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Bruce Thomas Hope, Ph.D.

Bruce T. Hope, Ph.D.

Position

Chief, Neuronal Ensembles in Drug Addiction Section

Contact

Biomedical Research Center
251 Bayview Boulevard
Suite 200
Room 06A719
Baltimore, MD 21224

Phone: 443-740-2585

Email: bhope@mail.nih.gov

Education

Post-doctoral Training – Laboratory of Molecular Psychiatry, Department of Psychiatry, Yale University (advisor: Dr. Eric Nestler)

Ph.D. – Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver, Canada (thesis advisor: Dr. Steven R. Vincent)

B.Sc. – Biochemistry, University of British Columbia, Vancouver, Canada

Research Interests

When using drugs of abuse, learned associations are formed between the drugs and stimuli present in the drug-taking environment. With continued use, these stimuli can become cues that promote drug relapse. Our research is focused on figuring out how these memories are stored in the brain. We have identified sparsely distributed patterns of neurons in the brain called ‘neuronal ensembles’ that are selectively activated by drug-related cues and thought to encode the learned associations that mediate drug seeking behavior. Drug-related cues activate specific genes such as c-fos within these neuronal ensembles and allow us to identify them in the brain. We exploit the c-fos promoter to turn on different transgenes in transgenic rats that allow us to manipulate specific neuronal ensembles and assess their role in drug-related memories. We also developed a fluorescence-activated cell sorting (FACS) procedure for purifying these activated ensembles and found unique molecular alterations within their cell bodies and synapses. We have developed novel c-fos-GFP transgenic rats that produce green fluorescent protein (GFP) in activated neurons and found unique synaptic alterations using slice electrophysiology. Using a combination of novel viruses and transgenic rats developed in collaboration with Dr. Brandon Harvey, we continue to search and characterize drug-related memory engrams in the brain that promote drug relapse.

Publications


PubMed | Google Scholar

Selected Publications

2012

Koya, Eisuke; Cruz, Fabio C; Ator, Robert; Golden, Sam A; Hoffman, Alexander F; Lupica, Carl R; Hope, Bruce T

Silent synapses in selectively activated nucleus accumbens neurons following cocaine sensitization. Journal Article

In: Nat Neurosci, vol. 15, no. 11, pp. 1556–1562, 2012, ISSN: 1546-1726 (Electronic); 1097-6256 (Linking).

Abstract | Links

@article{Koya2012,
title = {Silent synapses in selectively activated nucleus accumbens neurons following cocaine sensitization.},
author = {Eisuke Koya and Fabio C Cruz and Robert Ator and Sam A Golden and Alexander F Hoffman and Carl R Lupica and Bruce T Hope},
url = {https://www.ncbi.nlm.nih.gov/pubmed/23023294},
doi = {10.1038/nn.3232},
issn = {1546-1726 (Electronic); 1097-6256 (Linking)},
year = {2012},
date = {2012-11-01},
journal = {Nat Neurosci},
volume = {15},
number = {11},
pages = {1556--1562},
address = {Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland, USA.},
abstract = {Cocaine-induced alterations in synaptic glutamate function in nucleus accumbens are thought to mediate drug-related behaviors such as psychomotor sensitization. However, previous studies have examined global alterations in randomly selected accumbens neurons regardless of their activation state during cocaine-induced behavior. We recently found that a minority of strongly activated Fos-expressing accumbens neurons are necessary for cocaine-induced psychomotor sensitization, whereas the majority of accumbens neurons are less directly involved. We assessed synaptic alterations in these strongly activated accumbens neurons in Fos-GFP mice, which express a fusion protein of Fos and GFP in strongly activated neurons, and compared these alterations with those in surrounding non-activated neurons. Cocaine sensitization produced higher levels of 'silent synapses', which contained functional NMDA receptors and nonfunctional AMPA receptors only in GFP-positive neurons, 6-11 d after sensitization. Thus, distinct synaptic alterations are induced in the most strongly activated accumbens neurons that mediate psychomotor sensitization.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

Close

Cocaine-induced alterations in synaptic glutamate function in nucleus accumbens are thought to mediate drug-related behaviors such as psychomotor sensitization. However, previous studies have examined global alterations in randomly selected accumbens neurons regardless of their activation state during cocaine-induced behavior. We recently found that a minority of strongly activated Fos-expressing accumbens neurons are necessary for cocaine-induced psychomotor sensitization, whereas the majority of accumbens neurons are less directly involved. We assessed synaptic alterations in these strongly activated accumbens neurons in Fos-GFP mice, which express a fusion protein of Fos and GFP in strongly activated neurons, and compared these alterations with those in surrounding non-activated neurons. Cocaine sensitization produced higher levels of 'silent synapses', which contained functional NMDA receptors and nonfunctional AMPA receptors only in GFP-positive neurons, 6-11 d after sensitization. Thus, distinct synaptic alterations are induced in the most strongly activated accumbens neurons that mediate psychomotor sensitization.

