LE-Tg(Drd1a-iCre)3Ottc

@article{pmid36446928,

title = {High frequency DBS-like optogenetic stimulation of nucleus accumbens dopamine D2 receptor-containing neurons attenuates cocaine reinstatement in male rats},

author = {Sarah E Swinford-Jackson and Phillip J Huffman and Melissa C Knouse and Arthur S Thomas and Matthew T Rich and Sharvari Mankame and Samantha J Worobey and Mateo Sarmiento and Ayanna Coleman and R Christopher Pierce},

url = {https://pubmed.ncbi.nlm.nih.gov/36446928/},

doi = {10.1038/s41386-022-01495-y},

issn = {1740-634X},

year  = {2023},

date = {2023-02-01},

urldate = {2023-02-01},

journal = {Neuropsychopharmacology},

volume = {48},

number = {3},

pages = {459--467},

abstract = {Previous work indicated that deep brain stimulation (DBS) of the nucleus accumbens shell in male rats attenuated reinstatement of cocaine seeking, an animal model of craving. However, the potential differential impact of DBS on specific populations of neurons to drive the suppression of cocaine seeking is unknown. Medium spiny neurons in the nucleus accumbens are differentiated by expression of dopamine D1 receptors (D1DRs) or D2DRs, activation of which promotes or inhibits cocaine-related behaviors, respectively. The advent of transgenic rat lines expressing Cre recombinase selectively in D1DR-containing or D2DR-containing neurons, when coupled with Cre-dependent virally mediated gene transfer of channelrhodopsin (ChR2), enabled mimicry of DBS in a selective subpopulation of neurons during complex tasks. We tested the hypothesis that high frequency DBS-like optogenetic stimulation of D1DR-containing neurons in the accumbens shell would potentiate, whereas stimulation of D2DR-containing neurons in the accumbens shell would attenuate, cocaine-primed reinstatement of cocaine seeking. Results indicated that high frequency, DBS-like optogenetic stimulation of D2DR-containing neurons attenuated reinstatement of cocaine seeking in male rats, whereas DBS-like stimulation of D1DR-containing neurons did not alter cocaine-primed reinstatement. Surprisingly, DBS-like optogenetic stimulation did not alter reinstatement of cocaine seeking in female rats. In rats which only expressed eYFP, intra-accumbens optogenetic stimulation did not alter cocaine reinstatement, indicating that the effect of DBS-like stimulation to attenuate cocaine reinstatement is mediated specifically by ChR2 rather than by prolonged light delivery. These results suggest that DBS of the accumbens may attenuate cocaine-primed reinstatement in male rats through the selective manipulation of D2DR-containing neurons.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Strong:2020tx,

title = {Chemogenetic selective manipulation of nucleus accumbens medium spiny neurons bidirectionally controls alcohol intake in male and female rats},

author = {C. E. Strong and D. P. Hagarty and A. Brea Guerrero and K. J. Schoepfer and S. M. Cajuste and M. Kabbaj},

url = {https://pubmed.ncbi.nlm.nih.gov/33154463/},

doi = {10.1038/s41598-020-76183-2},

isbn = {2045-2322},

year  = {2020},

date = {2020-11-05},

urldate = {2020-11-05},

journal = {Scientific Reports},

volume = {10},

number = {1},

pages = {19178},

abstract = {The nucleus accumbens (NAc), considered the hub of reward circuitry, is comprised of two medium spiny neuron (MSN) subtypes that are classified by their enrichment of dopamine 1 (D1) or 2 (D2) receptors. While reports indicate that alcohol increases excitatory neurotransmission exclusively on NAc D1-MSNs in male rats, it remains unknown how NAc MSNs control alcohol intake in either sex. Therefore, this study investigated how NAc MSNs mediate alcohol intake by using Drd1a-iCre and Drd2-iCre transgenic rats of both sexes. Intra-NAc infusions of Cre-inducible viral vectors containing stimulatory (hM3Dq) or inhibitory (hM4Di) designer receptors exclusively activated by designer drugs (DREADDs) were delivered after 4-weeks of alcohol intake, and clozapine-N-oxide (CNO) was administered to selectively manipulate NAc MSNs. Our results show that activation of NAc D1-MSNs increased alcohol intake 1-, 4-, and 24-h after the start of drinking while inhibition decreased it 1-h after the start of drinking, with no sex differences observed at any time point. Activation of NAc D2-MSNs had no impact on alcohol intake while inhibition increased alcohol intake in Drd2-iCre rats for 1-h in males and 4-h in females. These findings suggest opposing roles for how NAc D1- and D2-MSNs modulate alcohol intake in rats of both sexes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Baez-Cordero:2020aa,

title = {Unbalanced Inhibitory/Excitatory Responses in the Substantia Nigra Pars Reticulata Underlie Cannabinoid-Related Slowness of Movements},

author = {Ana S Báez-Cordero and Ana K Pimentel-Farfan and Teresa Pe{~n}a-Rangel and Pavel E Rueda-Orozco},

