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Rachael L Neve

Publications and source records attributed to Rachael L Neve.

At least 19 recordsLinked to original sources
PubMed2026

E2F3a transcription factor mediates behavioral, cellular, and DNA-protein regulation of cocaine reward in the nucleus accumbens.

Drug addiction is characterized by orchestrated transcriptional changes in brain reward regions, including the nucleus accumbens (NAc). The transcription factor E2F3a has emerged as a novel regulator of cocaine's rewarding effects, yet its sex- and cell-specific mechanisms, as well as its genome-wide targets, remain undetermined. Here, we investigated the motivational and reinforcing roles of E2F3a in cocaine reward using conditioned place preference (CPP) and self-administration, combined with behavioral economics and viral-mediated gene manipulation. Selective overexpression of E2F3a in D1-type medium spiny neurons (MSNs), but not D2-MSNs, increased cocaine CPP in both male and female mice, whereas knockdown produced the opposite effects. Behavioral economics analyses further revealed that E2F3a regulates specific aspects of cocaine reinforcement. Genome-wide mapping revealed increased E2F3a binding to DNA at genes associated with cocaine exposure. Together, these results establish E2F3a as a central substrate of cocaine reward via the recruitment of D1-MSNs and coordinated expression of both proven and new molecular drivers.

Journal Article↗
PubMed2006

IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates.

Chronic morphine administration (via subcutaneous pellet) decreases the size of dopamine neurons in the ventral tegmental area (VTA), a key reward region in the brain, yet the molecular basis and functional consequences of this effect are unknown. In this study, we used viral-mediated gene transfer in rat to show that chronic morphine-induced downregulation of the insulin receptor substrate 2 (IRS2)-thymoma viral proto-oncogene (Akt) signaling pathway in the VTA mediates the decrease in dopamine cell size seen after morphine exposure and that this downregulation diminishes morphine reward, as measured by conditioned place preference. We further show that the reduction in size of VTA dopamine neurons persists up to 2 weeks after morphine withdrawal, which parallels the tolerance to morphine's rewarding effects caused by previous chronic morphine exposure. These findings directly implicate the IRS2-Akt signaling pathway as a critical regulator of dopamine cell morphology and opiate reward.

Animals↗
PubMed2006

Brain reward regulated by AMPA receptor subunits in nucleus accumbens shell.

Drugs of abuse alter expression of AMPA-type glutamate receptor subunits (GluRs) in the nucleus accumbens (NAc), a key component of brain reward systems. The impact of this regulation on general motivational states is unclear. Here, we used herpes simplex virus vectors to examine how transient increases in the expression of GluR1 or GluR2 protein in the shell component of NAc affect the rewarding impact of electrical stimulation of the medial forebrain bundle, as reflected by intracranial self-stimulation (ICSS) thresholds in rats. We found that elevated GluR1 in NAc shell increases ICSS thresholds, an effect similar to that caused by treatments that cause anhedonia and dysphoria (prodepressive effects) in rats and humans (e.g., drug withdrawal, kappa-opioid agonists). In contrast, elevated GluR2 decreases ICSS thresholds, an effect similar to that caused by rewarding treatments (e.g., drugs of abuse). To confirm that viral vector-mediated elevations of GluR1 in the NAc shell produce molecular consequences that are different from those of elevated GluR2, we examined the expression of a set of drug-regulated genes 3 d after treatment using quantitative PCR. Elevated GluR1 was accompanied by sustained increases in the gene for GluR1, whereas elevated GluR2 was accompanied by decreases in prodynorphin. These data suggest that GluR1 and GluR2 in the NAc shell play opposing roles in the regulation of motivated behavior.

Analysis of Variance↗
PubMed2006

Dysfunction of amyloid precursor protein signaling in neurons leads to DNA synthesis and apoptosis.

The classic neuropathological diagnostic markers for AD are amyloid plaques and neurofibrillary tangles, but their role in the etiology and progression of the disease remains incompletely defined. Research over the last decade has revealed that cell cycle abnormalities also represent a major neuropathological feature of AD. These abnormalities appear very early in the disease process, prior to the appearance of plaques and tangles; and it has been suggested that neuronal cell cycle regulatory failure may be a significant component of the pathogenesis of AD. The amyloid precursor protein (APP) is most commonly known as the source of the beta-amyloid (Abeta) peptides that accumulate in the brains of patients with AD. However, a large body of work supports the idea that APP is also a signaling receptor. Most recently, it has been shown that familial AD (FAD) mutations in APP or simple overexpression of wild type APP cause dysfunction of APP signaling, resulting in initiation of DNA synthesis in neurons and consequent apoptosis. In this article, we review the evidence that APP has the potential to activate aberrant neuronal cell cycle re-entry in AD, and we describe a signal transduction pathway that may mediate this abnormal activation of the cell cycle.