Close

  • https://www.ncbi.nlm.nih.gov/pubmed/23023294
  • doi:10.1038/nn.3232

Close

Guez-Barber, Danielle; Fanous, Sanya; Harvey, Brandon K; Zhang, Yongqing; Lehrmann, Elin; Becker, Kevin G; Picciotto, Marina R; Hope, Bruce T

FACS purification of immunolabeled cell types from adult rat brain. Journal Article

In: J Neurosci Methods, vol. 203, no. 1, pp. 10–18, 2012, ISSN: 1872-678X (Electronic); 0165-0270 (Linking).

Abstract | Links

@article{Guez-Barber2012,
title = {FACS purification of immunolabeled cell types from adult rat brain.},
author = {Danielle Guez-Barber and Sanya Fanous and Brandon K Harvey and Yongqing Zhang and Elin Lehrmann and Kevin G Becker and Marina R Picciotto and Bruce T Hope},
url = {https://www.ncbi.nlm.nih.gov/pubmed/21911005},
doi = {10.1016/j.jneumeth.2011.08.045},
issn = {1872-678X (Electronic); 0165-0270 (Linking)},
year = {2012},
date = {2012-01-15},
journal = {J Neurosci Methods},
volume = {203},
number = {1},
pages = {10--18},
address = {Behavioral Neuroscience Branch, IRP/NIDA/NIH/DHHS, 251 Bayview Boulevard, Baltimore, MD 21224, USA. danielle.guez@yale.edu},
abstract = {Molecular analysis of brain tissue is greatly complicated by having many different classes of neurons and glia interspersed throughout the brain. Fluorescence-activated cell sorting (FACS) has been used to purify selected cell types from brain tissue. However, its use has been limited to brain tissue from embryos or transgenic mice with promoter-driven reporter genes. To overcome these limitations, we developed a FACS procedure for dissociating intact cell bodies from adult wild-type rat brains and sorting them using commercially available antibodies against intracellular and extracellular proteins. As an example, we isolated neurons using a NeuN antibody and confirmed their identity using microarray and real time PCR of mRNA from the sorted cells. Our FACS procedure allows rapid, high-throughput, quantitative assays of molecular alterations in identified cell types with widespread applications in neuroscience.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

Close

Molecular analysis of brain tissue is greatly complicated by having many different classes of neurons and glia interspersed throughout the brain. Fluorescence-activated cell sorting (FACS) has been used to purify selected cell types from brain tissue. However, its use has been limited to brain tissue from embryos or transgenic mice with promoter-driven reporter genes. To overcome these limitations, we developed a FACS procedure for dissociating intact cell bodies from adult wild-type rat brains and sorting them using commercially available antibodies against intracellular and extracellular proteins. As an example, we isolated neurons using a NeuN antibody and confirmed their identity using microarray and real time PCR of mRNA from the sorted cells. Our FACS procedure allows rapid, high-throughput, quantitative assays of molecular alterations in identified cell types with widespread applications in neuroscience.

Close

  • https://www.ncbi.nlm.nih.gov/pubmed/21911005
  • doi:10.1016/j.jneumeth.2011.08.045

Close

2011

Bossert, Jennifer M; Stern, Anna L; Theberge, Florence R M; Cifani, Carlo; Koya, Eisuke; Hope, Bruce T; Shaham, Yavin

Ventral medial prefrontal cortex neuronal ensembles mediate context-induced relapse to heroin. Journal Article

In: Nat Neurosci, vol. 14, no. 4, pp. 420–422, 2011, ISSN: 1546-1726 (Electronic); 1097-6256 (Linking).

Abstract | Links

@article{Bossert2011,
title = {Ventral medial prefrontal cortex neuronal ensembles mediate context-induced relapse to heroin.},
author = {Jennifer M Bossert and Anna L Stern and Florence R M Theberge and Carlo Cifani and Eisuke Koya and Bruce T Hope and Yavin Shaham},
url = {https://www.ncbi.nlm.nih.gov/pubmed/21336273},
doi = {10.1038/nn.2758},
issn = {1546-1726 (Electronic); 1097-6256 (Linking)},
year = {2011},
date = {2011-04-01},
journal = {Nat Neurosci},
volume = {14},
number = {4},
pages = {420--422},
address = {Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland, USA.},
abstract = {In a rat model of context-induced relapse to heroin, we identified sparsely distributed ventral medial prefrontal cortex (mPFC) neurons that were activated by the heroin-associated context. Selective pharmacogenetic inactivation of these neurons inhibited context-induced drug relapse. A small subset of ventral mPFC neurons formed neuronal ensembles that encode the learned associations between heroin reward and heroin-associated contexts; re-activation of these neuronal ensembles by drug-associated contexts during abstinence provoked drug relapse.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

