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1.  Orexin-1 receptor mediates the increased food and water intake induced by intracerebroventricular injection of stable somatostatin pan-agonist, ODT8-SST in rats 
Neuroscience letters  2014;576:88-92.
Intracerebroventricular (icv) injection of the stable somatostatin pan-agonist, ODT8-SST induces a somatostatin 2 receptor (sst2) mediated robust feeding response that involves neuropeptide Y and opioid systems in rats. We investigated whether the orexigenic system driven by orexin also plays a role. Food and water intake after icv injection was measured concomitantly in non-fasted and non-water deprived rats during the light phase. In vehicle treated rats (100% DMSO, icv), ODT8-SST (1 μg/rat, icv) significantly increased the 2-h food and water intake compared to icv vehicle plus saline (5.1 ± 1.0 g vs. 1.2 ± 0.4 g and 11.3 ± 1.9 mL vs. 2.5 ± 1.2 mL, respectively). The orexin-1 receptor antagonist, SB-334867 (16 μg/rat, icv) completely inhibited the 2-h food and water intake induced by icv ODT8-SST. In contrast, the icv pretreatment with the selective somatostatin sst2 antagonist, S-406-028, established to block the orexigenic effect of icv ODT8-SST, did not modify the increased food and water intake induced by icv orexin-A (10.7 μg/rat). These data indicate that orexin-1 receptor signaling system is part of the brain neurocircuitry contributing to the orexigenic and dipsogenic responses induced by icv ODT8-SST and that orexin-A stimulates food intake independently from brain sst2 activation.
PMCID: PMC4096604  PMID: 24915296
food intake; orexin-A; ODT8-SST; SB-334867; somatostatin 2 receptor; water intake
2.  Sex Differences in Δ9-Tetrahydrocannabinol Metabolism and In Vivo Pharmacology Following Acute and Repeated Dosing in Adolescent Rats 
Neuroscience letters  2014;576:51-55.
Mechanisms that may underlie age and sex differences in the pharmacological effects of cannabinoids are relatively unexplored. The purpose of the present study was to determine whether sex differences in metabolism of Δ9-tetrahydrocannabinol (THC), similar to those observed previously in adult rats, also occurred in adolescent rats and might contribute to age and sex differences in its in vivo pharmacology. Male and female adolescent rats were exposed to THC acutely or repeatedly for 10 days. Subsequently, some of the rats were sacrificed and blood and brain levels of THC and one of its metabolites, 11-hydrox-Δ9-THC (11-OH-THC), were measured. Other rats were evaluated in a battery of in vivo tests that are sensitive to cannabinoids. Concentrations of 11-OH-THC in the brains of female adult and adolescent rats exceeded those observed in male conspecifics, particularly after repeated THC administration. In contrast, brain levels of THC did not differ between the sexes. In vivo, acute THC produced dose-related hypothermia, catalepsy and suppression of locomotion in adolescent rats of both sexes, with tolerance developing after repeated administration. With a minor exception, sex differences in THC’s effects in the in vivo assays were not apparent. Together with previous findings, the present results suggest that sex differences in pharmacokinetics cannot fully explain the patterns of sex differences (and lack of sex differences) in cannabinoid effects across behaviors. Hormonal and/or pharmacodynamic factors are also likely to play a role.
PMCID: PMC4106361  PMID: 24909619
adolescence; cannabinoids; in vivo pharmacology; metabolism; pharmacokinetics; rats; sex differences; delta-9-tetrahydrocannabinol; tolerance
3.  Acute Estrogen Surge Enhances Inflammatory Nociception Without Altering Spinal Fos Expression 
Neuroscience letters  2014;575:91-95.
Chronic pain is a major neurological disorder that can manifest differently between genders or sexes. The complex actions of sex hormones may underlie these differences; previous studies have suggested that elevated estrogen levels can enhance pain perception. The purpose of this study was to investigate the hypothesis that acute, activational effects of estradiol (E2) increase persistent inflammatory nociception, and anatomically where this modulation occurs. Spinal expression of Fos is widely used as a marker of nociceptive activation. This study used formalin-evoked nociception in ovariectomized (OVX) adult female rats and measured late-phase hindlimb flinching and Fos expression in the spinal cord, and their modification by acute estrogen supplementation similar to a proestrus surge. Six days after ovariectomy, female rats were injected subcutaneously (s.c.) with 10μg/kg E2 or vehicle. Twenty-four hours later, 50 μL of 1.25% or 100 μL of 5% formalin was injected into the right hindpaw; hindlimb flinches were counted, and spinal cords removed two hours after formalin injection. The numbers of Fos-expressing neurons in sections of the lumbar spinal cord were analyzed using immunohistochemistry. Formalin-induced inflammation produced a dose-dependent increase in late-phase hindlimb flinching, and E2 pretreatment increased flinching following 5%, but not 1.25% formalin injection. Despite the modification of behavior by E2, the number of spinal Fos-positive neurons was not altered by E2 pretreatment. These findings demonstrate that an acute proestrus-like surge in serum estrogen can produce a stimulus-intensity-dependent increase in inflammation-evoked nociceptive behavior. However, the lack of effect on spinal Fos expression suggests that this enhancement of nociceptive signaling by estrogen is independent of changes in peripheral activation of, expression of the immediate early gene Fos by, or signal throughput of spinal nociceptive neurons.
