes a 52 amino acid long region in the N-terminal part of the protein, increased neonatal death and reduced body weight of surviving homozygous mice. Magnetic resonance imaging analyses revealed reduced brain volume and attenuated size of white matter tracts such as the anterior commissure, corpus callosum, and optic nerve. Adult Olfm1 mutant mice demonstrated abnormal behavior in several tests including reduced marble digging, elevated plus maze test, nesting activity and latency on balance beam tests as compared with their wild-type littermates. The olfactory system was both structurally and functionally disturbed by the mutation in the Olfm1 gene as shown by functional magnetic resonance imaging analysis and a smell test. Deficiencies of the olfactory system may contribute to the neonatal death and loss of body weight of Olfm1 mutant. Shotgun proteomics revealed 59 candidate proteins that co-precipitated with wild-type or mutant Olfm1 proteins in postnatal day 1 brain. Olfm1-binding targets included GluR2, Cav2.1, Teneurin-4 and Kidins220. Modified interaction of Olfm1 with binding targets led to an increase in intracellular Ca2+ concentration and activation of ERK1/2, MEK1 and CaMKII in the hippocampus and olfactory bulb of Olfm1 mutant mice compared with their wild-type littermates. Excessive activation of the CaMKII and Ras-ERK pathways in the Olfm1 mutant olfactory bulb and hippocampus by elevated intracellular calcium may contribute to the abnormal behavior and olfactory activity of Olfm1 mutant mice.
PMCID: PMC3875227  PMID: 24095980
olfactomedin 1; AMPA receptor; neurobiology; proteomics; cell signaling; mouse; anxiety behavior; olfactory defects
20.  Endogenous PI3K/Akt and NMDAR act independently in the regulation of CREB activity in lumbosacral spinal cord in cystitis 
Experimental neurology  2013;250:10.1016/j.expneurol.2013.10.015.
The integral interaction of signaling components in the regulation of visceral inflammation-induced central sensitization in the spinal cord has not been well studied. Here we report that phosphoinositide 3-kinase (PI3K)-dependent Akt activation and N-Methyl-D-aspartic acid receptor (NMDAR) in lumbosacral spinal cord independently regulates the activation of cAMP response element-binding protein (CREB) in vivo in a rat visceral pain model of cystitis induced by intraperitoneal injection of cyclophosphamide (CYP). We demonstrate that suppression of endogenous PI3K/Akt activity with a potent PI3K inhibitor LY294002 reverses CYP-induced phosphorylation of CREB, however, it has no effect on CYP-induced phosphorylation of NR1 at Ser897 and Ser896; conversely, inhibition of NMDAR in vivo with MK801 fails to block CYP-induced Akt activation but significantly attenuates CYP-induced CREB phosphorylation in lumbosacral spinal cord. This novel interrelationship of PI3K/Akt, NMDAR, and CREB activation in lumbosacral spinal cord is further confirmed in an ex vivo spinal slice culture system exposed to an excitatory neurotransmitter calcitonin gene-related peptide (CGRP). Consistently we found that CGRP-triggered CREB activation can be blocked by both PI3K inhibitor LY294002 and NMDAR antagonists MK801 and D-AP5. However, CGRP-triggered Akt activation cannot be blocked by MK801 or D-AP5; vice versa, LY294002 pretreatment that suppresses the Akt activity fails to reverse CGRP-elicited NR1 phosphorylation. These results suggest that PI3K/Akt and NMDAR independently regulates spinal plasticity in visceral pain model, and target of a single pathway is necessary but not sufficient in treatment of visceral hypersensitivity.
