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Humans suffering damage to the orbitofrontal cortex (OFC) are often described as impulsive. The most famous example is Phineas Gage, a railway worker, who in 1848 suffered extreme frontal lobe damage when a long iron rod was projected through his skull after an accidental explosion. Gage survived, but was reported to have an extreme change in personality, including increased inappropriate behavior (impulsiveness) [1–2]. People with OFC lesions are more impulsive compared to both normal controls and people with non-OFC frontal cortex damage, as measured by self-report and by cognitive/behavioral tasks [3]. But, how is impulsivity defined and how can it be measured? Impulsivity involves behaviors that are inappropriate for the context, premature, poorly planned and often resulting in adverse consequences. Impulsive behaviors have been described as having three dimensions: 1) an inability to use available information to reflect on the consequences of actions; 2) an inability to forego an immediate small reward in favor of a delayed larger reward; 3) a deficit in suppressing prepotent motor responses [4]. Taken together, these three dimensions of impulsivity reflect an inability to evaluate and subsequently respond flexibly in search of a specific goal or outcome under changing environmental conditions. In this commentary, we reflect on the similarities between impulsive, compulsive and habitual behavior and hypothesize a common neurobiological circuit that depends critically on the function of the OFC.

The mesolimbic dopamine (DA) system has been implicated in conditioned reward (CR), locomotor sensitization, and the reinforcing properties of psychomotor stimulants. Stimuli with formerly motivationally neutral properties that gain incentive properties by their predictive association with primary reinforcers are termed conditioned, or secondary, reinforcers. In these experiments, we investigated whether cocaine sensitization could potentiate augmented responding for CR produced by intra-accumbens amphetamine. After subjects were trained on the CR paradigm for 14 days, they received a regimen of cocaine sensitization or saline injections. On 2 test days, 8-10 days later, subjects were given amphetamine (6 microg/0.5 microl) or saline infusions into the nucleus accumbens (NAc) and responding for CR was measured using the "acquisition of a new response" paradigm. Responding on one novel lever resulted in the delivery of the conditioned stimulus (conditioned reinforcer, or CR lever), whereas responding on the other lever resulted in no CR stimulus presentation (NCR lever). Animals sensitized to cocaine showed increased responding on the CR lever after intra-NAc saline and potentiated CR lever responding after intra-NAc amphetamine. No differences in responding between the cocaine- and saline-treated groups on the NCR lever after the challenge were found. Locomotor sensitization under these conditions was confirmed in a separate group of subjects. These findings show that prior exposures to cocaine results in changes that potentiate the ability of intra-NAc amphetamine to enhance CR. Repeated stimulant drug use may induce long-term neuronal adaptations that result in increased sensitivity to the behavioral, or incentive motivational, effects of stimulant drugs.

Previous studies have shown that repeated exposures to phencyclidine (PCP) induces prefrontal cortical dopaminergic and cognitive deficits in rats and monkeys, producing a possible model of schizophrenic frontal cortical dysfunction. In the current study, the effects of subchronic PCP exposure on forebrain dopaminergic function and behavior were further explored. Prefrontal cortical dopamine utilization was reduced 3 weeks after subchronic PCP administration, and the cortical dopaminergic deficit was mimicked by repeated dizocilpine exposure. In contrast, stress- and amphetamine-induced hyperlocomotion, behavior believed to be mediated by activation of mesolimbic dopamine transmission, was enhanced after PCP exposures. Furthermore, haloperidol-induced increases in nucleus accumbens dopamine utilization were larger in magnitude in PCP-treated rats relative to control subjects. These data are the first to demonstrate that repeated exposures to PCP causes prefrontal cortical dopaminergic hypoactivity and subcortical dopaminergic hyper-responsivity in rats, perhaps mimicking alterations in dopaminergic transmission that underlie the behavioral pathology of schizophrenia.

The majority of investigations into the degree of restoration of neural circuitry following transplantation of the embryonic ventral mesencephalon to the striatum have focused upon the particular neurochemical subtypes of the fibers exchanged between graft and host. Visualization of neurites of specific neurotransmitter type while informative regarding the specificity of graft-host interactions, vastly underrepresents overall synaptogenesis as it may occur in the grafting situation. The present approach of using a molecular marker characteristic of all normal, functional synapses provides broader information about the synaptic remodeling that occurs after tissue grafting. Synaptophysin (SY), an integral membrane protein of the synaptic vesicle, is a reliable marker of nerve terminal differentiation. Immunohistochemical staining with antibodies directed against SY and the dopamine synthetic enzyme tyrosine hydroxylase (TH) was used to assess overall synaptic differentiation as well as the relationship between SY immunoreactivity and the distribution of grafted dopamine (DA) neurons and processes in mesencephalic grafts and mesencephalic-striatal co-grafts implanted in the striatum of MPTP-treated African green monkeys. Grafted embryonic cerebellar tissue was used as a comparison graft type that does not normally exchange prominent direct projections with striatum. Dense pericellular arrays of SY-positive terminals were associated with TH-positive neurons in mesencephalic grafts. In mixed mesencephalic-striatal co-grafts, TH-positive fiber patches within the striatal portion of the graft demonstrated a high degree of correspondence with SY immunoreactivity. In contrast, grafts of cerebellar tissue did not display the same pattern of prominent pericellular arrays of SY staining. These observations suggest that functional synapses are abundantly present within grafted mesencephalon, and that these contacts are enriched in areas of the graft occupied by DA neurons. Implantation of an inappropriate striatal target, the cerebellum, results in visibly diminished innervation. The pattern of SY labeling observed suggests that tissue grafts are extensively innervated, probably both from extrinsic and intrinsic sources, and that the pattern and density of this innervation corresponds to the appropriateness of the graft-host interaction.

