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1.  Differential Effect of Traumatic Brain Injury on the Nuclear Factor of Activated T Cells C3 and C4 Isoforms in the Rat Hippocampus 
Brain research  2013;1548:63-72.
The interaction between the phosphatase calcineurin and transcription factor nuclear factor of activated T cells (NFAT) plays an important role numerous signaling and the regulatory events. Although NFAT is mostly known for its transcription function in the immune system, NFAT also has essential functions even in the central nervous system (CNS). The effects of traumatic brain injury (TBI) on NFAT are currently unknown. To determine if there is an alteration in NFAT after TBI, we examined NFATc3 and c4 levels at 6 hours, 1 day, 1 week, 2 weeks and 4 weeks post injury. Rats were anesthetized and surgically prepared for controlled cortical impact (CCI) injury or sham surgery. Semi-quantitative measurements of NFATc3 and c4 in the hippocampal homogenates from injured and sham rats sacrificed at the appropriate time after injury were assessed using Western blot analysis. After TBI insult, in the hippocampus ipsilateral to the injury, NFATc3 expression levels were decreased both in the cytoplasmic and nuclear fractions. However, NFATc4 expression levels were increased in the cytoplasmic fraction but decreased in the nuclear fraction. Double labeling (with NeuN and GFAP) immunohistochemistry revealed that NFATc3 was expressed in subset of astrocytes and NFATc4 was expressed primarily in neurons. These differential responses in NFATc3 and c4 expression after TBI insult may indicate long-term changes in hippocampal excitability and may contribute to behavioral deficits. Further study is warranted to illustrate the role of NFATc3 and c4 in the setting of TBI.
PMCID: PMC4017626  PMID: 24389074
Nuclear factor of activated T cells (NFAT); Immunohistochemistry; Rat; Traumatic brain injury (TBI); Calcineurin
2.  Redistribution of Kv2.1 ion channels on spinal motoneurons following peripheral nerve injury 
Brain research  2013;1547:1-15.
Pathophysiological responses to peripheral nerve injury include alterations in the activity, intrinsic membrane properties and excitability of spinal neurons. The intrinsic excitability of α-motoneurons is controlled in part by the expression, regulation, and distribution of membrane-bound ion channels. Ion channels, such as Kv2.1 and SK, which underlie delayed rectifier potassium currents and afterhyperpolarization respectively, are localized in high-density clusters at specific postsynaptic sites (Deardorff et al., 2013; Muennich and Fyffe, 2004). Previous work has indicated that Kv2.1 channel clustering and kinetics are regulated by a variety of stimuli including ischemia, hypoxia, neuromodulator action and increased activity. Regulation occurs via channel dephosphorylation leading to both declustering and alterations in channel kinetics, thus normalizing activity (Misonou et al., 2004; Misonou et al., 2005; Misonou et al., 2008; Mohapatra et al., 2009; Park et al., 2006). Here we demonstrate using immunohistochemistry that peripheral nerve injury is also sufficient to alter the surface distribution of Kv2.1 channels on motoneurons. The dynamic changes in channel localization include a rapid progressive decline in cluster size, beginning immediately after axotomy, reaching maximum within one week. With reinnervation, the organization and size of Kv2.1 clusters do not fully recover. However, in the absence of reinnervation Kv2.1 cluster sizes fully recover. Moreover, unilateral peripheral nerve injury evokes parallel, but smaller, effects bilaterally. These results suggest that homeostatic regulation of motoneuron Kv2.1 membrane distribution after axon injury is largely independent of axon reinnervation.
PMCID: PMC3970712  PMID: 24355600
Kv2.1; Peripheral Nerve Injury; Voltage-gated ion channels; Motoneuron
3.  Electrophysiological evidence for attenuated auditory recovery cycles in children with specific language impairment 
Brain research  2011;1438:35-47.
Previous research indicates that at least some children with specific language impairment (SLI) show a reduced neural response when non-linguistic tones were presented at rapid rates. However, this past research has examined older children, and it is unclear whether such deficits emerge earlier in development. It is also unclear whether atypical refractory effects differ for linguistic versus non-linguistic stimuli or can be explained by deficits in selective auditory attention reported among children with SLI. In the present study, auditory refractory periods were compared in a group of 24 young children with SLI (age 3–8 years) and 24 matched control children. Event-related brain potentials (ERPs) were recorded and compared to 100 ms linguistic and non-linguistic probe stimuli presented at inter-stimulus intervals (ISIs) of 200, 500, or 1000 ms. These probes were superimposed on story narratives when attended and ignored, permitting an experimental manipulation of selective attention within the same paradigm. Across participants, clear refractory effects were observed with this paradigm, evidenced as a reduced amplitude response from 100 to 200 ms at shorter ISIs. Children with SLI showed reduced amplitude ERPs relative to the typically-developing group at only the shortest, 200 ms, ISI and this difference was over the left-hemisphere for linguistic probes and over the right-hemisphere for non-linguistic probes. None of these effects was influenced by the direction of selective attention. Taken together, these findings suggest that deficits in the neural representation of rapidly presented auditory stimuli may be one risk factor for atypical language development.