PMCID: PMC3878196  PMID: 24184018
Akt; NMDAR; CREB; spinal cord; central sensitization
21.  The angiotensin converting enzyme inhibitor captopril protects nigrostriatal dopamine neurons in animal models of parkinsonism 
Experimental neurology  2013;250:376-383.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by a prominent loss of nigrostriatal dopamine (DA) neurons with an accompanying neuroinflammation. The peptide angiotensin II (AngII) plays a role in oxidative-stress induced disorders and is thought to mediate its detrimental actions via activation of AngII AT1 receptors. The brain renin-angiotensin system is implicated in neurodegenerative disorders including PD. Blockade of the angiotensin converting enzyme or AT1 receptors provides protection in acute animal models of parkinsonism. We demonstrate here that treatment of mice with the angiotensin converting enzyme inhibitor captopril protects the striatum from acutely administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrine (MPTP), and that chronic captopril protects the nigral DA cell bodies from degeneration in a progressive rat model of parkinsonism created by the chronic intracerebral infusion of 1-methyl-4-phenylpyridinium (MPP+). The accompanying activation of microglia in the substantia nigra of MPP+-treated rats was reduced by the chronic captopril treatment. These findings indicate that captopril is neuroprotective for nigrostriatal DA neurons in both acute and chronic rodent PD models. Targeting the brain AngII pathway may be a feasible approach to slowing neurodegeneration in PD.
PMCID: PMC3889207  PMID: 24184050
Parkinson’s disease; captopril; angiotensin converting enzyme; dopamine neurodegeneration; mice; rats; MPTP; MPP+; microglia; osmotic minipump
22.  Juvenile traumatic brain injury evolves into a chronic brain disorder: behavioral and histological changes over 6 Months 
Experimental neurology  2013;250:8-19.
Traumatic brain injury (TBI) refers to physical trauma to the brain that can lead to motor and cognitive dysfunctions. TBI is particularly serious in infants and young children, often leading to long-term functional impairments. Although clinical research is useful for quantifying and observing the effects of these injuries, few studies have empirically assessed the long-term effects of juvenile TBI (jTBI) on behavior and histology.
After a controlled cortical impact delivered to postnatal 17d rats, functional abilities were measured after 3, 5, and 6 months using open field (activity levels), zero maze (anxiety-like behaviors), rotarod (sensorimotor abilities, coordination, and balance), and water maze (spatial learning and memory, swim speed, turn bias). Sensorimotor function was impaired for up to 6 months in jTBI animals, which showed no improvement from repeated test exposure. Although spatial learning was not impaired, spatial memory deficits were observed in jTBI animals starting at 3 months after injury. Magnetic resonance imaging and histological data revealed that the effects of jTBI were evolving for up to 6 months post-injury, with reduced cortical thickness, decreased corpus callosum area and CA1 neuronal cell death in jTBI animals distant of the impact site.
These findings suggest that this model of jTBI produces long-term impairments comparable to those reported clinically. Although some deficits were stable over time, the variable nature of other deficits (e.g., memory) as well as changing properties of the lesion itself, suggest that the effects of a single jTBI produce a chronic brain disorder with long-term complications.
PMCID: PMC3895624  PMID: 24076005
traumatic brain injury; pediatric; behavior; neurodegeneration; MRI
23.  Combination therapy in a transgenic model of Alzheimer’s disease 
Experimental neurology  2013;250:228-238.
The pathological accumulation of the β-amyloid protein (Aβ) has been closely associated with synaptic loss and neurotoxicity contributing to cognitive dysfunction in Alzheimer’s disease (AD). Oligomers of Aβ42 appear to be the most neurotoxic form. Two of the most promising attempts to reduce Aβ accumulation have been with scyllo-inositol, an inositol steroisomer, that stabilizes Aβ42 peptide and prevents it from progressing to oligomers and fibrils and R-flurbiprofen, a purified enantiomer of the classical racemic non-steroidal anti-inflammatory drugs (NSAID), flurbiprofen, that retains the ability to specifically lower Aβ42. In the present study we evaluated the effects of scyllo-inositol and the combination treatment of scyllo-inositol + R-flurbiprofen on amyloid pathology and hippocampal-dependent memory function in 5XFAD mice, a model of Aβ pathology characterized by an enormous production of Aβ42. Our expectations were that the combination treatment of scylloinositol + R-flurbiprofen would have an additive effect in preventing Aβ accumulation and that cognition would be improved. Mice treated with scyllo-inositol exhibit 41 and 35% reduction in the deposition of the amyloid plaques stained by antibody against Aβ42 and Aβ40 respectively. Scyllo-inositol was not more effective when combined with R-flurbiprofen for the measures tested. Scyllo-inositol treated mice performed significantly better at the radial arm water maze (RAWM) task than untreated and scyllo-inositol + R-flurbiprofen treated mice.