Amyloid beta-Protein Precursor↗
PubMed2006

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit composition and cAMP-response element-binding protein regulate oligodendrocyte excitotoxicity.

Developing oligodendrocytes (OLs) are highly vulnerable to glutamate excitotoxicity. Although OL excitotoxicity is mainly mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors (AMPARs) and is Ca2+-dependent, the molecular basis for AMPAR-mediated Ca2+ influx in OLs remains largely unclear. Ca2+ permeability of AMPARs is inversely correlated with the abundance of the AMPAR subunit glutamate receptor 2 (GluR2). Here we report that GluR2-containing and GluR2-lacking AMPARs are co-expressed in individual OLs and that a subset of AMPARs on each OL are Ca2+-permeable and mediate OL excitotoxicity. Virus-mediated overexpression of GluR2 reduces OL excitotoxicity, whereas expression of its unedited form GluR2(Q) enhances the excitotoxicity. These findings indicate that GluR2 critically controls OL excitotoxicity. During OL excitotoxicity, the transcriptional factor cAMP-response element-binding protein (CREB) is transiently phosphorylated and subsequently down-regulated. Virus-mediated expression of a constitutively active form of CREB, both in cultured OLs in vitro and in developing cerebral white matter in vivo, up-regulates GluR2, inhibits Ca2+ permeability, and protects OLs from excitotoxicity. Overall, these data suggest that targeting GluR2-lacking AMPARs or CREB may be a useful strategy for treating nervous system disorders associated with OL excitotoxicity.

Animals↗
PubMed2006

Induction of inducible cAMP early repressor expression in nucleus accumbens by stress or amphetamine increases behavioral responses to emotional stimuli.

Previous research has shown that cAMP response element (CRE)-mediated transcription is activated in the nucleus accumbens, a major brain reward region, by a variety of environmental stimuli and contributes to neuroadaptations to these stimuli. CRE-binding protein (CREB) is the most studied activator of CRE transcription and has been implicated in this brain region as a gating mechanism for behavioral responses to emotional stimuli. Little attention, however, has been given to naturally occurring inhibitors of CRE-mediated transcription, such as the inducible cAMP early repressor (ICER), an inhibitory product of the CRE modulator gene. In the present study, we investigated the extent to which ICER is induced in the nucleus accumbens by two types of environmental stimuli, stress and amphetamine, and characterized how induction of ICER in this region affects complex behavior. We show that stress and amphetamine each induces ICER expression and that overexpression of ICER in the nucleus accumbens, using viral-mediated gene transfer, increases behavioral responses to both rewarding and aversive emotional stimuli. For example, ICER overexpression increases sensitivity to amphetamine-stimulated locomotor activity as well as to natural rewards such as sucrose and social grooming. However, ICER overexpression also increases measures of anxiety in the elevated plus maze and neophobia to novel tastes. Finally, ICER produces an antidepressant-like effect in the forced swim test, further indication of an enhanced active response to stress. These results suggest that ICER is an important mechanism for modulating CRE-mediated transcription in the nucleus accumbens.

Amphetamine↗
PubMed2006

Instructive effect of visual experience in mouse visual cortex.

We describe a form of experience-dependent response enhancement in the visual cortex of awake mice. Repeated presentations of grating stimuli of a single orientation result in a persistent enhancement of responses evoked by the test stimulus. Response potentiation is specific to the orientation of the test stimulus, develops gradually over the course of several training sessions, and occurs in both juvenile and adult mice. The stimulus-selective response potentiation (SRP) can mask deprivation-induced response depression in adult mice. SRP requires NMDA receptor activation and is prevented by viral delivery of a peptide that interferes with AMPA receptor trafficking. SRP may reveal the mechanisms involved in certain forms of perceptual learning.

Animals↗
PubMed2006

Bi-directional control of motor neuron dendrite remodeling by the calcium permeability of AMPA receptors.