PMCID: PMC4318634  PMID: 22265331
Specific language impairment (SLI); Refractory periods; ERP; Auditory processing
4.  Depression, anxiety-like behavior and memory impairment are associated with increased oxidative stress and inflammation in a rat model of social stress 
Brain research  2013;1539:73-86.
In the present study, we have examined the behavioral and biochemical effect of induction of psychological stress using a modified version of the resident-intruder model for social stress (social defeat). At the end of the social defeat protocol, body weights, food and water intake were recorded, depression and anxiety-like behaviors as well as learning-memory function was examined. Biochemical analysis including oxidative stress measurement, inflammatory markers and other molecular parameters, critical to behavioral effects were examined. We observed a significant decrease in the body weight in the socially defeated rats as compared to the controls. Furthermore, social defeat increased anxiety-like behavior and caused memory impairment in rats (P<0.05). Socially defeated rats made significantly more errors in long term memory tests (P<0.05) as compared to control rats. Furthermore, brain extracellular signal-regulated kinase-1/2 (ERK1/2), and an inflammatory marker, interleukin (IL)-6 were activated (P<0.05), while the protein levels of glyoxalase (GLO)-1, glutathione reductase (GSR)-1, calcium/calmodulin-dependent protein kinase type (CAMK)-IV, cAMP-response-element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were significantly less (P<0.05) in the hippocampus, but not in the prefrontal cortex and amygdala of socially defeated rats, when compared to control rats. We suggest that social defeat stress alters ERK1/2, IL-6, GLO1, GSR1, CAMKIV, CREB, and BDNF levels in specific brain areas, leading to oxidative stress-induced anxiety-depression-like behaviors and as well as memory impairment in rats.
PMCID: PMC4316676  PMID: 24096214
5.  [No title available] 
PMCID: PMC3919041  PMID: 24361977
6.  [No title available] 
PMCID: PMC3919455  PMID: 24355597
7.  Oxytocin eliminates the own-race bias in face recognition memory☆ 
Brain research  2013;1580:180-187.
The neuropeptide Oxytocin influences a number of social behaviors, including processing of faces. We examined whether Oxytocin facilitates the processing of out-group faces and reduce the own-race bias (ORB). The ORB is a robust phenomenon characterized by poor recognition memory of other-race faces compared to the same-race faces. In Experiment 1, participants received intranasal solutions of Oxytocin or placebo prior to viewing White and Black faces. On a subsequent recognition test, whereas in the placebo condition the same-race faces were better recognized than other-race faces, in the Oxytocin condition Black and White faces were equally well recognized, effectively eliminating the ORB. In Experiment 2, Oxytocin was administered after the study phase. The ORB resulted, but Oxytocin did not significantly reduce the effect. This study is the first to show that Oxytocin can enhance face memory of out-group members and underscore the importance of social encoding mechanisms underlying the own-race bias.
PMCID: PMC4311875  PMID: 23872107
Oxytocin; Other-race bias; Face recognition; Encoding
8.  Enhanced expression of transforming growth factor β1 in the rat brain after a localized cerebral injury 
Brain research  1992;587(2):216-225.
It is becoming clear that transforming growth factor β (TGFβ) may be a key factor regulating inflammatory and tissue specific wound responses. Because the formation of a glial-collagen scar at CNS lesion sites is thought to contribute to the pathology associated with penetrating CNS injuries, and because in the periphery TGFβ1 stimulates fibroblast deposition of scar tissue, we used in situ hybridization and immunohistochemistry to investigate the effect of a defined cerebral lesion on the local expression of TGFβ1. Induction of TGFβ1 mRNA and protein is relatively diffuse in the neuropile around the margins of the lesion at 1, 2 and 3 days, but becomes localized to the region of the glial scar at 7 and 14 days. The signal intensity for TGFβ1 mRNA and protein is maximal between 2 and 3 days and decreases between 7 and 14 days after lesion. The predominant cell types in the neuropile localizing TGFβ1 mRNA and protein have the morphological characteristics of astrocytes, although macrophages are also detected. An induction of TGFβ1 mRNA was also observed in endothelial cells of the meninges, hippocampal fissure and choroid plexus, at 2 and 3 days, However, this is dramatically reduced by 7 days and has disappeared by 14 days. These results suggest a role for TGPβ1, not only in inflammation, but also in the tissue-specific glial scar formation that occurs in the CNS. Furthermore, they suggest a potential therapeutic use of TGFβ1 antagonists in the CNS to help limit the pathogenesis associated with matrix deposition in the wound.