ential display-PCR indicated that the greatest number of absolute differences in PCR products was between Guard cell protoplasts (GCP) of Nicotiana glauca FGCP and Type II cells; the fewest number was (Graham), tree tobacco, were cultured at 32° Co r at between FGCP and Type IV cells. Both the blue light 38°C in media containing or lacking 0.1 mM ABA. Cells photoreceptor and the signal transduction pathway cultured at 32°C exhibited large increases in cell linking blue light photoreception to activation of the volume, dedifferentiated, and divided (Type II cells). plasma membrane H+-translocating ATPase of guard Cells cultured at 38°C increased less in volume, cells remain intact in cultured Type IV cells. Culture retained the general morphology of guard cells, and conditions alter both photochemical and nondid not divide (Type III cells). Cells cultured at 38°C photochemical processes of chloroplasts of Type III in media containing ABA (Type IV cells) neither grew and Type IV cells, but chloroplasts of Type IV cells nor divided; they retained the morphology of freshly- retain the capacity to acidify the thylakoid lumen to isolated GCP (FGCP). Experiments were performed to activate a functional violaxanthin-antheraxanthin determine the extent to which selected cell types de-epoxidase in the thylakoid membrane. The data retained certain physiological, biochemical, and support the hypothesis that each cell type exists in a molecular characteristics of FGCP. Type IV cells differentiated state more or less similar to that of increased in volume by ~40% when illuminated with FGCP, with Type II cells having the least similarity, low-intensity blue light (15 mmol m’2 s’1) over back- Type III cells having greater similarity, and Type IV ground red light (300 mmol m’2 s’1). Blue light-induced cells having the greatest similarity. swelling of GCP was inhibited fully by 10 mM m-chlorophenylhydrazone and 5 mM dithiothreitol. Chloroplasts Key words: Nicotiana, stomatal physiology, guard cell of Type II cells underwent senescence. The capacity protoplasts, plant cell culture, differentiation. of chloroplasts of Type III and Type IV cells for photochemical quenching of Chl a fluorescence was reduced compared to that of FGCP, and cultured cells Introduction lost all capacity for non-photochemical quenching. The guard cells that flank stomatal pores are diVerentiated Zeaxanthin (Z) has been identified as the putative blue from other plant cells both by their unique morphology

Reconsolidation-the stabilization of a memory after retrieval-is hypothesized to be a critical and distinct component of memory processing, the disruption of which results in memory impairment. In the rat, we found that activation of amygdalar protein kinase A (PKA) was sufficient to enhance memory only when it was retrieved; in contrast, PKA inhibition impaired reconsolidation. This study demonstrates both a selective enhancement and an impairment of memory reconsolidation dependent on amygdalar PKA.

Musculoskeletal disorders (MSDs) are a significant occupational health issue for the dental hygiene profession. There is increasing evidence that these problems commence during undergraduate training; however, there is a surprising lack of studies investigating how MSD develops in student groups over the course of their study. The aim of this study was to determine the longitudinal MSD trends among a cohort of undergraduate dental hygiene students at an Australian university.A previously validated self-reporting questionnaire was distributed to dental hygiene students in 3 consecutive years from 2008 to 2010.MSDs were most commonly reported in the neck (ranging from 66 to 68%) and lower back (ranging from 61 to 68%), with a marked increase in reported lower back pain by the final year of study.This study not only supports mounting evidence that MSDs are a common problem for dental hygiene students, but further demonstrates the magnitude of this occupational health issue across the training program. These findings are concerning for a group yet to embark on their professional careers, given that it raises some serious questions about career longevity and the efficacy of preventive measures.

The intracellular mechanisms underlying memory reconsolidation critically involve cAMP signaling. These events were originally attributed to PKA activation by cAMP, but the identification of Exchange Protein Activated by cAMP (Epac), as a distinct mediator of cAMP signaling, suggests that cAMP-regulated processes that subserve memory reconsolidation are more complex. Here we investigated how activation of Epac with 8-pCPT-cAMP (8-CPT) impacts reconsolidation of a memory that had been associated with cocaine self-administration. Rats were trained to lever press for cocaine on an FR-1 schedule, in which each cocaine delivery was paired with a tone+light cue. Lever pressing was then extinguished in the absence of cue presentations and cocaine delivery. Following the last day of extinction, rats were put in a novel context, in which the conditioned cue was presented to reactivate the cocaine-associated memory. Immediate bilateral infusions of 8-CPT into the basolateral amygdala (BLA) following reactivation disrupted subsequent cue-induced reinstatement in a dose-dependent manner, and modestly reduced responding for conditioned reinforcement. When 8-CPT infusions were delayed for 3 hours after the cue reactivation session or were given after a cue extinction session, no effect on cue-induced reinstatement was observed. Co-administration of 8-CPT and the PKA activator 6-Bnz-cAMP (10 nmol/side) rescued memory reconsolidation while 6-Bnz alone had no effect, suggesting an antagonizing interaction between the two cAMP signaling substrates. Taken together, these studies suggest that activation of Epac represents a parallel cAMP-dependent pathway that can inhibit reconsolidation of cocaine-cue memories and reduce the ability of the cue to produce reinstatement of cocaine-seeking behavior.