PMCID: PMC4104118  PMID: 24861514
Pain; Rat; Formalin Test; Spinal cord; Behavior; Estrogen
4.  Molecular and functional identification of a mitochondrial ryanodine receptor in neurons 
Neuroscience letters  2014;575:7-12.
Mitochondrial Ca2+ controls numerous cell functions, such as energy metabolism, reactive oxygen species generation, spatiotemporal dynamics of Ca2+ signaling, cell growth and death in various cell types including neurons. Mitochondrial Ca2+ accumulation is mainly mediated by the mitochondrial Ca2+ uniporter (MCU), but recent reports also indicate that mitochondrial Ca2+-influx mechanisms are regulated not only by MCU, but also by multiple channels/transporters. We previously reported that ryanodine receptor (RyR), which is a one of the main Ca2+-release channels at endoplasmic/sarcoplasmic reticulum (SR/ER) in excitable cells, is expressed at the mitochondrial inner membrane (IMM) and serves as a part of the Ca2+ uptake mechanism in cardiomyocytes. Although RyR is also expressed in neuronal cells and works as a Ca2+-release channel at ER, it has not been well investigated whether neuronal mitochondria possess RyR and, if so, whether this mitochondrial RyR has physiological functions in neuronal cells. Here we show that neuronal mitochondria express RyR at IMM and accumulate Ca2+ through this channel in response to cytosolic Ca2+ elevation, which is similar to what we observed in another excitable cell-type, cardiomyocytes. In addition, the RyR blockers dantrolene or ryanodine significantly inhibits mitochondrial Ca2+ uptake in permeabilized striatal neurons. Taken together, we identify RyR as an additional mitochondrial Ca2+ uptake mechanism in response to the elevation of [Ca2+]c in neurons, suggesting that this channel may play a critical role in mitochondrial Ca2+-mediated functions such as energy metabolism.
PMCID: PMC4122666  PMID: 24861510
Striatal neurons; calcium; ryanodine receptor; [3H]ryanodine binding; mitochondria; dantrolene
5.  Neuroprotective effect of aquaporin-4 deficiency in a mouse model of severe global cerebral ischemia produced by transient 4-vessel occlusion 
Neuroscience letters  2014;574:70-75.
Astrocyte water channel aquaporin-4 (AQP4) facilitates water movement across the blood–brain barrier and into injured astrocytes. We previously showed reduced cytotoxic brain edema with improved neurological outcome in AQP4 knockout mice in water intoxication, infection and cerebral ischemia. Here, we established a 4-vessel transient occlusion model to test the hypothesis that AQP4 deficiency in mice could improve neurological outcome following severe global cerebral ischemia as occurs in cardiac arrest/resuscitation. Mice were subjected to 10-min transient bilateral carotid artery occlusion at 24 h after bilateral vertebral artery cauterization. Cerebral blood flow was reduced during occlusion by >94% in both AQP4+/+ and AQP4−/− mice. The primary outcome, neurological score, was remarkably better at 3 and 5 days after occlusion in AQP4−/− than in AQP4+/+ mice, and survival was significantly improved as well. Brain water content was increased by 2.8 ± 0.4% in occluded AQP4+/+ mice, significantly greater than that of 0.3 ± 0.6% in AQP4−/− mice. Histological examination and immunofluorescence of hippocampal sections at 5 days showed significantly greater neuronal loss in the CA1 region of hippocampus in AQP4+/+ than AQP4−/− mice. The neuroprotection in mice conferred by AQP4 deletion following severe global cerebral ischemia provides proof-of-concept for therapeutic AQP4 inhibition to improve neurological outcome in cardiac arrest.
PMCID: PMC4306422  PMID: 24717641
AQP4; Neuroprotection; Water transport; Astrocyte; Brain edema; Cerebral ischemia
6.  Platelet-derived nerve growth factor supports the survival of cholinergic neurons in organotypic rat brain slices 
Neuroscience letters  2014;574:64-69.
Platelets play a role in repair of vessels and contain different growth factors, including nerve growth factor (NGF). Since NGF is the most potent growth factor to support survival of cholinergic neurons, we aimed to study the effects of platelet-derived NGF on cholinergic neurons in organotypic brain slices. Brain slices of the nucleus basalis of Meynert (nBM) were cultured with or without NGF (10 ng/ml) or platelet extracts (100 μg/ml) or fresh platelets (108 platelets/ml). In order to enhance NGF in platelets recombinant NGF (100 ng) was loaded into platelets using ultrasound (3 h). Our data show that recombinant NGF markedly supports survival of cholinergic neurons. The addition of fresh platelets showed a tendency for enhancing cholinergic neuron numbers, while platelet extracts had no effects. Ultrasound was highly effective to load recombinant NGF into platelets. The addition of NGF-loaded platelets markedly enhanced cholinergic neuron numbers. In conclusion, our data provide evidence that NGF-derived platelets may counteract cell death of cholinergic neurons.