PMCID: PMC4310563  PMID: 1525658
Transforming growth factor β1; mRNA; Injury; Central nervous system; Glial scar; Astrocyte
9.  The role of hypocretin in driving arousal and goal-oriented behaviors 
Brain research  2009;1314:103-111.
The hypocretins (Hcrts), also called orexins, are two neuropeptides secreted by a few thousand neurons restricted to the lateral hypothalamus. The Hcrt peptides bind to two receptors located in nuclei associated with diverse cognitive and physiological functions. Experimental evidence has demonstrated that the physiological roles of hypocretins extend far beyond its initial role in food consumption, and has emerged as a key system in the fields of sleep disorders and drug addiction. Here, we discuss recent evidence demonstrating a key role of hypocretin in the motivation for reward seeking in general, and drug taking in particular, and we delineate a physiological framework for this peptidergic system in orchestrating the appropriate levels of alertness required for the elaboration and the execution of goal-oriented behaviors. We propose a general role for hypocretins in mediating arousal, especially when an organism must respond to unexpected stressors and environmental challenges, which serve to shape survival behaviors. We also discuss the limit of the current experimental paradigms to address the question of how a system normally involved in the regulation of vigilance states and hyperarousal may promote a pathological state that elicits compulsive craving and relapse to drug seeking.
PMCID: PMC4307927  PMID: 19948148
10.  Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders 
Brain research  2014;1580:199-218.
Oxytocin (OT) and arginine vasopressin (AVP) are two small, related neuropeptide hormones found in many mammalian species, including humans. Dysregulation of these neuropeptides have been associated with changes in behavior, especially social interactions. We review how the OT and AVP systems have been investigated in Autism Spectrum Disorder (ASD), Prader–Willi Syndrome (PWS), Williams Syndrome (WS) and Fragile X syndrome (FXS). All of these neurodevelopmental disorders (NDD) are marked by social deficits. While PWS, WS and FXS have identified genetic mutations, ASD stems from multiple genes with complex interactions. Animal models of NDD are invaluable for studying the role and relatedness of OT and AVP in the developing brain. We present data from a FXS mouse model affecting the fragile X mental retardation 1 (Fmr1) gene, resulting in decreased OT and AVP staining cells in some brain regions. Reviewing the research about OT and AVP in these NDD suggests that altered OT pathways may be downstream from different etiological factors and perturbations in development. This has implications for ongoing studies of the therapeutic application of OT in NDD.
PMCID: PMC4305432  PMID: 24462936
Oxytocin; Vasopressin; Autism; Prader–Willi; Williams; Fragile X
11.  Progesterone-associated increase in ERP amplitude correlates with an improvement in performance in a spatial attention paradigm 
Brain Research  2015;1595:74-83.
Ovarian sex hormones modulate neuronal circuits not directly involved in reproductive functions. In the present study, we investigated whether endogenous fluctuations of estradiol and progesterone during the menstrual cycle are associated with early cortical processing stages in a cued spatial attention paradigm. EEG was monitored while young women responded to acoustically cued visual stimuli. Women with large mean amplitude of the event-related potential (ERP) (80–120 ms following visual stimuli) responded faster to visual stimuli. In luteal women, mean amplitude of the ERP as well as alpha amplitude, an indicator of attentional modulation, correlated positively with progesterone. Further, cerebral asymmetry in ERP amplitude in the alpha frequency band following target presentation was restricted to luteal women. Critically, early follicular women responded slower to right hemifield compared to left hemifield targets. In late follicular or luteal women, we did not detect a right hemifield disadvantage. Progesterone correlated negatively with RTs in luteal women. Therefore, whereas our behavioral data indicate a functional cerebral asymmetry in early follicular women, EEG recording reveal a physiological cerebral hemisphere asymmetry in the alpha frequency band in luteal women. We assume that a progesterone-associated enhancement in synchronization of synaptic activity in the alpha frequency band in luteal women improves early categorization of visual targets in a cued spatial attention paradigm.