Differential screening of a cDNA library generated from RNA extracted from ethylene-treated leaflet abscission zones of Sambucus nigra resulted in the isolation of 20 abscission-related clones. These clones could be grouped into seven families. Sequencing of members of these families revealed that the majority encoded pathogenesis-related (PR) proteins, and these could be identified by sequence homology as a polyphenol oxidase (PPO), a PR-1 type protein, a Chial type chitinase, a PR-4 type protein similar to the potato win peptides, a PR-6 type proteinase inhibitor, a Chia4 type chitinase and a metallothionein-like protein (Coupe, Taylor & Roberts 1995, Planta 197, 442–447). Northern analysis revealed that these mRNAs were not expressed in freshly excised material but accumulated primarily in the abscission zone tissue after 18 h of exposure to ethylene at a time when abscission of the leaflet explants had reached 70%. Expression of the PPO and the Chia4-type chitinase was ethylene-dependent while that of the PR-4 type was up-regulated in the abscission zone tissue in the absence of the gas. The characterization of these mRNAs and their encoded proteins is presented and their possible roles during abscission are discussed.

Although previous research has emphasized the beneficial effects of dopamine (DA) on functions of the prefrontal cortex (PFC), recent studies of animals exposed to mild stress indicate that excessive DA receptor stimulation may be detrimental to the spatial working memory functions of the PFC (Arnsten and Goldman-Rakic, 1990; Murphy et al., 1994, 1996a,b, 1997). In particular, these studies have suggested that supranormal stimulation of D1receptors may contribute to the detrimental actions of DA in the PFC (Murphy et al., 1994, 1996a). The current study directly tested this hypothesis by examining the effects of infusing a full D1receptor agonist, SKF 81297, into the PFC of rats performing a spatial working memory task, delayed alternation. SKF 81297 produced a dose-related impairment in delayed-alternation performance. The impairment was reversed by pretreatment with a D1receptor antagonist, SCH 23390, consistent with drug actions at D1receptors. SCH 23390 by itself had no effect on performance, although slightly higher doses impaired performance (Murphy et al., 1994, 1996a). There was a significant relationship between infusion location and drug efficacy; animals with cannulae anterior to the PFC were not impaired by SKF 81297 infusions. Taken together, these results demonstrate that supranormal D1receptor stimulation in the PFC is sufficient to impair PFC working memory function. These cognitive data are consistent with recent electrophysiological studies of D1receptor mechanisms affecting the PFC (Williams and Goldman-Rakic, 1995; Yang and Seamans, 1996). Increased D1receptor stimulation during stress may serve to take the PFC “off-line” to allow posterior cortical and subcortical structures to regulate behavior, but may contribute to the vulnerability of the PFC in many neuropsychiatric disorders.

Histochemistry for visualization of the mitochondrial enzyme cytochrome oxidase has been used to detect cellular and regional differences in brain energy metabolism. We have examined the pattern of cytochrome oxidase (CO) staining in grafts of embryonic ventral mesencephalic tissue, and in the implanted striatum, of MPTP-treated monkeys as one index of the functional activity of grafted tissue and its influence on the host brain. Four monkeys were selected for study based on interesting variations in dopamine (DA) neuron content of their bilateral grafts as demonstrated with tyrosine-hydroxylase (TH) immunocytochemistry. The results suggest that grafts rich in DA neurons increase the metabolic activity of the implanted striatum of DA-depleted monkeys, and that this improvement of local energy metabolism is greater in the vicinity of grafts containing greater numbers of DA neurons. In addition, the pattern of CO staining within tissue transplants indicates that DA neurons exhibit the highest rate of metabolic activity among all cell types contained in the ventral mesencephalic grafts, and that the transplants receive metabolically active innervation from outside or within the grafted tissue.

A cDNA clone (TAB7) encoding a putative wound-induced (Win) protein has been isolated from a tomato (Lycopersicon esculentum Mill. cv. Ailsa Craig) leaf abscission zone cDNA library using a differential screening strategy. The clone has a high degree of homology at the amino acid level to both the potato win1 and 2 genes, Hevea brasiliensis hevein and Nicotiana tabacum PR-4a and PR-4b proteins. The mRNA encoded by TAB7 is up-regulated within 12 h of exposure to ethylene (10 μl l -1 ) and its expression increases steadily within the cells comprising the leaf abscission zone and to a lesser extent in the adjacent non-zone tissue. This rise precedes the onset of cell separation. Southern analysis indicates that the mRNA is encoded by either a single gene or a small gene family. The role of the protein during abscission is discussed.

Schizophrenia is a disorder characterized by positive, negative, and cognitive symptoms. While positive symptoms can be effectively treated with typical antipsychotic medication, which generally affects the dopaminergic system, negative and cognitive symptoms, including attentional deficits and impulsive behavior, are less sensitive to standard treatments. It has further been well documented that schizophrenic patients use tobacco products at a rate much higher than the general population, and this persists despite treatment. It has been argued this behavior may be a form of self-medication, to alleviate some symptoms of schizophrenia. It has further been posited that prefrontal glutamatergic hypofunction may underlie some aspects of schizophrenia, and in accordance with this model, systemic phencyclidine has been used to model the disease. We employed a modified 5-choice serial reaction time test, a paradigm that is often used to investigate many of the treatment-resistant symptoms of schizophrenia including impulsivity, selective attention, and sustained attention/cognitive vigilance, to determine the medicinal effects of nicotine. We demonstrate that chronic oral, but not acute injections of, nicotine can selectively attenuate phencyclidine-induced increases in impulsivity without affecting other measures of attention. This suggests that nicotine use by schizophrenics may provide some relief of distinct symptoms that involve impulsive behaviors.