PMCID: PMC4311057  PMID: 24861506
Platelets; Nerve growth factor; Neuroprotection; Cholinergic neurons
7.  A radical scavenger edaravone inhibits matrix metalloproteinase-9 upregulation and blood-brain barrier breakdown in a mouse model of prolonged cerebral hypoperfusion 
Neuroscience letters  2014;573:40-45.
Matrix metalloproteinase-9 (MMP-9) plays key roles in the brain pathophysiology, especially in blood-brain barrier (BBB) breakdown. Therefore, inhibiting MMP-9 activity may be a promising therapy for protecting brains in cerebrovascular diseases. Here we show that in a mouse prolonged cerebral hypoperfusion model, a clinically proven radical scavenger edaravone suppressed MMP-9 and reduced BBB damage in cerebral white matter. Prolonged cerebral hypoperfusion was induced by bilateral common carotid artery stenosis in male adult C57BL/6J mice (10 weeks old). After 7 days of cerebral hypoperfusion, white matter region (e.g. corpus callosum) exhibited significant BBB leakage, assessed by IgG staining. Correspondingly, immunostaining and western blotting showed that MMP-9 was upregulated in the white matter. Edaravone treatment (3 mg/kg, i.p. at day 0 and 3) inhibited both BBB leakage and MMP-9 increase. Under the early phase of cerebral hypoperfusion conditions, oligodendrocyte precursor cells (OPCs) mainly contribute to the MMP-9 increase, but our immunostaining data showed that very little OPCs expressed MMP-9 in the edaravone-treated animals at day 7. Therefore, in vitro studies with primary rat OPCs were conducted to examine whether edaravone would directly suppressed MMP-9 expressions in OPCs. OPC cultures were exposed to sub-lethal CoCl2 for 7 days to induce prolonged chemical hypoxic stress. Prolonged chemical hypoxic stress increased MMP-9 expression in OPCs, and radical scavenging with edaravone (10 μM for 7 days) ameliorated the increase. Taken together, our proof-of-concept study demonstrates that radical scavengers may provide a potential therapeutic approach for white matter injury by suppressing BBB damage.
PMCID: PMC4055517  PMID: 24820542
white matter injury; prolonged cerebral hypoperfusion; matrix metalloproteinase-9; blood-brain barrier; edaravone
8.  PTEN inhibitor bisperoxovanadium protects oligodendrocytes and myelin and prevents neuronal atrophy in adult rats following cervical hemicontusive spinal cord injury 
Neuroscience letters  2014;573:64-68.
Cervical spinal cord injury (SCI) damages axons and motor neurons responsible for ipsilateral forelimb function and causes demyelination and oligodendrocyte death. Inhibition of the phosphatase and tensin homologue, PTEN, promotes neural cell survival, neuroprotection and regeneration in vivo and in vitro. PTEN inhibition can also promote oligodendrocyte-mediated myelination of axons in vitro likely through Akt activation. We recently demonstrated that acute treatment with phosphatase PTEN inhibitor, bisperoxovanadium (bpV)-pic reduced tissue damage, neuron death, and promoted functional recovery after cervical hemi-contusion SCI. Evidence suggests bpV can promote myelin stability; however, bpV effects on myelination and oligodendrocytes in contusive SCI models are unclear. We hypothesized that bpV could increase myelin around the injury site through sparing or remyelination, and that bpV treatment may promote increased numbers of oligodendrocytes. Using histological and immunofluorescence labeling, we found that bpV treatment promoted significant spared white matter (30%; p < 0.01) and Luxol Fast Blue (LFB)+ myelin area rostral (Veh: 0.56 ± 0.01 vs. bpV: 0.64 ± 0.02; p < 0.05) and at the epicenter (Veh: 0.4175 ± 0.03 vs. bpV: 0.5400 ± 0.03; p < 0.05). VLF oligodendrocytes were also significantly greater with bpV therapy (109 ± 5.3 vs. Veh: 77 ± 2.7/mm2; p < 0.01). In addition, bpV increased mean motor neuron soma area versus vehicle-treatment (1.0 ± 0.02 vs. Veh: 0.77 ± 0.02) relative to Sham neuron size. This study provides key insight into additional cell and tissue effects that could contribute to bpV-mediated functional recovery observed after contusive cervical SCI.
PMCID: PMC4055541  PMID: 24582904
bpV; PTEN; spinal cord injury; oligodendrocyte survival; neuron atrophy
9.  Early life stress disrupts social behavior and prefrontal cortex parvalbumin interneurons at an earlier time-point in females than in males 
Neuroscience letters  2014;566:131-136.