Motor neurons express particularly high levels of the AMPA receptor subunit GluR1(Q)flip (GluR1(Q)i) during the period in early postnatal life when their dendritic tree grows and becomes more branched. To investigate how GluR1-containing AMPA receptors contribute to dendrite morphogenesis, we characterized a mutant form of GluR1 (containing a histidine in the Q/R editing site) with unique electrophysiological properties. Most notably, AMPA receptors assembled from GluR1(H)i display less calcium permeability than AMPA receptors assembled from GluR1(Q)i. Expression of GluR1(Q)i in vivo or in vitro led to an increase in dendrite branching with no net change in the overall tree size while GluR1(H)i led to a loss of branches and a net reduction in overall tree size. GluR1(H)i-dependent dendrite atrophy is mediated by protein phosphatase 2B. The results suggest that the electrophysiological properties of cell surface AMPA receptors, specifically their permeability to calcium, can be a central determinant of whether the dendrites undergo activity-dependent branching or atrophy.

Animals↗
PubMed2006

Role of cAMP response element-binding protein in the rat locus ceruleus: regulation of neuronal activity and opiate withdrawal behaviors.

The transcription factor cAMP response element-binding protein (CREB) is implicated in mediating the actions of chronic morphine in the locus ceruleus (LC), but direct evidence to support such a role is limited. Here, we investigated the influence of CREB on LC neuronal activity and opiate withdrawal behaviors by selectively manipulating CREB activity in the LC using viral vectors encoding genes for CREBGFP (wild-type CREB tagged with green fluorescent protein), caCREBGFP (a constitutively active CREB mutant), dnCREBGFP (a dominant-negative CREB mutant), or GFP alone as a control. Our results show that in vivo overexpression of CREBGFP in the LC significantly aggravated particular morphine withdrawal behaviors, whereas dnCREBGFP expression attenuated these behaviors. At the cellular level, CREBGFP expression in the LC in vivo and in vitro had no significant effect on neuronal firing at baseline but enhanced the excitatory effect of forskolin (an activator of adenylyl cyclase) on these neurons, which suggests that the cAMP signaling pathway in these neurons was sensitized after CREB expression. Moreover, in vitro studies showed that caCREBGFP-expressing LC neurons fired significantly faster and had a more depolarized resting membrane potential compared with GFP-expressing control cells. Conversely, LC neuronal activity was decreased by dnCREBGFP, and the neurons were hyperpolarized by this treatment. Together, these data provide direct evidence that CREB plays an important role in controlling the electrical excitability of LC neurons and that morphine-induced increases in CREB activity contribute to the behavioral and neural adaptations associated with opiate dependence and withdrawal.

Action Potentials↗
PubMed2006

Intracellular zinc release and ERK phosphorylation are required upstream of 12-lipoxygenase activation in peroxynitrite toxicity to mature rat oligodendrocytes.

Peroxynitrite toxicity has been implicated in the pathogenesis of white matter injury. The mechanisms of peroxynitrite toxicity to oligodendrocytes (OLs), the major cell type of the white matter, are unknown. Using primary cultures of mature OLs that express myelin basic protein, we found that 3-morpholinosydnonimine, a peroxynitrite generator, caused toxicity to OLs. N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine, a zinc chelator, completely blocked peroxynitrite-induced toxicity. Use of FluoZin-3, a specific fluorescence zinc indicator, demonstrated the liberation of zinc from intracellular stores by peroxynitrite. Peroxynitrite caused the sequential activation of extracellular signal-regulated kinase 42/44 (ERK42/44), 12-lipoxygenase, and generation of reactive oxygen species, which were all dependent upon the intracellular release of zinc. The same cell death pathway was also activated when exogenous zinc was used. These results suggest that in addition to preventing the formation of peroxynitrite, useful strategies in preventing disease progression in pathologies in which peroxynitrite toxicity plays a critical role might include maintaining intracellular zinc homeostasis, blocking phosphorylation of ERK42/44, inhibiting activation of 12-lipoxygenase, and eliminating the accumulation of reactive oxygen species.