•We correlated sex hormones with RT and ERP amplitudes in an attention task.•Progesterone correlated negatively with response times in luteal phase.•Progesterone correlated positively with ERP amplitude in luteal phase.•Functional cerebral asymmetry was detectable in early follicular phase.•Cerebral hemisphere asymmetry in ERP amplitudes was restricted to luteal phase.
PMCID: PMC4302164  PMID: 25446456
Attention; Menstrual cycle; Progesterone; Event-related potential; Alpha oscillation
12.  Expression of the CHOP-inducible carbonic anhydrase CAVI-b is required for BDNF-mediated protection from hypoxia 
Brain research  2013;1543:28-37.
Carbonic anhydrases (CAs) comprise a family of zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide. CAs contribute to a myriad of physiological processes, including pH regulation, anion transport and water balance. To date, 16 known members of the mammalian alpha-CA family have been identified. Given that the catalytic family members share identical reaction chemistry, their physiologic roles are influenced greatly by their tissue and sub-cellular locations. CAVI is the lone secreted CA and exists in both saliva and the gastrointestinal mucosa. An alternative, stress-inducible isoform of CAVI (CAVI-b) has been shown to be expressed from a cryptic promoter that is activated by the CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP). The CAVI-b isoform is not secreted and is currently of unknown physiological function. Here we use neuronal models, including a model derived using Car6 and CHOP gene ablations, to delineate a role for CAVI-b in ischemic protection. Our results demonstrate that CAVI-b expression, which is increased through CHOP-signaling in response to unfolded protein stress, is also increased by oxygen-glucose deprivation (OGD). While enforced expression of CAVI-b is not sufficient to protect against ischemia, CHOP regulation of CAVI-b is necessary for adaptive changes mediated by BDNF that reduce subsequent ischemic damage. These results suggest that CAVI-b comprises a necessary component of a larger adaptive signaling pathway downstream of CHOP.
PMCID: PMC3888505  PMID: 24275196
carbonic anhydrase; ischemia; neurosphere; unfolded protein response (UPR); oxygen glucose deprivation (OGD); brain-derived neurotrophic factor (BDNF)
Brain research  2013;1543:101-108.
In rodents, many aspects of sociosexual behavior are mediated by chemosignals released by opposite-sex conspecifics. These chemosignals are relayed via the main (MOS) and accessory olfactory systems (AOS) to the medial amygdala (Me). The Me is subdivided into anterior (MeA) and posterior (MeP) subnuclei, and lesions targeting these regions have different effects on proceptive courtship behaviors in female mice. Differential behavioral effects of MeA vs. MeP lesions could reflect a difference in the projections of neurons located in these Me subnuclei. To examine this question, we injected female mice with the anterograde tracer, Fluoro-Ruby into either the MeA or MeP and quantified labeled puncta in 11 forebrain target sites implicated in courtship behaviors using confocal fluorescence microscopy. We found that the MeP more densely innervates the medial and intermediate regions of the posterior bed nucleus of the stria terminalis (pBNST) and the posteromedial cortical amygdala (PMCo), while the MeA more densely innervates the horizontal diagonal band of Broca (HDB) and the medial olfactory tubercle (mOT), a region that may be a component of the circuitry responsible for olfactory-mediated motivated behaviors.
PMCID: PMC3888110  PMID: 24262912
Medial Amygdala; axon terminal; sociosexual behavior; olfactory; anterograde tracing
14.  Cocaine reduces cytochrome oxidase activity in the prefrontal cortex and modifies its functional connectivity with brainstem nuclei 
Brain research  2014;1542:56-69.
Cocaine-induced psychomotor stimulation may be mediated by metabolic hypofrontality and modification of brain functional connectivity. Functional connectivity refers to the pattern of relationships among brain regions, and one way to evaluate this pattern is using interactivity correlations of the metabolic marker cytochrome oxidase among different regions. This is the first study of how repeated cocaine modifies: (1) mean cytochrome oxidase activity in neural areas using quantitative enzyme histochemistry, and (2) functional connectivity among brain regions using inter-correlations of cytochrome oxidase activity. Rats were injected with 15 mg/kg i.p. cocaine or saline for 5 days, which lead to cocaine-enhanced total locomotion. Mean cytochrome oxidase activity was significantly decreased in cocaine-treated animals in the superficial dorsal and lateral frontal cortical association areas Fr2 and Fr3 when compared to saline-treated animals. Functional connectivity showed that the cytochrome oxidase activity of the noradrenergic locus coeruleus and the infralimbic cortex were positively inter-correlated in cocaine but not in control rats. Positive cytochrome oxidase activity inter-correlations were also observed between the dopaminergic substantia nigra compacta and Fr2 and Fr3 areas and the lateral orbital cortex in cocaine-treated animals. In contrast, cytochrome oxidase activity in the interpeduncular nucleus was negatively correlated with that of Fr2, anterior insular cortex, and lateral orbital cortex in saline but not in cocaine groups. After repeated cocaine specific prefrontal areas became hypometabolic and their functional connectivity changed in networks involving noradrenergic and dopaminergic brainstem nuclei. We suggest that this pattern of hypofrontality and altered functional connectivity may contribute to cocaine-induced psychomotor stimulation.