Early life stress exposure (ELS) yields risk for psychiatric disorders that might occur though a population-specific mechanism that impacts prefrontal cortical development. Sex differences in ELS effects are largely unknown and are also essential to understand social and cognitive development. ELS can cause dysfunction within parvalbumin (PVB)-containing inhibitory interneurons in the prefrontal cortex and in several prefrontal cortex-mediated behaviors including social interaction. Social behavior deficits are often the earliest observed changes in psychiatric disorders, therefore the time-course and causation of social interaction deficits after ELS are important to determine. PVB interneuron dysfunction can disrupt social behavior, and has been correlated in males with elevated markers of oxidative stress and inflammation, such as cyclooxygenase-2 after ELS. Here, we measured the effects of maternal separation ELS on social interaction behaviors in males and females. Prefrontal cortex PVB and cyclooxygenase-2 were also measured in juveniles and adolescents using Western blots. ELS led to social interaction alterations earlier in females than males. Sexually dimorphic behavioral changes were consistent with prefrontal cortex PVB loss after ELS. PVB levels were decreased in ELS-exposed juvenile females, while males exposed to ELS do not display parvalbumin decreases until adolescence. Early behavioral and PVB changes in females did not appear to be mediated through cyclooxygenase-2, since levels were not affected in ELS females. Therefore, these data suggest that ELS affects males and females differently and with distinct developmental profiles.
PMCID: PMC4476267  PMID: 24565933
10.  Disruption of Lateral Olivocochlear Neurons With a Dopaminergic Neurotoxin Depresses Spontaneous Auditory Nerve Activity 
Neuroscience letters  2014;582:54-58.
Neurons of the lateral olivocochlear (LOC) system project from the auditory brainstem to the cochlea, where they synapse on radial dendrites of auditory nerve fibers. Selective LOC disruption depresses sound-evoked auditory nerve activity in the guinea pig, but enhances it in the mouse. Here, LOC disruption depressed spontaneous auditory nerve activity in the guinea pig. Recordings from single auditory nerve fibers revealed a significantly reduced proportion of fibers with the highest spontaneous firing rates (SRs) and an increased proportion of neurons with lower SRs. Ensemble activity, estimated using round window noise, also decreased after LOC disruption. Decreased spontaneous activity after LOC disruption may be a consequence of reduced tonic release of excitatory transmitters from the LOC terminals in guinea pigs.
PMCID: PMC4469127  PMID: 25175420
olivocochlear efferents; auditory nerve; spontaneous activity; MPTP; guinea pig
11.  Orexin A decreases lipid peroxidation and apoptosis in a novel hypothalamic cell model 
Neuroscience letters  2012;524(1):30-34.
Current data support the idea that hypothalamic neuropeptide orexin A (OxA; hypocretin 1) mediates resistance to high fat diet-induced obesity. We previously demonstrated that OxA elevates spontaneous physical activity (SPA), that rodents with high SPA have higher endogenous orexin sensitivity, and that OxA-induced SPA contributes to obesity resistance in rodents. Recent reports show that OxA can confer neuroprotection against ischemic damage, and may decrease lipid peroxidation. This is noteworthy as independent lines of evidence indicate that diets high in saturated fats can decrease SPA, increase hypothalamic apoptosis, and lead to obesity. Together data suggest OxA may protect against obesity both by inducing SPA and by modulation of anti-apoptotic mechanisms. While OxA effects on SPA are well characterized, little is known about the short- and long-term effects of hypothalamic OxA signaling on intracellular neuronal metabolic status, or the physiological relevance of such signaling to SPA. To address this issue, we evaluated the neuroprotective effects of OxA in a novel immortalized primary embryonic rat hypothalamic cell line. We demonstrate for the first time that OxA increases cell viability during hydrogen peroxide challenge, decreases hydrogen peroxide-induced lipid peroxidative stress, and decreases caspase 3/7 induced apoptosis in an in vitro hypothalamic model. Our data support the hypothesis that OxA may promote obesity resistance both by increasing SPA, and by influencing survival of OxA-responsive hypothalamic neurons. Further identification of the individual mediators of the anti-apoptotic and peroxidative effects of OxA on target neurons could lead to therapies designed to maintain elevated SPA and increase obesity resistance.
PMCID: PMC4467811  PMID: 22796468
Orexin; Hypothalamus; Lipid peroxidation; Apoptosis; Caspase-3; Neuroprotection
12.  Dynorphin release by the lateral olivocochlear efferents may inhibit auditory nerve activity: a cochlear drug delivery study 
Neuroscience letters  2014;571:17-22.
Dynorphin (dyn) is suggested to excite the auditory nerve (AN) when released by the lateral olivocochlear (LOC) efferents. However, previous studies evaluated either intravenously delivered dyn-like agents, raising the potential for systemic (central) effects, or agent concentrations unlikely to be achieved via endogenous cochlear release. This study tested the hypothesis that biologically relevant increases in dyn levels in the cochlea achieved via diffusion of the drug of (−)pentazocine across the round window membrane enhances AN firing. In general, amplitude of the cochlear whole-nerve action potential (CAP) was depressed following drug application. These results suggest that dyn released by the LOC neurons would likely act as an inhibitory transmitter substance in the LOC system; neurotransmission is one of the LOC system's vast unknowns.