Animals↗
PubMed2005

The cell cycle as a therapeutic target for Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide. It is a progressive, incurable disease whose predominant clinical manifestation is memory loss, and which always ends in death. The classic neuropathological diagnostic markers for AD are amyloid plaques and neurofibrillary tangles, but our understanding of the role that these features of AD play in the etiology and progression of the disease remains incomplete. Research over the last decade has revealed that cell cycle abnormalities also represent a major neuropathological feature of AD. These abnormalities appear very early in the disease process, prior to the appearance of plaques and tangles. Growing evidence suggests that neuronal cell cycle regulatory failure, leading to apoptosis, may be a significant component of the pathogenesis of AD. A number of signaling pathways with the potential to activate aberrant cell cycle re-entry in AD have been described. The relationships among these signaling cascades, which involve the amyloid precursor protein (APP), cyclin-dependent kinases (cdks), and the cell cycle protein Pin1, have not yet been fully elucidated, but details of the individual pathways are beginning to emerge. This review summarizes the current state of knowledge with respect to specific neuronal signaling events that are thought to underlie cell cycle regulatory failure in AD brain. The elements of these pathways that represent potential new therapeutic targets for AD are described. Drugs and peptides that can inhibit molecular steps leading to AD neurodegeneration by intervening in the activation of cell cycle re-entry in neurons represent an entirely new approach to the development of treatments for AD.

Alzheimer Disease↗
PubMed2005

Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum.

Given that cocaine induces neuroadaptations through regulation of gene expression, we investigated whether chromatin remodeling at specific gene promoters may be a key mechanism. We show that cocaine induces specific histone modifications at different gene promoters in striatum, a major neural substrate for cocaine's behavioral effects. At the cFos promoter, H4 hyperacetylation is seen within 30 min of a single cocaine injection, whereas no histone modifications were seen with chronic cocaine, consistent with cocaine's ability to induce cFos acutely, but not chronically. In contrast, at the BDNF and Cdk5 promoters, genes that are induced by chronic, but not acute, cocaine, H3 hyperacetylation was observed with chronic cocaine only. DeltaFosB, a cocaine-induced transcription factor, appears to mediate this regulation of the Cdk5 gene. Furthermore, modulating histone deacetylase activity alters locomotor and rewarding responses to cocaine. Thus, chromatin remodeling is an important regulatory mechanism underlying cocaine-induced neural and behavioral plasticity.

Acetylation↗
PubMed2005

Amyloid precursor protein interacts with notch receptors.

The amyloid precursor protein (APP) must fulfill important roles based on its sequence conservation from fly to human. Although multiple functions for APP have been proposed, the best-known role for this protein is as the precursor of Abeta peptide, a neurotoxic 39-43-amino acid peptide crucial to the pathogenesis of Alzheimer's disease. To investigate additional roles for APP with an eye toward understanding the molecular basis of the pleiotropic effects ascribed to APP, we isolated proteins that interacted with the plasma membrane isoform of APP. We employed a membrane-impermeable crosslinker to immobilize proteins binding to transmembrane APP in human embryonic kidney (HEK)293 cells expressing APP751 (HEK275) or rat embryonic day 18 primary neurons infected with a virus expressing APP. Notch2 was identified as a potential APP binding partner based on mass spectrometry analysis of APP complexes immunopurified from neurons. To confirm the interaction between Notch2 and APP, we carried out immunoprecipitation studies in HEK275 cells transiently expressing full-length Notch2 using Notch2 antibodies. The results indicated that APP and Notch2 interact in mammalian cells, and confirmed our initial findings. Interestingly, Notch1 also coimmunoprecipitated with APP, suggesting that APP and Notch family members may engage in intermolecular cross talk to modulate cell function. Finally, cotransfection of APP/CFP and Notch2/YFP into COS cells revealed that these two proteins colocalize on the plasma membrane. Intracellularly, however, although some APP and Notch molecules colocalize, others reside in distinct locations. The discovery of proteins that interact with APP may aid in the identification of new functions for APP.

Amyloid beta-Protein Precursor↗
PubMed2005

Regulation of drug reward by cAMP response element-binding protein: evidence for two functionally distinct subregions of the ventral tegmental area.

The transcription factor cAMP response element binding protein (CREB) is implicated in the actions of drugs of abuse in several brain areas, but little information is available about a role for CREB in the ventral tegmental area (VTA), one of the key reward regions of the brain. Here, we demonstrate that chronic exposure to drugs of abuse induces CREB activity throughout the VTA. Using viral-mediated gene transfer, we expressed green fluorescent protein (GFP)-tagged CREB or mCREB (a dominant-negative form of CREB) in the VTA and, using a conditioned place-preference paradigm, found that CREB activation within the rostral versus caudal subregions of the VTA produces opposite effects on drug reward. We identified VTA subregion-specific differences in the proportion of dopaminergic and GABAergic neurons and in the dopaminergic projections to the nucleus accumbens, another brain region implicated in drug reward, and suggest that this may contribute to behavioral differences in this study. We also measured expression levels of tyrosine hydroxylase and the AMPA glutamate receptor subunit GluR1, both of which are known to contribute to drug reward in the VTA, and found that both of these genes are upregulated following the expression of CREB-GFP and downregulated following expression of mCREB-GFP, raising the possibility that CREB may exert its effects on drug reward, in part, via regulation of these genes. These results suggest a novel role for CREB in mediating drug-induced plasticity in the VTA and establish two functionally distinct subregions of the VTA in which CREB differentially regulates drug reward.