Delusions are the persistent and often bizarre beliefs that characterise psychosis. Previous studies have suggested that their emergence may be explained by disturbances in prediction error-dependent learning. Here we set up complementary studies in order to examine whether such a disturbance also modulates memory reconsolidation and hence explains their remarkable persistence. First, we quantified individual brain responses to prediction error in a causal learning task in 18 human subjects (8 female). Next, a placebo-controlled within-subjects study of the impact of ketamine was set up on the same individuals. We determined the influence of this NMDA receptor antagonist (previously shown to induce aberrant prediction error signal and lead to transient alterations in perception and belief) on the evolution of a fear memory over a 72 hour period: they initially underwent Pavlovian fear conditioning; 24 hours later, during ketamine or placebo administration, the conditioned stimulus (CS) was presented once, without reinforcement; memory strength was then tested again 24 hours later. Re-presentation of the CS under ketamine led to a stronger subsequent memory than under placebo. Moreover, the degree of strengthening correlated with individual vulnerability to ketamine's psychotogenic effects and with prediction error brain signal. This finding was partially replicated in an independent sample with an appetitive learning procedure (in 8 human subjects, 4 female). These results suggest a link between altered prediction error, memory strength and psychosis. They point to a core disruption that may explain not only the emergence of delusional beliefs but also their persistence.

One strategy proposed to treat addictive disorders is to extinguish the association between environmental stimuli (cues) and actions associated with drug use to reduce relapse. The context specificity of extinction learning, however, impairs the ability of addicts to generalize extinction training to the drug-taking context. We previously reported that the NMDA receptor partial agonistd-cycloserine administered after pavlovian extinction of cocaine cues in the nucleus accumbens core (NAc) reduced cue-induced renewal. Nevertheless, it was unclear whether this was due to disrupted contextual encoding of extinction or enhanced extinction consolidation. Thus, we examined the effect of the NMDA receptor antagonistd-AP5 on context encoding versus cue extinction learning. We also determined the role of the anterior cingulate cortex (ACC) in encoding the cue extinction memory or the context, due to its projections to NAc, and hypothesized the role in conflict monitoring and contextual modulation of decision making. Using rats, we observed that NMDA receptor antagonism in the NAc did not alter context encoding but did interfere with acquisition of the cue extinction memory, i.e., learning, conversely inactivation of the ACC reduced the contextual encoding of extinction but did not interfere with the acquisition or expression of extinction. The observed effects were not present in the absence of cue extinction training. Additionally, the contextual memory did not appear to be consolidated in the ACC as neither postsession inactivation nor protein synthesis inhibition impaired context-appropriate responding. These results have implications for overcoming the context specificity of extinction to treat psychiatric disorders including addiction.

Transplantation of fetal dopamine neurons to the adult striatum potentially offers a means to reverse the striatal dopamine deficiency that characterizes Parkinson's disease. Many investigations in rodents have supported the hope that neural grafting may be a useful treatment for parkinsonism. However, clinical studies have generally produced more modest improvements in motor abnormalities than observed in lower species. It is possible that the number of fetal dopamine neurons that survive transplantation is insufficient to restore dopaminergic innervation of the large human striatum to a level where striking recovery is obtained. In fact, there has been no quantitative study of graft outgrowth to indicate what portion of the dopamine-depleted striatum might be reinner-vated with present techniques. Furthermore, it has been speculated that regeneration of the host dopamine system in response to the implantation surgery may play an important role in the beneficial effects of neural grafting in primates. The present study used nine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian monkeys to investigate these issues. Sham implantation procedures produced no increase in either dopamine transporter density (measured by quantitative autoradiography) or tissue dopamine concentration (measured by HPLC) in the striatum of MPTP-treated monkeys. In sham-grafted and nonimplanted MPTP-treated monkeys, the striatal dopamine concentration was reduced by 99%, based on analysis of 16 sampled sites in the caudate nucleus and putamen of each monkey. No behavioral recovery was seen in the sham-grafted and nonimplanted MPTP-treated groups. In contrast, transplantation of fetal dopamine neurons to the caudate nucleus or putamen of MPTP-treated monkeys resulted in a significant elevation of dopamine transporter density and dopamine levels in the grafted striatal nucleus. Each grafted MPTP-treated monkey received ventral mesencephalon dopamine neurons from one donor harvested during putative neurogenesis. Donor ventral mesencephalon was divided equally and implanted into six sites either in the caudate nucleus or putamen. One graft site in each monkey was examined by dopamine transporter autoradiography. In sections in which graft fibers were present, a mean of one-third of the volume of the grafted nucleus was occupied by an elevated density of dopamine transporters. This increase in dopamine transporter density was defined to be at least 5-10% of the control density. However, full behavioral recovery was not observed in the grafted MPTP-treated group. These data provide no support for the hypothesis that regeneration of the host dopamine system occurs in response to a sham implantation procedure in severely parkinsonian monkeys. The current study illustrates the power of the applied techniques for delineating the relationship between the level of host dopamine depletion, the extent of graft-induced dopaminergic restoration, and behavioral recovery.

The alkylation of (2R,4S)-3-benzoyl-4-benzyl-2-phenyloxazolidin-5-one 7 with diphenylmethyl bromoacetate proceeded with high diastereoselectivity, and the resulting product was hydrolysed to give [(2′R,4′S)-3′-benzoyl-4′benzyl-5′-oxo-2′-phenyloxazolidin-4′-yl]acetic acid 9. The self-addition by-product (2R,4S,1′S)-3-benzoyl-4-[benzoylamino(phenyl)methyl]-4-benzyl-2-phenyl-1,3-oxazolidin-5-one 11 was also isolated. The structures of compound of 11 and the related self-addition products (2R,4S,1′S and 1′R)-3-benzoyl-4-[benzoylamino(phenyl)methyl]-4-isopropyl-2-phenyl-1,3-oxazolidin-5-one 20 and 21 were determined by X-ray crystallography. The mechanism of formation of the self-addition products is discussed.

What is the future of copyright and authors’ rights in the light of what is being called “the digital information society?”It is generally recognised that the law responds to a given situation: if the legal fraternity doesn't take the time to observe and understand what is actually happening, it will be almost impossible to ascertain where and what the problems are. Only by careful observation can the lawmakers suggest possible solutions and appreciate their value.