PMCID: PMC3942664  PMID: 24505625
Functional connectivity; Cytochrome oxidase; Cocaine; Prefrontal networks; Hypofrontality
15.  Chronic cannabinoid agonist (WIN 55,212-2) exposure alters hippocampal dentate gyrus spine density in adult rats 
Brain research  2013;1542:10.1016/j.brainres.2013.10.039.
Chronic abuse of drugs can result in vast negative repercussions on behavioral and biological systems by altering underlying neurocircuitry. Long-term cannabinoid administration in rats leads to detrimental cellular and dendritic morphology changes. Previous studies have found that chronic treatment with delta-9-THC selectively decreases dendritic morphology and spine density in the dentate gyrus of young rats (Rubino et al., 2009), however, whether these changes are specific to a particular developmental age is not known. The present study evaluated the effects of chronic exposure (7 or 21 days) to WIN 55, 212-2 (i.p., 3.7 mg/kg), a potent cannabinoid agonist, on dendritic morphology of dentate gyrus neurons in adult rats. Upon completion of treatment brains were processed for Golgi-Cox staining. No significant effects of WIN 55, 212-2 exposure were observed for dendritic branching or length. Spine density was quantified in the inner (proximal), middle, and outer (distal) thirds of the dendritic fields selected to approximate the spatial loci of afferents comprising the associational-commissural pathway, medial perforant path, and lateral perforant path, respectively. Compared to vehicle controls there was a significant reduction in spine density (~1 spine/10μm) in the inner and middle dendritic segments. The spine density reduction was significant in inner segments following 7 days of treatment. These results suggest that chronic cannabinoid treatment specifically alters spine density in the dendritic targets of the associational-commissural afferents and medial perforant path projections, but not lateral perforant path. The resulting loss of dendritic spine density may be an important factor underlying cannabinoid induced memory impairments.
PMCID: PMC3883362  PMID: 24183783
Cannabinoid; Dendritic spines; Hippocampus; Dentate Gyrus; Synaptic Plasticity; Golgi-Cox
16.  Effect of dopamine D1 and D2 receptor antagonism in the lateral hypothalamus on the expression and acquisition of fructose-conditioned flavor preference in rats 
Brain research  2013;1542:10.1016/j.brainres.2013.10.030.
The attraction to sugar-rich foods is influenced by conditioned flavor preferences (CFP) produced by the sweet taste of sugar (flavor-flavor learning) and the sugar’s post-oral actions (flavor-nutrient) learning. Brain dopamine (DA) circuits are involved in both types of flavor learning, but to different degrees. This study investigated the role of DA receptors in the lateral hypothalamus (LH) on the flavor-flavor learning produced the sweet taste of fructose. In an acquisition study, food-restricted rats received bilateral LH injections of a DA D1 receptor antagonist (SCH23390), a D2 antagonist (RAC, raclopride) or vehicle prior to 1-bottle training sessions with a flavored 8% fructose + 0.2% saccharin solution (CS+/F) and a less-preferred flavored 0.2% saccharin solution (CS−). Drug-free 2-bottle tests were then conducted with the CS+ and CS− flavors presented in saccharin. The fructose-CFP did not differ among groups given vehicle (76%), 12 nmol SCH (78%), 24 nmol (82%) or 24 nmol RAC (90%) during training. In an expression study with rats trained drug-free, LH injections of 12 or 24 nmol SCH or 12-48 nmol RAC prior to 2-bottle tests did not alter CS+ preferences (77-90%) relative to vehicle injection (86%). Only a 48 nmol SCH dose suppressed the CS+ preference (61%). The minimal effect of LH DA receptor antagonism upon fructose flavor-flavor conditioning differs with the ability of LH SCH injections to block the acquisition of glucose flavor-nutrient learning.
PMCID: PMC3884559  PMID: 24211237
Flavor-flavor learning; sweet taste; saccharin; SCH23390; Raclopride
Brain research  2013;1542:85-92.