Close

In a rat model of context-induced relapse to heroin, we identified sparsely distributed ventral medial prefrontal cortex (mPFC) neurons that were activated by the heroin-associated context. Selective pharmacogenetic inactivation of these neurons inhibited context-induced drug relapse. A small subset of ventral mPFC neurons formed neuronal ensembles that encode the learned associations between heroin reward and heroin-associated contexts; re-activation of these neuronal ensembles by drug-associated contexts during abstinence provoked drug relapse.

Close

  • https://www.ncbi.nlm.nih.gov/pubmed/21336273
  • doi:10.1038/nn.2758

Close

Guez-Barber, Danielle; Fanous, Sanya; Golden, Sam A; Schrama, Regina; Koya, Eisuke; Stern, Anna L; Bossert, Jennifer M; Harvey, Brandon K; Picciotto, Marina R; Hope, Bruce T

FACS identifies unique cocaine-induced gene regulation in selectively activated adult striatal neurons. Journal Article

In: J Neurosci, vol. 31, no. 11, pp. 4251–4259, 2011, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).

Abstract | Links

@article{Guez-Barber2011,
title = {FACS identifies unique cocaine-induced gene regulation in selectively activated adult striatal neurons.},
author = {Danielle Guez-Barber and Sanya Fanous and Sam A Golden and Regina Schrama and Eisuke Koya and Anna L Stern and Jennifer M Bossert and Brandon K Harvey and Marina R Picciotto and Bruce T Hope},
url = {https://www.ncbi.nlm.nih.gov/pubmed/21411666},
doi = {10.1523/JNEUROSCI.6195-10.2011},
issn = {1529-2401 (Electronic); 0270-6474 (Linking)},
year = {2011},
date = {2011-03-16},
journal = {J Neurosci},
volume = {31},
number = {11},
pages = {4251--4259},
address = {Behavioral Neuroscience Branch, Intramural Research Program/National Institute on Drug Abuse/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland 21224, USA.},
abstract = {Numerous studies with the neural activity marker Fos indicate that cocaine activates only a small proportion of sparsely distributed striatal neurons. Until now, efficient methods were not available to assess neuroadaptations induced specifically within these activated neurons. We used fluorescence-activated cell sorting (FACS) to purify striatal neurons activated during cocaine-induced locomotion in naive and cocaine-sensitized cfos-lacZ transgenic rats. Activated neurons were labeled with an antibody against beta-galactosidase, the protein product of the lacZ gene. Cocaine induced a unique gene expression profile selectively in the small proportion of activated neurons that was not observed in the nonactivated majority of neurons. These genes included altered levels of the immediate early genes arc, fosB, and nr4a3, as well as genes involved in p38 MAPK signaling and cell-type specificity. We propose that this FACS method can be used to study molecular neuroadaptations in specific neurons encoding the behavioral effects of abused drugs and other learned behaviors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

Close

Numerous studies with the neural activity marker Fos indicate that cocaine activates only a small proportion of sparsely distributed striatal neurons. Until now, efficient methods were not available to assess neuroadaptations induced specifically within these activated neurons. We used fluorescence-activated cell sorting (FACS) to purify striatal neurons activated during cocaine-induced locomotion in naive and cocaine-sensitized cfos-lacZ transgenic rats. Activated neurons were labeled with an antibody against beta-galactosidase, the protein product of the lacZ gene. Cocaine induced a unique gene expression profile selectively in the small proportion of activated neurons that was not observed in the nonactivated majority of neurons. These genes included altered levels of the immediate early genes arc, fosB, and nr4a3, as well as genes involved in p38 MAPK signaling and cell-type specificity. We propose that this FACS method can be used to study molecular neuroadaptations in specific neurons encoding the behavioral effects of abused drugs and other learned behaviors.

Close

  • https://www.ncbi.nlm.nih.gov/pubmed/21411666
  • doi:10.1523/JNEUROSCI.6195-10.2011

Close

2009

Marin, Marcelo T; Berkow, Alexander; Golden, Sam A; Koya, Eisuke; Planeta, Cleopatra S; Hope, Bruce T

Context-specific modulation of cocaine-induced locomotor sensitization and ERK and CREB phosphorylation in the rat nucleus accumbens. Journal Article

In: Eur J Neurosci, vol. 30, no. 10, pp. 1931–1940, 2009, ISSN: 1460-9568 (Electronic); 0953-816X (Linking).