Memories represent a means through which we bring to bear past experience on current processing in order to respond adaptively and predict the future. One process that reflects this utility is reconsolidation. When memories are retrieved, they sometimes return into a labile state so that they can be updated and consolidated anew. This represents a potential therapeutic window for illnesses in which memory processing has gone awry; that is, it might be possible to render memories labile and excise the aberrant and maladaptive. In this chapter, we discuss this opportunity with regard to serious mental illnesses such as post-traumatic stress disorder, psychosis, and drug addiction. Although the preclinical data are promising, that preclinical potential has yet to be realized. We discuss some of the ethical implications of memory erasure as well as some of the practical impediments to this approach.

Alkylation of the (S)-phenylalanine-derived syn-oxazolidinone 8 with BrCH2CO2CHPh2 gave compound 9, a key precursor to the β-keto ester 11 and the keto acid phosphorane 17. Compound 17 gave the enolactone 24 on heating and the bromo enolactones 19 and 20 on treatment with bromine and triethylamine. Compounds 11, 19, 20 and 24 were treated with glycine ethyl ester to give the Phe-Gly dipeptide mimics 22, 23 and 26. The enolactone 24 also gave the Phe-Ala mimic 39 and the Phe-Gly-Gly mimic 34.

The Oxford English Dictionary defines crosstalk as 'unwanted transfer of signals between communication channels'. How does this definition relate to the way in which we view the organization and function of signalling pathways? Recent advances in the field of plant signalling have challenged the traditional view of a signalling transduction cascade as isolated linear pathways. Instead the picture emerging of the mechanisms by which plants transduce environmental signals is of the interaction between transduction chains. The manner in which these interactions occur (and indeed whether the transfer of these signals is 'unwanted' or beneficial) is currently the topic of intense research.

Child neglect is the most prevalent form of child maltreatment in the United States, and poses a serious public health concern. Children who survive such episodes go on to experience long-lasting psychological and behavioral problems, including higher rates of post-traumatic stress disorder symptoms, depression, alcohol and drug abuse, attention-deficit/hyperactivity disorder, and cognitive deficits. To date, most research into the causes of these life-long problems has focused on well-established targets such as stress responsive systems, including the hypothalamus–pituitary–adrenal axis. Using the maternal separation and early weaning model, we have attempted to provide comprehensive molecular profiling of a model of early-life neglect in an organism amenable to genomic manipulation: the mouse. In this article, we report new findings generated with this model using chromatin immunoprecipitation sequencing, diffuse tensor magnetic resonance imaging, and behavioral analyses. We also review the validity of the maternal separation and early weaning model, which reflects behavioral deficits observed in neglected humans including hyperactivity, anxiety, and attentional deficits. Finally, we summarize the molecular characterization of these animals, including RNA profiling and label-free proteomics, which highlight protein translation and myelination as novel pathways of interest.

While placements in external locations are being increasingly used in dental education globally, few studies have explored the student learning experience at such placements. The purpose of this study was to investigate student experiences while on external placement in a baccalaureate dental hygiene program. A self-reporting questionnaire was distributed to final-year dental hygiene students (n=77) at the University of Newcastle, Australia, in 2010. The questionnaire included questions regarding the type of placement, experiences offered, supervision, resources available, and lasting impressions. Responding students were generally positive about their external placement experience and indicated that the majority of facilities provided them with the opportunity to provide direct patient care and perform clinical tasks typical of a practicing hygienist. However, there was a statistically significant difference in their opinions about discipline-focused and community placements. Students indicated that their external placement experience provided opportunities to learn more about time and patient management, including hands-on experience with specific clinical tasks. Ongoing evaluations are necessary to ensure that external placements meet both student needs and intended learning outcomes within dental hygiene programs.

Cyclic AMP response element binding protein (CREB) plays a critical role in fear memory formation. Here we determined the role of CREB selectively within the amygdala in reconsolidation and extinction of auditory fear. Viral overexpression of the inducible cAMP early repressor (ICER) or the dominant-negative mCREB, specifically within the lateral amygdala disrupted reconsolidation of auditory fear memories. In contrast, manipulations of CREB in the amygdala did not modify extinction of fear. These findings suggest that the role of CREB in modulation of memory after retrieval is dynamic and that CREB activity in the basolateral amygdala is involved in fear memory reconsolidation.

Integrins are heterodimeric extracellular matrix receptors that are essential for the proper development of the vertebrate nervous system. We report here that selective loss of integrin β1 in excitatory neurons leads to reductions in the size and complexity of hippocampal dendritic arbors, hippocampal synapse loss, impaired hippocampus-dependent learning, and exaggerated psychomotor sensitivity to cocaine in mice. Our biochemical and genetic experiments demonstrate that the intracellular tail of integrin β1 binds directly to Arg kinase and that this interaction stimulates activity of the Arg substrate p190RhoGAP, an inactivator of the RhoA GTPase. Moreover, genetic manipulations that reduce integrin β1 signaling through Arg recapitulate the integrin β1 knock-out phenotype in a gene dose-sensitive manner. Together, these results describe a novel integrin β1–Arg–p190RhoGAP pathway that regulates dendritic arbor size, promotes synapse maintenance, supports proper hippocampal function, and mitigates the behavioral consequences of cocaine exposure.