Prolyl carboxypeptidase (PRCP), a serine protease, is widely expressed in the body including liver, lung, kidney and brain, with a variety of known substrates such as plasma prekallikrein, bradykinin, angiotensins II and III, and -MSH, suggesting its role in the processing of tissue-specific substrates. In the brain, PRCP has been shown to inactivate hypothalamic -MSH, thus modulating melanocortin signaling in the control of energy metabolism. While its expression pattern has been reported in the hypothalamus, little is known on the distribution of PRCP throughout the mouse brain. This study was undertaken to determine PRCP expression in the mouse brain. Radioactive in situ hybridization was performed to determine endogenous PRCP mRNA expression. In addition, using a gene-trap mouse model for PRCP deletion, X-gal staining was performed to further determine PRCP distribution. Results from both approaches showed that PRCP gene is broadly expressed in the brain.
PMCID: PMC3893042  PMID: 24161824
Prolyl carboxypeptidase; brain; distribution
18.  Excitotoxic glutamate insults block autophagic flux in hippocampal neurons 
Brain research  2014;1542:12-19.
Excitotoxic insults such as cerebral ischemia are thought to enhance neuronal autophagy, which is then thought to promote neuronal cell death. Excitotoxic insults indeed increase autophagy markers. Notably, however, autophagy markers can be increased either by autophagy induction (as this enhances their production) or by late-stage autophagy inhibition (as this prevents their degradation during autophagic flux). By comparing each condition with and without protease inhibitors that prevent autophagic degradation of the autophagy marker, the results of this study show that excitotoxic glutamate increases autophagy markers by a late-stage block of autophagy. Initially, this study set out to test if the CaMKII inhibitor tatCN21 mediates its post-insult neuroprotection by regulating autophagy. While tatCN21 partially inhibited basal autophagy in hippocampal neurons, it had no effects on the already blocked autophagy after excitotoxic glutamate insults, indicating that autophagy inhibition is not its neuroprotective mechanism. Additionally, while the autophagy inhibitor chloroquine had no effect, significant neuroprotection was seen instead with two drugs that enhance autophagy induction by different mechanisms, rapamycin (mTOR dependent) and trehalose (mTOR-independent). This suggests that therapeutic approaches should seek to enhance rather than inhibit autophagy, not only in neurodegenerative diseases (where such approach is widely accepted) but also after acute excitotoxic insults. Together, these findings significantly reshape the current view on the mutual cross-regulation of autophagy and excitotoxicity.
PMCID: PMC3934833  PMID: 24505621
CaMKII; glutamate; excitotoxicity; autophagy; neuronal cell death
19.  Neocortical dynamics due to axon propagation delays in cortico-cortical fibers: EEG traveling and standing waves with implications for top-down influences on local networks and white matter disease 
Brain research  2014;1542:138-166.
The brain is treated as a nested hierarchical complex system with substantial interactions across spatial scales. Local networks are pictured as embedded within global fields of synaptic action and action potentials. Global fields may act top-down on multiple networks, acting to bind remote networks. Because of scale-dependent properties, experimental electrophysiology requires both local and global models that match observational scales. Multiple local alpha rhythms are embedded in a global alpha rhythm.
Global models are outlined in which cm-scale dynamic behaviors result largely from propagation delays in cortico-cortical axons and cortical background excitation level, controlled by neuromodulators on long time scales. The idealized global models ignore the bottom-up influences of local networks on global fields so as to employ relatively simple mathematics. The resulting models are transparently related to several EEG and steady state visually evoked potentials correlated with cognitive states, including estimates of neocortical coherence structure, traveling waves, and standing waves.
The global models suggest that global oscillatory behavior of self-sustained (limit-cycle) modes lower than about 20 Hz may easily occur in neocortical/white matter systems provided: Background cortical excitability is sufficiently high; the strength of long cortico-cortical axon systems is sufficiently high; and the bottom-up influence of local networks on the global dynamic field is sufficiently weak. The global models provide "entry points" to more detailed studies of global top-down influences, including binding of weakly connected networks, modulation of gamma oscillations by theta or alpha rhythms, and the effects of white matter deficits.
PMCID: PMC3942804  PMID: 24505628
electroencephalography; global fields; axon propagation; cross-frequency interactions; white matter disease
20.  [No title available] 
PMCID: PMC4292841  PMID: 21352816
21.  R-flurbiprofen improves tau, but not Aß pathology in a triple transgenic model of Alzheimer's disease 
Brain research  2013;1541:10.1016/j.brainres.2013.10.025.