PMCID: PMC4083833  PMID: 24780562
lateral olivocochlear efferent; auditory nerve; cochlear whole nerve action potential; dynorphin; kappa opioid receptor
13.  Expression and nuclear translocation of glucocorticoid receptors in type 2 taste receptor cells 
Neuroscience letters  2014;571:72-77.
Stress increases the secretion of glucocorticoids (GCs), potent steroid hormones that exert their effects on numerous target tissues by acting through glucocorticoid receptors (GRs). GC signaling significantly affects ingestive behavior and taste preferences in humans and rodent models, but far less is known about the hormonal modulation of the peripheral sensory system that detects and assesses nutrient content of foods. A previous study linked restraint stress in rats to diminished expression of mRNA for one subunit of the sweet taste receptor (Tas1r3) in taste tissue and reduced gustatory nerve excitation by sweet compounds. Using RT-PCR, we detected mRNAs for GRα in circumvallate taste papillae and in oral epithelium devoid of taste buds (“non-taste” tissue). Further, circumvallate tissue was significantly enriched in GR mRNA compared to non-taste tissue based on quantitative PCR. Histologically, GR protein was expressed in all taste bud populations examined (circumvallate, foliate and fungiform papillae). Using transgenic mice expressing green fluorescent protein, almost all (97%) Tas1r3-positive taste cells (sweet-/umami-sensitive) expressed GR compared to a significantly smaller percentage (89%) of TrpM5-positive taste cells (sweet-, umami- and bitter-sensitive). When mice (n = 4) were restrain stressed, GR protein mobilized to the nucleus in Tas1r3-GFP taste cells (1.7-fold over controls). Our results suggest that GR can be activated in taste receptor cells and may play a role in specific taste qualities (e.g., sweet, umami, and bitter) to shape how the taste system responds to stress.
PMCID: PMC4126247  PMID: 24814581
Glucocorticoid receptor; Stress; Taste; Steroid hormone receptor; Taste receptor cell; Tas1r3
14.  Association of APOE Polymorphisms and Stressful Life Events with Dementia in a Pakistani Population 
Neuroscience letters  2014;570:42-46.
Dementia is a major public health problem worldwide. Alzheimer’s disease (AD) is a major form of dementia and the APOE*4 allele is an established genetic risk factor for AD. Similarly, stressful life events are also associated with dementia. The objective of this study was to examine the association of APOE*4 and stressful life events with dementia in a Pakistani sample, which to our knowledge has not been reported previously. We also tested for an interaction between stressful life events and APOE*4 on dementia risk. A total of 176 subjects (61 cases and 115 controls) were recruited. All cases and healthy controls were interviewed to assess cognition, co-morbidities, history of stressful life events and demographics. Blood genotyping for the APOE polymorphism (E2/E3/E4) was performed. APOE*4 and stressful life events were each independently and significantly associated with the risk of dementia (APOE*4: P=0.00697; stressful life events: P=5.29E-09). However, we did not find a significant interaction between APOE*4 carrier status and stressful life events on risk of dementia (P=0.677). Although the sample size of this study was small, the established association of APOE*4 with dementia was confirmed the first time in a Pakistani sample. Furthermore, stressful life events were also found to be significantly associated with dementia in this population.
PMCID: PMC4059994  PMID: 24746929
dementia; Pakistan; stressful life events; APOE
15.  Altered object exploration but not temporal order memory retrieval in an object recognition test following treatment of rats with the group II metabotropic glutamate receptor agonist LY379268 
Neuroscience letters  2013;560:41-45.
Temporal order memory refers to the ability to distinguish past experiences in the order that they occurred. Temporal order memory for objects is often tested in rodents using spontaneous object recognition paradigms. The circuitry mediating memory in these tests is distributed and involves ionotropic glutamate receptors in the perirhinal cortex and medial prefrontal cortex. It is unknown what role, if any, metabotropic glutamate receptors have in temporal order memory for objects. The present experiment examined the role of metabotropic glutamate receptors in temporal memory retrieval using the group II metabotropic glutamate receptor selective agonist LY379268. Rats were trained on a temporal memory test with three phases: two sample phases (60 min between them) in which rats explored two novel objects and a test phase (60 min after the second sample phase) which included a copy of each object previously encountered. Under these conditions, we confirmed that rats showed a significant exploratory preference for the object presented during the first sample phase. In a second experiment, we found that LY379268 (0.3, 1.0, or 3.0 mg/kg; i.p.; 30 min before the test phase) had no effect on temporal memory retrieval but dose-dependently reduced time spent exploring the objects. Our results show that enhancing mGluR2 activity under conditions when TM is intact does not influence memory retrieval.