Abstract | Links

@article{Marin2009,
title = {Context-specific modulation of cocaine-induced locomotor sensitization and ERK and CREB phosphorylation in the rat nucleus accumbens.},
author = {Marcelo T Marin and Alexander Berkow and Sam A Golden and Eisuke Koya and Cleopatra S Planeta and Bruce T Hope},
url = {https://www.ncbi.nlm.nih.gov/pubmed/19912338},
doi = {10.1111/j.1460-9568.2009.06982.x},
issn = {1460-9568 (Electronic); 0953-816X (Linking)},
year = {2009},
date = {2009-11-01},
journal = {Eur J Neurosci},
volume = {30},
number = {10},
pages = {1931--1940},
address = {School of Pharmaceutical Sciences, Sao Paulo State University (UNESP), Araraquara-SP, Brazil.},
abstract = {Learned associations are hypothesized to develop between drug effects and contextual stimuli during repeated drug administration to produce context-specific sensitization that is expressed only in the drug-associated environment and not in a non-drug-paired environment. The neuroadaptations that mediate such context-specific behavior are largely unknown. We investigated context-specific modulation of cAMP-response element-binding protein (CREB) phosphorylation and that of four upstream kinases in the nucleus accumbens that phosphorylate CREB, including extracellular signal-regulated kinase (ERK), cAMP-dependent protein kinase, calcium/calmodulin-dependent kinase (CaMK) II and CaMKIV. Rats received seven once-daily injections of cocaine or saline in one of two distinct environments outside their home cages. Seven days later, test injections of cocaine or saline were administered in either the paired or the non-paired environment. CREB and ERK phosphorylation were assessed with immunohistochemistry, and phosphorylation of the remaining kinases, as well as of CREB and ERK, was assessed by western blotting. Repeated cocaine administration produced context-specific sensitized locomotor responses accompanied by context-specific enhancement of the number of cocaine-induced phosphoCREB-immunoreactive and phosphoERK-immunoreactive nuclei in a minority of neurons. In contrast, CREB and CaMKIV phosphorylation in nucleus accumbens homogenates were decreased by cocaine test injections. We have recently shown that a small number of cocaine-activated accumbens neurons mediate the learned association between cocaine effects and the drug administration environment to produce context-specific sensitization. Context-specific phosphorylation of ERK and CREB in the present study suggests that this signal transduction pathway is selectively activated in the same set of cocaine-activated accumbens neurons that mediate this learned association.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

Close

Learned associations are hypothesized to develop between drug effects and contextual stimuli during repeated drug administration to produce context-specific sensitization that is expressed only in the drug-associated environment and not in a non-drug-paired environment. The neuroadaptations that mediate such context-specific behavior are largely unknown. We investigated context-specific modulation of cAMP-response element-binding protein (CREB) phosphorylation and that of four upstream kinases in the nucleus accumbens that phosphorylate CREB, including extracellular signal-regulated kinase (ERK), cAMP-dependent protein kinase, calcium/calmodulin-dependent kinase (CaMK) II and CaMKIV. Rats received seven once-daily injections of cocaine or saline in one of two distinct environments outside their home cages. Seven days later, test injections of cocaine or saline were administered in either the paired or the non-paired environment. CREB and ERK phosphorylation were assessed with immunohistochemistry, and phosphorylation of the remaining kinases, as well as of CREB and ERK, was assessed by western blotting. Repeated cocaine administration produced context-specific sensitized locomotor responses accompanied by context-specific enhancement of the number of cocaine-induced phosphoCREB-immunoreactive and phosphoERK-immunoreactive nuclei in a minority of neurons. In contrast, CREB and CaMKIV phosphorylation in nucleus accumbens homogenates were decreased by cocaine test injections. We have recently shown that a small number of cocaine-activated accumbens neurons mediate the learned association between cocaine effects and the drug administration environment to produce context-specific sensitization. Context-specific phosphorylation of ERK and CREB in the present study suggests that this signal transduction pathway is selectively activated in the same set of cocaine-activated accumbens neurons that mediate this learned association.