Finding effective long-lasting treatments for drug addiction has been an elusive goal. Consequently, researchers are beginning to investigate novel treatment strategies including manipulations of drug-associated memories. When environmental stimuli (cues) become associated with drug use, they become powerful motivators of continued drug use and relapse after abstinence. Reducing the strength of these cue–drug memories could decrease the number of factors that induce craving and relapse to aid in the treatment of addiction. Enhancing the consolidation of extinction learning and/or disrupting cue–drug memory reconsolidation are two strategies that have been proposed to reduce the strength of cues in motivating drug-seeking and drug-taking behavior. Here, we review the latest basic and clinical research elucidating the mechanisms underlying consolidation of extinction and reconsolidation of cue–drug memories in the hopes of developing pharmacological tools that exploit these signaling systems to treat addiction.

Regulator of calmodulin (CaM) signaling (RCS), when phosphorylated by protein kinase A (PKA) on Ser55, binds to CaM and inhibits CaM-dependent signaling. RCS expression is high in the dorsal striatum, nucleus accumbens and amygdala, suggesting that the protein is involved in limbic-striatal function. To test this hypothesis, we examined RCS knockout (KO) mice in behavioral models dependent on these brain areas. Mice were tested for food-reinforced instrumental conditioning and responding under a progressive ratio (PR) schedule of reinforcement and in models of anxiety (elevated plus maze and open field). While RCS KO mice showed normal acquisition of a food-motivated instrumental response, they exhibited a lower breakpoint value when tested on responding under a PR schedule of reinforcement. RCS KO mice also displayed decreased exploration in both the open arms of an elevated plus maze and in the center region of an open field, suggesting an enhanced anxiety response. Biochemical studies revealed a reduction in the levels of dopamine and cAMP-regulated phosphoprotein (DARPP-32) in the striatum of RCS KO mice. DARPP-32 is important in reward-mediated behavior, suggestive of a possible role for DARPP-32 in mediating some of the effects of RCS. Together these results implicate a novel PKA-regulated phosphoprotein, RCS, in the etiology of motivational deficits and anxiety.

A cDNA library was produced using mRNA extracted from ethylene-treated leaflet abscission zones of common elder (Sambucus nigra). Screening of the library with the insert from pBAC10, which encodes an abscission beta-1,4-glucanase (cellulase) from bean (Phaseolus vulgaris), resulted in the isolation of a near-full-length cDNA which was designated JET 1. Northern analysis, using JET 1 as a probe, detected a transcript of 1.9 kb that accumulated prior to the first visible signs of cell separation. Accumulation of the JET 1 transcript is promoted by ethylene and primarily restricted to the tissue comprising the abscission zone. Sequence analysis of JET 1 indicates it is 1768 bp in length and shares significant homology at the amino acid level with beta-1,4-glucanases from the leaf abscission zone of P. vulgaris (67%) and ripening avocado fruit (48%). The predicted peptide sequence of the S. nigra enzyme contains two potential glycosylation sites. Genomic Southern analysis of S. nigra DNA reveals that JET 1 may belong to a multi-gene family.

Aging in humans is associated with parallel changes in cognition, motivation, and motoric performance. Based on the human aging literature, we hypothesized that this constellation of age-related changes is mediated by the medial prefrontal cortex and that it would be observed in aging mice. Toward this end, we performed detailed assessments of cognition, motivation, and motoric behavior in aging mice. We assessed behavioral and cognitive performance in C57Bl/6 mice aged 6, 18, and 24 months, and followed this with microarray analysis of tissue from the medial prefrontal cortex and analysis of serum cytokine levels. Multivariate modeling of these data suggested that the age-related changes in cognition, motivation, motor performance, and prefrontal immune gene expression were highly correlated. Peripheral cytokine levels were also correlated with these variables, but less strongly than measures of prefrontal immune gene upregulation. To determine whether the observed immune gene expression changes were due to prefrontal microglial cells, we isolated CD11b-positive cells from the prefrontal cortex and subject them to next-generation RNA sequencing. Many of the immune changes present in whole medial prefrontal cortex were enriched in this cell population. These data suggest that, as in humans, cognition, motivation, and motoric performance in the mouse change together with age and are strongly associated with CNS immune gene upregulation.

While the behavioral effects of cocaine are generally ascribed to its ability to inhibit the uptake of dopamine, there is evidence to indicate that some of the other pharmacological properties of cocaine may play a significant role in its actions. Behavioral, biochemical, and electrophysiological data suggest that the potent inhibition of serotonin uptake elicited by cocaine is a mechanism that may contribute to its overall effects in vivo. Cocaethylene is the ethyl ester of benzoylecognine which is formed in vivo during concurrent ingestion of cocaine and ethanol. Cocaethylene is equipotent with cocaine as an inhibitor of dopamine uptake, but less potent as an inhibitor of serotonin uptake. We have compared the effects of acute and chronic cocaine and cocaethylene on rat locomotor activity in an attempt to determine the serotonin component in this behavior. Acute dose-response studies revealed that at higher doses (20 mg/kg ip) cocaethylene produced less stimulation of locomotor activity than cocaine. Prior exposure to cocaine resulted in an augmented response to a subsequent challenge dose of either cocaine (sensitization) or cocaethylene (cross-sensitization). However, previous treatment with cocaethylene did not significantly affect the locomotor activity produced by challenges with cocaethylene or cocaine. The involvement of serotonergic systems in the development of cocaine-induced sensitization is one intriguing possible explanation of these data. Biochemical studies have shown that other cocaine analogs possess even more selectivity for the dopamine uptake site than cocaethylene. In terms of comparative potency as inhibitors of dopamine, serotonin, and norepinephrine uptake, isopropylcocaine (isopropyl ester of benzoylecognine) is more selective than even cocaethylene. A metabolically resistant analog of cocaine, β-CIT (2β-carbomethoxy-3β-(4-iodophenyl)tropane), was shown to be extraordinarily long-acting, stimulating locomotor activity for 10 h following a dose of 0.1 mg/kg ip. Furthermore, β-CIT was extremely potent, inhibiting dopamine or serotonin uptake in vitro at a concentration 100 times lower than is required for cocaine. Thus, isopropyl or other substitutions at the carbomethoxy position of the cocaine or β-CIT structures may provide useful tools for the analysis of the serotonin or norepinephrine components in cocaine's actions and as selective probes of central dopamine systems in imaging studies. © 1993 wiley-Liss, Inc.