PMCID: PMC4457522  PMID: 24361135 CAMSID: cams4647
Medial prefrontal cortex; Metabotropic glutamate receptor; Spontaneous object recognition; Cognition; Delayed recency discrimination
16.  Extinction of conditioned opiate withdrawal in rats is blocked by intracerebroventricular infusion of an NMDA receptor antagonist 
Neuroscience letters  2013;541:39-42.
Maladaptive conditioned responses (CRs) contribute to psychiatric disorders including anxiety disorders and addiction. Methods of reducing these CRs have been considered as possible therapeutic approaches. One such method is extinction, which involves exposure to CR-eliciting cues in the absence of the event they once predicted. In animal models, extinction reduces both fear and addiction-related CRs, and in humans, extinction-based cue exposure therapy (CET) reduces fear CRs. However, CET is less effective in drug addicts, for reasons that are not clear. Increased understanding of the neurobiology of extinction of drug-related CRs as compared to fear CRs may help illuminate this issue. Here, we examine the N-methyl-D-aspartate (NMDA) receptor-dependence of extinction of conditioned opiate withdrawal in rats. Using a place conditioning paradigm, we trained morphine-dependent rats to associate an environment with naloxone-precipitated withdrawal. We then extinguished that association by returning the rats repeatedly to the environment in the absence of acute withdrawal. In some rats we administered the NMDA receptor antagonist D,L-2-amino-5-phosphovaleric acid (AP5) intracerebroventricularly immediately prior to extinction training. In a subsequent test session, these rats avoided the formerly naloxone-paired environment, similar to rats that had not undergone extinction training. By contrast, rats that received vehicle prior to extinction training did not avoid the formerly naloxone-paired environment. This finding indicates that extinction of a drug-related CR (conditioned opiate withdrawal) is dependent on NMDA receptors, similar to extinction of conditioned fear. The locus of the critical NMDA receptors is unclear but may include basolateral amygdala and/or medial prefrontal cortex.
PMCID: PMC4451069  PMID: 23416323
addiction; extinction; glutamate; morphine; NMDA receptor; withdrawal
17.  Organization of a unique net-like meshwork of CGRP+ sensory fibers in the mouse periosteum: Implications for the generation and maintenance of bone fracture pain 
Neuroscience letters  2007;427(3):148-152.
Although bone fracture frequently results in significant pain and can lead to increased morbidity and mortality, it is still not clearly understood how sensory neurons are organized to detect fracture pain. In the present report we focused on the periosteum, as this thin tissue is highly innervated and tightly adherent to the outer surface of bone. To define the organization and distribution of the sensory and sympathetic fibers in the mouse femoral periosteum, we used whole mount preparations, transverse sections, immunofluoresence, and laser scanning confocal microscopy. While both the outer fibrous layer and the inner more cellular cambium layer of the periosteum receive an extensive innervation by calcitonin gene related peptide (CGRP) and 200-kDa neurofilament (NF200) positive sensory fibers as well as tyrosine hydroxylase (TH) positive sympathetic fibers, there is a differential organization of sensory vs. sympathetic fibers within the periosteum. In both layers, the great majority of TH+ fibers are closely associated with CD31+ blood vessels and wind around the larger vessels in a corkscrew pattern. In contrast, the majority of CGRP+ and NF200+ sensory fibers in both layers lack a clear association with CD31+ blood vessels and appear to be organized in a dense net-like meshwork to detect mechanical distortion of periosteum and bone. This organization would explain why stabilization/fixation causes a marked attenuation of movement-evoked fracture pain. Understanding the organization, plasticity and molecular characteristics of sensory and sympathetic nerve fibers innervating the skeleton may permit the development of novel mechanism-based therapies for treating non-malignant skeletal pain.
PMCID: PMC4444220  PMID: 17950532
non-malignant skeletal pain; blast injury; poly-trauma; mechanotransducers
18.  Divalent Metal Ions Enhance DOPAL-induced Oligomerization of Alpha-Synuclein 
Neuroscience letters  2014;569:27-32.
Parkinson disease (PD) features profound striatal dopamine depletion and Lewy bodies containing abundant precipitated alpha-synuclein. Mechanisms linking alpha-synucleinopathy with the death of dopamine neurons remain incompletely understood. One such link may be 3,4-dihydroxyphenylacetaldehyde (DOPAL). All of the intra-neuronal metabolism of dopamine passes through DOPAL, which is toxic. DOPAL also potently oligomerizes alpha-synuclein and alpha-synuclein oligomers are thought to be pathogenic in PD. Another implicated factor in PD pathogenesis is metal ions, and alpha-synuclein contains binding sites for these ions. In this study we tested whether divalent metal ions augment DOPAL-induced oligomerization of alpha-synuclein in cell-free system and in PC12 cells conditionally over-expressing alpha-synuclein. Incubation with divalent metal ions augmented DOPAL-induced oligomerization of alpha-synuclein (Cu2+>Fe2+>Mn2+), whereas monovalent Cu1+ and trivalent Fe3+ were without effect. Other dopamine metabolites, dopamine itself, and metal ions alone or in combination with dopamine, also had no effect. Antioxidant treatment with ascorbic acid and divalent cation chelation with EDTA attenuated the augmentation by Cu2+ of DOPAL-induced alpha-synuclein oligomerization. Incubation of PC12 cells with L-DOPA markedly increased intracellular DOPAL content and promoted alpha-synuclein dimerization. Co-incubation with Cu2+ amplified (p=0.01), while monoamine oxidase inhibition prevented, L-DOPA-related dimerization of alpha-synuclein (p=0.01). We conclude that divalent metal ions augment DOPAL-induced oligomerization of alpha-synuclein. Drugs that interfere with this interaction might constitute a novel approach for future treatment or prevention approaches.