Animals↗
PubMed2005

Phospholipase C gamma in distinct regions of the ventral tegmental area differentially regulates morphine-induced locomotor activity.

Neurotrophic factors and the signaling pathways they activate play a role in mediating long-term molecular, cellular, and behavioral adaptations associated with drug addiction. Here we mimicked the biological response of phospholipase C-gamma (PLC gamma) induction in the ventral tegmental area (VTA) observed after chronic morphine using viral-mediated gene transfer. Using a behavioral sensitization paradigm, we demonstrate that microinjections of PLC gamma 1 into distinct (rostral vs. caudal) regions of the VTA result in differential locomotor responses to morphine.

Animals↗
PubMed2005

Regulation of anxiety and initiation of sexual behavior by CREB in the nucleus accumbens.

Sexual deficits and other behavioral disturbances such as anxiety-like behaviors can be observed in animals that have undergone social isolation, especially in species having important social interactions. Using a model of protracted social isolation in adult rats, we observed increased anxiety-like behavior and deficits in both the latency to initiate sexual behavior and the latency to ejaculate. We show, using transgenic cAMP response element (CRE)-LacZ reporter mice, that protracted social isolation also reduces CRE-dependent transcription within the nucleus accumbens. This decrease in CRE-dependent transcription can be mimicked in nonisolated animals by local viral gene transfer of a dominant negative mutant of CRE-binding protein (CREB). We previously showed that this manipulation increases anxiety-like behavior. We show here that it also impairs initiation of sexual behavior in nonisolated animals, a deficit that can be corrected by anxiolytic drug treatment. This local reduction in CREB activity, however, has no influence on ejaculation parameters. Reciprocally, we used the viral transgenic approach to overexpress CREB in the nucleus accumbens of isolated animals. We show that this local increase in CREB activity completely rescued the anxiety phenotype of the isolated animals, as well as their deficit in initiating sexual behavior, but failed to rescue the deficit in ejaculation. Our data suggest a role for the nucleus accumbens in anxiety responses and in specific aspects of sexual behavior. The results also provide insight into the molecular mechanisms by which social interactions affect brain plasticity and behavior.

Animals↗
PubMed2005

Frontocortical 5-HT4 receptors exert positive feedback on serotonergic activity: viral transfections, subacute and chronic treatments with 5-HT4 agonists.

BACKGROUND: We recently identified a facilitory control exerted by serotonin4 (5-HT4) receptors on the in vivo firing activity of dorsal raphe nucleus (DRN) serotonergic (5-HT) neurons. However, these findings were based on acute administrations of 5-HT4 receptor agonists and antagonists, which were active only in a subpopulation of 5-HT neurons. We had no evidence that this influence was significant when considering the entire DRN, nor if it was persistent after chronic treatments. In addition, the poor distribution of 5-HT4 receptors within the DRN raised the question of the neuroanatomical bases underlying this control. METHODS AND RESULTS: Here we show that the subacute intraperitoneal (IP) injection of the 5-HT4 receptor agonists prucalopride (2.5 mg/kg) and RS 67333 (1.5 mg/kg) 30 minutes before the beginning of recordings augment the mean firing rate of DRN neurons by 40% and 66%, respectively. These increases remain stable when the compounds are administered continuously during 3 and 21 days; the effects of the 3-day treatment are blocked by the 5-HT4 receptor antagonist GR 125487 (1000 microg/kg, intravenous [i.v.]). In addition, stereotaxic microinjections of herpes simplex viruses, transformed to overexpress 5-HT4 receptors, increase DRN 5-HT neuronal mean activity when performed in the medial prefrontal cortex (mPFC) but not in the striatum or in the hippocampus. CONCLUSIONS: This finding suggests the existence of a 5-HT(4)-dependent activation of DRN that may involve the mPFC, unveiling the 5-HT4 receptor as a putative player in the physiopathology of several disorders related to central 5-HT dysfunction.

Aniline Compounds↗