Close

  • https://www.ncbi.nlm.nih.gov/pubmed/19912338
  • doi:10.1111/j.1460-9568.2009.06982.x

Close

Koya, Eisuke; Golden, Sam A; Harvey, Brandon K; Guez-Barber, Danielle H; Berkow, Alexander; Simmons, Danielle E; Bossert, Jennifer M; Nair, Sunila G; Uejima, Jamie L; Marin, Marcelo T; Mitchell, Timothy B; Farquhar, David; Ghosh, Sukhen C; Mattson, Brandi J; Hope, Bruce T

Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization. Journal Article

In: Nat Neurosci, vol. 12, no. 8, pp. 1069–1073, 2009, ISSN: 1546-1726 (Electronic); 1097-6256 (Linking).

Abstract | Links

@article{Koya2009,
title = {Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization.},
author = {Eisuke Koya and Sam A Golden and Brandon K Harvey and Danielle H Guez-Barber and Alexander Berkow and Danielle E Simmons and Jennifer M Bossert and Sunila G Nair and Jamie L Uejima and Marcelo T Marin and Timothy B Mitchell and David Farquhar and Sukhen C Ghosh and Brandi J Mattson and Bruce T Hope},
url = {https://www.ncbi.nlm.nih.gov/pubmed/19620976},
doi = {10.1038/nn.2364},
issn = {1546-1726 (Electronic); 1097-6256 (Linking)},
year = {2009},
date = {2009-08-01},
journal = {Nat Neurosci},
volume = {12},
number = {8},
pages = {1069--1073},
address = {Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland, USA.},
abstract = {Learned associations between effects of abused drugs and the drug administration environment are important in drug addiction. Histochemical and electrophysiological studies suggest that these associations are encoded in sparsely distributed nucleus accumbens neurons that are selectively activated by drugs and drug-associated cues. Although correlations have been observed between nucleus accumbens neuronal activity and responsivity to drugs and drug cues, no technique exists for selectively manipulating these activated neurons and establishing their causal role in behavioral effects of drugs and drug cues. Here we describe a new approach, which we term the 'Daun02 inactivation method', that selectively inactivates a minority of neurons previously activated by cocaine in an environment repeatedly paired with cocaine to demonstrate a causal role for these activated neurons in context-specific cocaine-induced psychomotor sensitization in rats. This method provides a new tool for studying the causal roles of selectively activated neurons in behavioral effects of drugs and drug cues and in other learned behaviors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

Close

Learned associations between effects of abused drugs and the drug administration environment are important in drug addiction. Histochemical and electrophysiological studies suggest that these associations are encoded in sparsely distributed nucleus accumbens neurons that are selectively activated by drugs and drug-associated cues. Although correlations have been observed between nucleus accumbens neuronal activity and responsivity to drugs and drug cues, no technique exists for selectively manipulating these activated neurons and establishing their causal role in behavioral effects of drugs and drug cues. Here we describe a new approach, which we term the 'Daun02 inactivation method', that selectively inactivates a minority of neurons previously activated by cocaine in an environment repeatedly paired with cocaine to demonstrate a causal role for these activated neurons in context-specific cocaine-induced psychomotor sensitization in rats. This method provides a new tool for studying the causal roles of selectively activated neurons in behavioral effects of drugs and drug cues and in other learned behaviors.

Close

  • https://www.ncbi.nlm.nih.gov/pubmed/19620976
  • doi:10.1038/nn.2364

Close

2008

Mattson, Brandi J; Koya, Eisuke; Simmons, Danielle E; Mitchell, Timothy B; Berkow, Alexander; Crombag, Hans S; Hope, Bruce T

Context-specific sensitization of cocaine-induced locomotor activity and associated neuronal ensembles in rat nucleus accumbens. Journal Article

In: Eur J Neurosci, vol. 27, no. 1, pp. 202–212, 2008, ISSN: 1460-9568 (Electronic); 0953-816X (Linking).

Abstract | Links

@article{Mattson2008,
title = {Context-specific sensitization of cocaine-induced locomotor activity and associated neuronal ensembles in rat nucleus accumbens.},
author = {Brandi J Mattson and Eisuke Koya and Danielle E Simmons and Timothy B Mitchell and Alexander Berkow and Hans S Crombag and Bruce T Hope},
url = {https://www.ncbi.nlm.nih.gov/pubmed/18093170},
doi = {10.1111/j.1460-9568.2007.05984.x},
issn = {1460-9568 (Electronic); 0953-816X (Linking)},
year = {2008},
date = {2008-01-01},
journal = {Eur J Neurosci},
volume = {27},
number = {1},
pages = {202--212},
address = {Behavioral Neuroscience Branch, Intramural Research Program, The National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.},
abstract = {Repeated cocaine administration to rats outside their home cage induces behavioral sensitization that is strongly modulated by the drug administration environment. We hypothesized that stimuli in the drug administration environment activate specific sets of striatal neurons, called neuronal ensembles, for further coc