PMCID: PMC3926203  PMID: 24120437
Alzheimer’s disease; Scyllo-inositol; R-flurbiprofen; Magnetic resonance spectroscopy
24.  Convergent effects of mouse Pet-1 deletion and human PET-1 variation on amygdala fear and threat processing 
Experimental neurology  2013;250:260-269.
Serotonin is critical for shaping the development of neural circuits regulating emotion. Pet-1 (FEV-1) is an ETS-domain transcription factor essential for differentiation and forebrain targeting of serotonin neurons. Constitutive Pet-1 knockout (KO) causes major loss of serotonin neurons and forebrain serotonin availability, and behavioral abnormalities. We phenotyped Pet-1 KO mice for fear conditioning and extinction, and on a battery of assays for anxiety- and depression-related behaviors. Morphology of Golgi-stained neurons in basolateral amygdala (BLA) and prelimbic cortex was examined. Using human imaging genetics, a common variant (rs860573) in the PET-1 (FEV) gene was tested for effects on threat-related amygdala reactivity and psychopathology in 88 Asian-ancestry subjects. Pet-1 KO mice exhibited increased acquisition and expression of fear, and elevated fear recovery following extinction, relative to wild-type (WT). BLA dendrites of Pet-1 KO mice were significantly longer than in WT. Human PET-1 variation associated with differences in amygdala threat processing and psychopathology. This novel evidence for the role of Pet-1 on fear processing and dendritic organization of amygdala neurons and on human amygdala threat processing extends a growing literature demonstrating the influence of genetic variation in the serotonin system on emotional regulation via effects on structure and function of underlying corticolimbic circuitry.
PMCID: PMC3932627  PMID: 24100022
asolateral amygdala; medial prefrontal cortex; fear conditioning; serotonin; FEV
Experimental neurology  2013;250:156-164.
Different experimental and clinical strategies have been used to promote survival of transplanted embryonic ventral mesencephalic (VM) neurons. However, few studies have focused on the long-distance growth of dopaminergic axons from VM transplants. The aim of this study is to identify some of the growth and guidance factors that support directed long-distance growth of dopaminergic axons from VM transplants. Lentivirus encoding either glial cell line-derived neurotrophic factor (GDNF) or netrin-1, or a combination of lenti-GDNF with either lenti-GDNF family receptor α1 (GFRα-1) or lenti-netrin-1 was injected to form a gradient along the corpus callosum. Two weeks later, a piece of embryonic day 14 VM tissue was transplanted into the corpus callosum adjacent to the low end of the gradient. Results showed that tyrosine hydroxylase (TH+) axons grew a very short distance from the VM transplants in control groups, with few axons reaching the midline. In GDNF or Netrin-1 expressing groups, more TH+ axons grew out of transplants and reached the midline. Pathways co-expressing GDNF with either GFRα-1 or netrin-1 showed significantly increased axonal outgrowth. Interestingly, only the GDNF/netrin-1 combination resulted in the majority of axons reaching the distal target (80%), whereas along the GDNF/GFRα-1 pathway only 20% of the axons leaving the transplant reached the distal target. This technique of long-distance axon guidance may prove to be a useful strategy in reconstructing damaged neuronal circuits, such as the nigrostriatal pathway in Parkinson’s disease.
PMCID: PMC4038353  PMID: 24099728
Axonal guidance; ventral mesencephalon (VM) transplantation; GDNF; netrin-1; lentivirus; tyrosine hydroxylase; Parkinson’s disease

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