PMCID: PMC4061610  PMID: 24670480
Alpha-synuclein; Oligomerization; Dopamine; Copper; DOPAL; Parkinson disease
19.  Effect of age and calorie restriction on corpus callosal integrity in rhesus macaques: a fiber tractography study 
Neuroscience letters  2014;569:38-42.
The rhesus macaque exhibits age-related brain changes similar to humans, making an excellent model of normal aging. Calorie restriction is a dietary intervention that reduces age-related comorbidities in short-lived animals, and its effects are still under study in rhesus macaques. Here, using deterministic fiber tracking method, we examined the effects of age and calorie restriction on a diffusion tensor imaging measure of white matter integrity, fractional anisotropy (FA), within white matter tracks traversing the anterior (genu) and posterior (splenium) corpus callosum in rhesus monkeys. Our results show: (1) a significant inverse relationship between age and mean FA of tracks traversing the genu and splenium; (2) higher mean FA of the splenium tracks as compared to that of genu tracks across groups; and (3) no significant diet effect on mean track FA through either location. These results are congruent with the age-related decline in white matter integrity reported in humans and monkeys, and the anterior-to-posterior gradient in white matter vulnerability to normal aging in humans. Further studies are warranted to critically evaluate the effect of calorie restriction on brain aging in this unique cohort of elderly primates.
PMCID: PMC4105191  PMID: 24686192
20.  Differential effects of dorsal hippocampal inactivation on expression of recent and remote drug and fear memory 
Neuroscience letters  2014;569:1-5.
Drugs of abuse generate strong drug-context associations, which can evoke powerful drug cravings that are linked to reinstatement in animal models and to relapse in humans. Work in learning and memory has demonstrated that contextual memories become more distributed over time, shifting from dependence on the hippocampus for retrieval to dependence on cortical structures. Implications for such changes in the structure of memory retrieval to addiction are unknown. Thus, to determine if the passage of time alters the substrates of conditioned place preference (CPP) memory retrieval, we investigated the effects of inactivation of the dorsal hippocampus (DH) with the GABA-A receptor agonist muscimol on expression of recent or remote CPP. We compared these effects with the same manipulation on expression of contextual fear conditioning. DH inactivation produced similar deficits in expression of both recent and remote CPP, but blocked expression of recent but not remote contextual fear memory. We describe the implications of these findings for mechanisms underlying long-term storage of contextual information.
PMCID: PMC4067241  PMID: 24686177
Cocaine; Conditioned Place Preference; Fear Conditioning, Systems Consolidation; Muscimol
21.  In vivo 1H MRS study of potential associations between glutathione, oxidative stress and anhedonia in major depressive disorder 
Neuroscience letters  2014;569:74-79.
Inflammation and oxidative stress are important mechanisms that have been implicated in the pathophysiology of major depressive disorder (MDD). Glutathione (GSH) is the most abundant antioxidant in human tissue, and a key index of antioxidant capacity and, hence, of oxidative stress. The aims of this investigation were to examine possible relationships between occipital GSH and dimensional measures of depressive symptom severity, including anhedonia – the reduced capacity to experience pleasure – and fatigue. We hypothesized that the magnitude of anhedonia and fatigue will be negatively correlated with occipital GSH levels in subjects with MDD and healthy controls (HC). Data for eleven adults with MDD and ten age- and sex-matched HC subjects were included in this secondary analysis of data from a previously published study. In vivo levels of GSH in a 3 cm × 3 cm × 2 cm voxel of occipital cortex were obtained by proton magnetic resonance spectroscopy (1H MRS) on a 3T MR system, using the standard J-edited spin-echo difference technique. Anhedonia was assessed by combining interest items from depression and fatigue rating scales, and fatigue by use of the multidimensional fatigue inventory. Across the full sample of participants, anhedonia severity and occipital GSH levels were negatively correlated (r = −0.55, p = 0.01). No associations were found between fatigue severity and GSH in this sample. These preliminary findings are potentially consistent with a pathophysiological role for GSH and oxidative stress in anhedonia and MDD. Larger studies in anhedonic depressed patients are indicated.
PMCID: PMC4108847  PMID: 24704328
Anhedonia; Glutathione; GSH; Oxidative stress; MRS
22.  Postural sway and perceived comfort in pointing tasks 
Neuroscience letters  2014;569:18-22.