We have previously reported that chronic ibuprofen treatment improves cognition and decreases intracellular Aß and phosphorylated-tau levels in 3xTg-AD mice. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) that independently of its anti-inflammatory effects has anti-amyloidogenic activity as a gamma-secretase modulator (GSM) and both activities have the potential to decrease Aß pathology. To further understand the effects of NSAIDs in 3xTg-AD mice, we treated 3xTg-AD mice with R-flurbiprofen, an enantiomer of the NSAID flurbiprofen that maintains the GSM activity but has greatly reduced anti-inflammatory activity, and analyzed its effect on cognition, Aß, tau, and the neurochemical profile of the hippocampus. Treatment with R-flurbiprofen from 5 to 7 months of age resulted in improved cognition on the radial arm water maze (RAWM) test and decreased the level of hyperphosphorylated tau immunostained with AT8 and PHF-1 antibodies. No significant changes in the level of Aß (using 6E10 and NU-1 antibodies) were detected. Using magnetic resonance spectroscopy (MRS) we found that R-flurbiprofen treatment decreased the elevated level of glutamine in 3xTg-AD mice down to the level detected in non-transgenic mice. Glutamine levels correlated with PHF-1 immunostained hyperphosphorylated tau. We also found an inverse correlation between the concentration of glutamate and learning across all the mice in the study. Glutamine and glutamate, neurochemicals that shuttles between neurons and astrocytes to maintain glutamate homeostasis in the synapses, deserve further attention as MR markers of cognitive function.
PMCID: PMC3863610  PMID: 24161403
R-flurbiprofen; hyperphosphorylated tau; Aß; 3xTg-AD mice; magnetic resonance spectroscopy
22.  Comparative analysis of the neurovascular injury and functional outcomes in experimental stroke models in diabetic Goto-Kakizaki rats 
Brain research  2013;1541:10.1016/j.brainres.2013.10.021.
Diabetes worsens functional outcome and is associated with greater hemorrhagic transformation (HT) after ischemic stroke. We have shown that diabetic Goto-Kakizaki (GK) rats develop greater HT and neurological deficit despite smaller infarcts after transient middle cerebral artery occlusion (MCAO) with the suture model. However, the impact of 1) the duration of ischemia/reperfusion (I/R); 2) the method of ischemia; and 3) acute glycemic control on neurovascular injury and functional outcome in diabetic stroke remained unanswered. Wistar and GK rats were subjected to variable MCAO by suture or embolus occlusion. A group of GK rats were treated with insulin or metformin before stroke with suture occlusion. In all groups, infarct size, edema, HT occurrence and severity, and functional outcome were measured. Infarct size at 24 h was smaller in GK rats with both suture and embolic MCAO, but expanded with longer reperfusion period. Edema and HT were increased in GK rats after 90 min and 3 h occlusion with the suture model, but not in the embolic MCAO. Neurological deficit was greater in diabetic rats. These findings suggest that diabetes accelerates the development of HT and amplifies vascular damage in the suture model where blood flow is rapidly reestablished. Acute metformin treatment worsened the infarct size, HT, and behavior outcome, whereas insulin treatment showed a protective effect. These results suggest that the impact of ischemia/reperfusion on neurovascular injury and functional outcome especially in disease models needs to be fully characterized using different models of stroke to model the human condition.
PMCID: PMC3878856  PMID: 24144674
Ischemic stroke; diabetes; infarct; edema; hemorrhagic transformation; middle cerebral artery occlusion
23.  Thalamic Post-Inhibitory Bursting Occurs in Patients with Organic Dystonia more often than Controls 
Brain research  2013;1541:81-91.
We now test the hypothesis that post-inhibitory bursting in the human pallidal receiving nucleus of the thalamus (ventral oral) mediates inhibitory pallido-thalamic transmission during dystonia. We have compared thalamic single neuron activity in nine patients with organic dystonia to that in a patient with psychogenic dystonia (Psyd) and in healthy waking monkeys.
In organic dystonia, EMG power is commonly concentrated at the lowest frequency of the smoothed autopower spectrum (0.39Hz). Therefore, segments of spike trains with a signal-to-noise ratio ≥ 2 at 0.39 Hz were termed dystonia frequency (DF) segments, which occurred more commonly during dystonia related to movement. Those with a SNR < 2 were termed non-dystonia frequency (nDF) segments, which are associated with spontaneous dystonia. We concentrated on nDF activity since neuronal activity in our controls was measured at rest. Neuronal spike trains were categorized into those with post-inhibitory bursts (G, grouped), with single spikes (NG, non-grouped), or with both single spikes and bursts (I, intermediate). nDF spike trains in ventral oral had more G category firing in dystonia than in controls. The burst rate and the pre-burst silent period in nDF firing of organic dystonia were consistently greater than those of both the monkeys and the patient with Psyd. The distribution of the pre-burst silent period was bimodal with a longer mode of approximately GABAb (gamma amino butyric acid receptor - type b) duration.