Each of the myogenic helix-loop-helix transcription factors (MyoD, Myogenin, Myf-5, and MRF4) is capable of activating muscle-specific gene expression, yet distinct functions have not been ascribed to the individual proteins. We report here that MyoD and Myogenin mRNAs selectively accumulate in hindlimb muscles of the adult rat that differ in contractile properties: MyoD is prevalent in fast twitch and Myogenin in slow twitch muscles. The distribution of MyoD and Myogenin transcripts also differ within a single muscle and correlate with the proportions of fast glycolytic and slow oxidative muscle fibres, respectively. Furthermore, the expression of a transgene consisting of a muscle-specific cis-regulatory region from the myoD gene controlling lacZ was primarily associated with the fast glycolytic fibres. Alteration of the fast/slow fibre type distribution by thyroid hormone treatment or by cross-reinnervation resulted in a corresponding alteration in the MyoD/Myogenin mRNA expression pattern. These findings show that the expression of specific myogenic helix-loop-helix regulators is under the control of innervation and humoral factors and may mediate differential control of contractile protein gene expression in adult muscle.

1. In 1989, mental illness costs increased an estimated 57% compared with a 17% increase in overall medical costs. Almost one half of U.S. workers felt stressed in 1991, and one fourth believed they suffered from work related illnesses. 2. The goal of health care cost management is to eliminate unnecessary and ineffective care. 3. Mental health/chemical dependency strategies should be integrated into an organization's other prevention programs. 4. A mental health plan must be designed in keeping with the individual nature of mental illness.

Leaflet abscission in Sambucus nigra is the result of cell wall breakdown at the site of separation. Associated with wall degradation is an increase in the activity of the enzyme β1,4 glucanase (E.C.3.1.2.4) in the cells that comprise the abscission zone. The enzyme has been extracted from abscission zone tissue and purified using a substrate affinity column. A qualitative enzyme assay procedure has been developed and this has facilitated the purification process. The β1,4 glucanase enzyme has a pH optimum of 7 and a molecular mass of 54kDa. Antibodies have been raised to the purified protein. The role of the enzyme in the abscission process is discussed.

Halolactonization of the keto acid phosphoranes 6a-f, 40, and 41 takes place with either Br 2 or SO 2 Cl 2 and Et 3 N to give the E- and Z-halo enol lactones 10-15, 42, and 43 in good yields. The cyclization proceeds via a halo phosphonium salt, e.g. 19. Halo phosphonium salts yield a halo allene when cyclization is not favoured as in the formation of the bromoallenes 24 and 37. The configuration of the halo enol lactones was determined by 1 H and 13 C NMR spectroscopy and via single-crystal X-ray determinations on 11a, 14c, and 42b. The barrier to interconversion of the biphenyl conformations of the bromo enol lactaones 42b and 43b was determined by 1 H NMR spectroscopy at elevated temperatures

Leaflet abscission in Sambucus nigra is precipitated by cell wall degradation which is restricted to the site of cell separation. Accompanying wall breakdown is an increase in the activity of the enzyme polygalacturonase (PG) (E.C. 3.2.1.15) and this rise is primarily confined to the abscission zone tissue. The polygalacturonase has a pH optimum of 4·4 and has the characteristics of an endo-acting enzyme. The elevation in enzyme activity is the result of an increase in at least two isoforms of PG as revealed by polyacrylamide gel electrophoresis of the natured protein. Leaflet abscission in S. nigra is associated with an increase in the solubility and depolymerization of polyuronides from the cell wall. These observations are discussed in relation to the mechanism of cell separation during ethylene-stimulated leaf abscission.

Evaluation of the behavioral “costs,” such as effort expenditure relative to the benefits of obtaining reward, is a major determinant of goal-directed action. Neuroimaging evidence suggests that the human medial orbitofrontal cortex (mOFC) is involved in this calculation and thereby guides goal-directed and choice behavior, but this region's functional significance in rodents is unknown despite extensive work characterizing the role of the lateral OFC in cuerelated response inhibition processes. We first tested mice with mOFC lesions in an instrumental reversal task lacking discrete cues signaling reinforcement; here, animals were required to shift responding based on the location of the reinforced aperture within the chamber. Mice with mOFC lesions acquired the reversal but failed to inhibit responding on the previously reinforced aperture, while mice with prelimbic prefrontal cortex lesions were unaffected. When tested on a progressive ratio schedule of reinforcement, mice with prelimbic cortical lesions were unable to maintain responding, resulting in declining response levels. Mice with mOFC lesions, by contrast, escalated responding. Neither lesion affected sensitivity to satiety-specific outcome devaluation or non-reinforcement (i.e., extinction), and neither had effects when placed after animals were trained on a progressive ratio response schedule. Lesions of the ventral hippocampus, which projects to the mOFC, resulted in similar response patterns, while lateral OFC and dorsal hippocampus lesions resulted in response acquisition, though not inhibition, deficits in an instrumental reversal. Our findings thus selectively implicate the rodent mOFC in braking reinforced goal-directed action when reinforcement requires the acquisition of novel response contingencies.