In this study, we explored relations between indices of postural sway and perceived comfort during pointing postures performed by standing participants. The participants stood on a force plate, grasped a pointer with the dominant (right) hand, and pointed to targets located at four positions and at two distances from the body. We quantified postural sway over 60-s intervals at each pointing posture, and found no effects of target location or distance on postural sway indices. In contrast, comfort ratings correlated significantly with indices of one of the sway components, trembling. Our observations support the hypothesis that rambling and trembling sway components involve different neurophysiological mechanisms. They also suggest that subjective perception of comfort may be more important than the actual posture for postural sway.
PMCID: PMC4128396  PMID: 24686189
End-state comfort; pointing; postural sway; rambling; trembling
23.  p-Tau immunotherapy reduces soluble and insoluble tau in aged 3xTg-AD mice 
Neuroscience letters  2014;575:96-100.
Alzheimer’s disease (AD) is a proteinopathy characterized by the accumulation of β-amyloid (Aβ) and tau. To date, clinical trials indicate that Aβ immunotherapy does not improve cognition. Consequently, it is critical to modulate other aspects of AD pathology. As such, tau represents an excellent target, as its accumulation better correlates with cognitive impairment. To determine the effectiveness of targeting pathological tau, with Aβ pathology present, we administered a single injection of AT8, or control antibody, into the hippocampus of aged 3xTg-AD mice. Extensive data indicates that phosphorylated Ser202 and Thr205 sites of tau (corresponding to the AT8 epitope) represent a pathologically relevant target for AD. We report that immunization with AT8 reduced somatodendritic tau load, p-tau immunoreactivity, and silver stained positive neurons, without affecting Aβ pathology. We also discovered that tau pathology soon reemerges post-injection, possibly due to persistent Aβ pathology. These studies provide evidence that targeting p-tau may represent an effective treatment strategy: potentially in conjunction with Aβ immunotherapy.
PMCID: PMC4437620  PMID: 24887583
Tau; Phosphorylated tau; Neurofibrillary tangles; Immunotherapy; Beta-amyloid; Alzheimer’s disease
24.  β-Glucan attenuates TLR2- and TLR4-mediated cytokine production by microglia 
Neuroscience letters  2009;458(3):111-115.
Microglia, the resident immune cells of the brain, are activated in response to any kind of CNS injury, and their activation is critical for maintaining homeostasis within the CNS. However, during inflammatory conditions, sustained microglial activation results in damage to surrounding neuronal cells. β-Glucans are widely recognized immunomodulators, but the molecular mechanisms underlying their immunomodulatory actions have not been fully explored. We previously reported that β-glucans activate microglia through Dectin-1 without inducing significant amount of cytokines and chemokines. Here, we show that particulate β-glucans attenuate cytokine production in response to TLR stimulation; this inhibitory activity of β-glucan is mediated by Dectin-1 and does not require particle internalization. At the molecular level, β-glucan suppressed TLR-mediated NF-κB activation, which may be responsible for the diminished capacity of microglia to produce cytokines in response to TLR stimulation. Overall, these results suggest that β-glucans may be used to prevent or treat excessive microglial activation during chronic inflammatory conditions.
PMCID: PMC4435685  PMID: 19393720
Microglia; Toll-like receptors; Neuroimmunology; Cell surface molecules; Cell activation; Glucan
25.  Changes in Ascorbate, Glutathione and α-tocopherol Concentrations in the Brain Regions during Normal Development and Moderate Hypoglycemia in Rats 
Neuroscience letters  2014;568:67-71.
Ascorbate, glutathione and α-tocopherol are the major low molecular weight antioxidants in the brain. The simultaneous changes in these compounds during normal development, and under a pro-oxidant condition are poorly understood. Ascorbate, glutathione and α-tocopherol concentrations in the olfactory bulb, cerebral cortex, hippocampus, striatum, hypothalamus, midbrain, cerebellum, pons and medulla oblongata were determined in postnatal day (P) 7, P14 and P60 male rats. A separate group of P14 and P60 rats were subjected to acute hypoglycemia, a pro-oxidant condition, prior to tissue collection. The concentrations of all three antioxidants were 100-600% higher in the brain regions at P7 and P14, relative to P60. The neuron-rich anterior brain regions (cerebral cortex and hippocampus) had higher concentrations of all three antioxidants than the myelin-rich posterior regions (pons and medulla oblongata) at P14 and P60. Hypoglycemia had a differential effect on the antioxidants. Glutathione was decreased at both P14 and P60. However, the decrease was localized at P14 and global at P60. Hypoglycemia had no effect on ascorbate and α-tocopherol at either age. Higher antioxidant concentrations in the developing brain may reflect the risk of oxidant stress during the early postnatal period and explain the relative resistance to oxidant-mediated injury at this age.
PMCID: PMC4021725  PMID: 24686186
α-tocopherol; ascorbate; brain; glutathione; hypoglycemia; rat

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