These results demonstrate distinct differences of post-inhibitory bursting in organic dystonia versus controls. The presence of inhibitory events consistent with GABAb duration suggests interventions for treatment of dystonia.
PMCID: PMC3889805  PMID: 24125808
dystonia; thalamus; single neuron analysis; low threshold spike bursts; thalamotomy
24.  Novel Song-Stimulated Dendritic Spine Formation and Arc/Arg 3.1 Expression in Zebra Finch Auditory Telencephalon are Disrupted by Cannabinoid Agonism 
Brain research  2013;1541:9-21.
Cannabinoids are well-established to alter processes of sensory perception; however neurophysiological mechanisms responsible remain unclear. Arc, an immediate-early gene (IEG) product involved in dendritic spine dynamics and necessary for plasticity changes such as long-term potentiation, is rapidly induced within zebra finch caudal medial nidopallium (NCM) following novel song exposure, a response that habituates after repeated stimuli. Arc appears unique in its rapid postsynaptic dendritic expression following excitatory input. Previously, we found that vocal development-altering cannabinoid treatments are associated with elevated dendritic spine densities in motor- (HVC) and learning-related (Area X) song regions of zebra finch telencephalon. Given Arc’s dendritic morphological role, we hypothesized that cannabinoid-altered spine densities may involve Arc-related signaling. To test this, we examined the ability of the cannabinoid agonist WIN55212-2 (WIN) to: (1) acutely disrupt song-induced Arc expression; (2) interfere with habituation to auditory stimuli and; (3) alter dendritic spine densities in auditory regions. We found that WIN (3 mg/kg) acutely reduced Arc expression within both NCM and Field L2 in an antagonist-reversible manner. WIN did not alter Arc expression in thalamic auditory relay Nucleus Ovoidalis (Ov), suggesting cannabinoid signaling selectively alters responses to auditory stimulation. Novel song stimulation rapidly increased dendritic spine densities within auditory telencephalon, an effect blocked by WIN pretreatments. Taken together, cannabinoid inhibition of both Arc induction and its habituation to repeated stimuli, combined with prevention of rapid increases in dendritic spine densities, implicates cannabinoid signaling in modulation of physiological processes important to auditory responsiveness and memory.
PMCID: PMC3891467  PMID: 24134952
dendritic spines; cannabinoid; auditory; sensory; songbird; Arc/Arg 3.1; learning; memory
25.  Oscillatory brain responses to own names uttered by unfamiliar and familiar voices 
Brain Research  2014;1591:63-73.
Among auditory stimuli, the own name is one of the most powerful and it is able to automatically capture attention and elicit a robust electrophysiological response. The subject’s own name (SON) is preferentially processed in the right hemisphere, mainly because of its self-relevance and emotional content, together with other personally relevant information such as the voice of a familiar person. Whether emotional and self-relevant information are able to attract attention and can be, in future, introduced in clinical studies remains unclear. In the present study we used EEG and asked participants to count a target name (active condition) or to just listen to the SON or other unfamiliar names uttered by a familiar or unfamiliar voice (passive condition). Data reveals that the target name elicits a strong alpha event related desynchronization with respect to non-target names and triggers in addition a left lateralized theta synchronization as well as delta synchronization.
In the passive condition alpha desynchronization was observed for familiar voice and SON stimuli in the right hemisphere.
Altogether we speculate that participants engage additional attentional resources when counting a target name or when listening to personally relevant stimuli which is indexed by alpha desynchronization whereas left lateralized theta synchronization may be related to verbal working memory load. After validating the present protocol in healthy volunteers it is suggested to move one step further and apply the protocol to patients with disorders of consciousness in which the degree of residual cognitive processing and self-awareness is still insufficiently understood.
•EEG during an active–passive task based on first names was time-frequency analyzed.•The presented names were uttered either by an unfamiliar or a familiar voice.•Counted names elicited alpha desynchronization and left theta synchronization.•Own name and familiar voices enhanced strong right alpha desynchronization.•Alpha desynchronization reflects attentional engagement and emotional processing.
PMCID: PMC4235780  PMID: 25307136
Oscillations; Disorders of consciousness; EEG; Subject’s own name; Familiar voice

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