The 100 billion neurons comprising the human brain are wired together using structural extensions termed axons, dendrites and dendritic spines. Addictive drugs remodel dendritic spine structure in certain brain regions and with repeated exposure, induce psychomotor sensitization and impair behavioral flexibility. We recently reported that low-dose cocaine exposure, in combination with knockout of Arg—an adhesion-regulated nonreceptor tyrosine kinase that stabilizes neuronal shape starting in adolescence—recapitulates both features of chronic drug exposure in rodents. In light of these and other recent findings in the field, we suggest that cell adhesion receptors and their downstream cytoskeletal effectors act as “first responders” to psychostimulant exposure. In this model, cell adhesion factors act to stabilize existing dendritic spines in response to cocaine, and reduced expression/function is expected to increase vulnerability. Moreover, this model anticipates that increased sensitivity to psychostimulants in adolescence relates to neuronal pruning processes that occur during this developmental period.

Halolactonization of the keto acid phosphoranes 6a-f, 40, and 41 takes place with either Br 2 or SO 2 Cl 2 and Et 3 N to give the E- and Z-halo enol lactones 10-15, 42, and 43 in good yields. The cyclization proceeds via a halo phosphonium salt, e.g. 19. Halo phosphonium salts yield a halo allene when cyclization is not favoured as in the formation of the bromoallenes 24 and 37. The configuration of the halo enol lactones was determined by 1 H and 13 C NMR spectroscopy and via single-crystal X-ray determinations on 11a, 14c, and 42b. The barrier to interconversion of the biphenyl conformations of the bromo enol lactaones 42b and 43b was determined by 1 H NMR spectroscopy at elevated temperatures

Extinction therapy has been proposed as a method to reduce the motivational impact of drug-associated cues to prevent relapse. Cue extinction therapy, however, takes place in a novel context (e.g., treatment facility), and is unlikely to be effective due to the context specificity of extinction. We tested the hypothesis thatd-cycloserine (DCS), which enhances extinction in other procedures, would enhance extinction of cocaine-associated cues in a novel context to reduce cue-induced reinstatement. Male Sprague Dawley rats were trained to self-administer cocaine associated with a cue. The cue was later extinguished in the drug-taking context (context A) or a novel context (context B) using a Pavlovian cue extinction procedure designed to mimic human cue exposure therapy. DCS was administered systemically or into a specific brain region immediately following the cue extinction sessions to enhance the consolidation of extinction learning. We demonstrate that DCS given postextinction session in context B reduces reinstatement in context A, indicating a reduction in the context specificity of extinction learning. The effect of systemic DCS was recapitulated by administration of DCS into the nucleus accumbens core, but not in the basolateral amygdala, dorsal hippocampus, infralimbic or prelimbic prefrontal cortex. DCS treatment caused a reduction in cue-induced reinstatement only when it was given after cue extinction sessions, and not when given 1) in the absence of extinction or 2) after a brief memory reactivation session. A pharmacological method that can render extinction context independent may provide an innovative method to reduce cue-induced relapse in addicts and to study the neurobiology of addiction.

Drug use disorders are often accompanied by deficits in the capacity to efficiently process reward-related information and to monitor, suppress, or override reward-controlled behavior when goals are in conflict with aversive or immediate outcomes. This emerging deficit in behavioral flexibility and impulse control may be a central component of the progression to addiction, as behavior becomes increasingly driven by drugs and drug-associated cues at the expense of more advantageous activities. Understanding how neural mechanisms implicated in impulse control are affected by addictive drugs may therefore prove a useful strategy in the search for new treatment options. Animal models of impulsivity and addiction could make a significant contribution to this endeavor. Here, some of the more common behavioral paradigms used to measure different aspects of impulsivity across species are outlined, and the importance of the response to reward-paired cues in such paradigms is discussed. Naturally occurring differences in forms of impulsivity have been found to be predictive of future drug self-administration, but drug exposure can also increase impulsive responding. Such data are in keeping with the suggestion that impulsivity may contribute to multiple stages within the spiral of addiction. From a neurobiological perspective, converging evidence from rat, monkey, and human studies suggest that compromised functioning within the orbitofrontal cortex may critically contribute to the cognitive sequelae of drug abuse. Changes in gene transcription and protein expression within this region may provide insight into the mechanism underlying drug-induced cortical hypofunction, reflecting new molecular targets for the treatment of uncontrolled drug-seeking and drug-taking behavior.

Drug addiction is a chronic disorder associated with recurrent craving and relapse often precipitated by the presence of drug-associated stimuli. Pharmacological and behavioral treatments that disrupt drug-associated stimulus memories could be beneficial in the treatment of addictive disorders. Memory restabilization (or reconsolidation) following retrieval of drug-paired stimuli depends upon the amygdala. Here we assessed whether amygdalar PKA is required for the reconsolidation of an appetitive, cocaine-paired stimulus. Rats were trained to lever press for intravenous cocaine infusions paired with a light/tone conditioned stimulus. After 12 d of acquisition, rats either underwent lever extinction (8–12 d) followed by light/tone reactivation and subsequent cue-induced and cocaine-induced (15 mg/kg, i.p.) reinstatement testing or were subsequently tested to assess the ability of the light/tone stimulus to serve as a conditioned reinforcer in the acquisition of a new instrumental response (nose poking). Bilateral intra-amygdalar infusions of the PKA inhibitor Rp-cAMPS (18 μg per side) given immediately following light/tone stimulus reactivation decreased subsequent cue-induced reinstatement and responding with a conditioned reinforcer, while having no effect on cocaine-induced reinstatement. Intra-amygdalar infusions of Rp-cAMPS made 3 h following reactivation or immediately following no stimulus reactivation had no effect on subsequent cue-induced reinstatement. These data show that memory reconsolidation for a cocaine-paired stimulus is retrieval dependent and time limited and critically depends upon amygdalar PKA.