url = {http://www.jneurosci.org/content/40/30/5769.abstract},

doi = {10.1523/JNEUROSCI.0045-20.2020},

year  = {2020},

date = {2020-07-22},

journal = {The Journal of Neuroscience},

volume = {40},

number = {30},

pages = {5769},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Garcia-Keller8463,

title = {Relapse-Associated Transient Synaptic Potentiation Requires Integrin-Mediated Activation of Focal Adhesion Kinase and Cofilin in D1-Expressing Neurons},

author = {Constanza Garcia-Keller and Michael D Scofield and Daniela Neuhofer and Swathi Varanasi and Matthew T Reeves and Brandon Hughes and Ethan Anderson and Christopher T Richie and Carlos Mejias-Aponte and James Pickel and Bruce T Hope and Brandon K Harvey and Christopher W Cowan and Peter W Kalivas},

url = {https://pubmed.ncbi.nlm.nih.gov/33051346/},

doi = {10.1523/JNEUROSCI.2666-19.2020},

issn = {0270-6474},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Journal of Neuroscience},

volume = {40},

number = {44},

pages = {8463--8477},

publisher = {Society for Neuroscience},

abstract = {Relapse to drug use can be initiated by drug-associated cues. The intensity of cue-induced drug seeking in rodent models correlates with the induction of transient synaptic potentiation (t-SP) at glutamatergic synapses in the nucleus accumbens core (NAcore). Matrix metalloproteinases (MMPs) are inducible endopeptidases that degrade extracellular matrix (ECM) proteins, and reveal tripeptide Arginine-Glycine-Aspartate (RGD) domains that bind and signal through integrins. Integrins are heterodimeric receptors composed of αβ subunits, and a primary signaling kinase is focal adhesion kinase (FAK). We previously showed that MMP activation is necessary for and potentiates cued reinstatement of cocaine seeking, and MMP-induced catalysis stimulates β3-integrins to induce t-SP. Here, we determined whether β3-integrin signaling through FAK and cofilin (actin depolymerization factor) is necessary to promote synaptic growth during t-SP. Using a small molecule inhibitor to prevent FAK activation, we blocked cued-induced cocaine reinstatement and increased spine head diameter (dh). Immunohistochemistry on NAcore labeled spines with ChR2-EYFP virus, showed increased immunoreactivity of phosphorylation of FAK (p-FAK) and p-cofilin in dendrites of reinstated animals compared with extinguished and yoked saline, and the p-FAK and cofilin depended on β3-integrin signaling. Next, male and female transgenic rats were used to selectively label D1 or D2 neurons with ChR2-mCherry. We found that p-FAK was increased during drug seeking in both D1 and D2-medium spiny neurons (MSNs), but increased p-cofilin was observed only in D1-MSNs. These data indicate that β3-integrin, FAK and cofilin constitute a signaling pathway downstream of MMP activation that is involved in promoting the transient synaptic enlargement in D1-MSNs induced during reinstated cocaine by drug-paired cues.SIGNIFICANCE STATEMENT Drug-associated cues precipitate relapse, which is correlated with transient synaptic enlargement in the accumbens core. We showed that cocaine cue-induced synaptic enlargement depends on matrix metalloprotease signaling in the extracellular matrix (ECM) through β3-integrin to activate focal adhesion kinase (FAK) and phosphorylate the actin binding protein cofilin. The nucleus accumbens core (NAcore) contains two predominate neuronal subtypes selectively expressing either D1-dopamine or D2-dopamine receptors. We used transgenic rats to study each cell type and found that cue-induced signaling through cofilin phosphorylation occurred only in D1-expressing neurons. Thus, cocaine-paired cues initiate cocaine reinstatement and synaptic enlargement through a signaling cascade selectively in D1-expressing neurons requiring ECM stimulation of β3-integrin-mediated phosphorylation of FAK (p-FAK) and cofilin.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Pardo-Garcia:2019aa,

title = {Ventral Pallidum Is the Primary Target for Accumbens D1 Projections Driving Cocaine Seeking.},

author = {Thibaut R Pardo-Garcia and Constanza Garcia-Keller and Tiffany Penaloza and Christopher T Richie and James Pickel and Bruce T Hope and Brandon K Harvey and Peter W Kalivas and Jasper A Heinsbroek},

doi = {10.1523/JNEUROSCI.2822-18.2018},

issn = {1529-2401 (Electronic); 0270-6474 (Linking)},

year  = {2019},

date = {2019-03-13},

urldate = {2019-03-13},

journal = {J Neurosci},

volume = {39},

number = {11},

pages = {2041--2051},

address = {Department of Neuroscience, University of Michigan, Ann Arbor, Michigan 48109.},

abstract = {Outputs from the nucleus accumbens (NAc) include projections to the ventral pallidum and the ventral tegmental area and subtantia nigra in the ventral mesencephalon. The medium spiny neurons (MSN) that give rise to these pathways are GABAergic and consist of two populations of equal number that are segregated by differentially expressed proteins, including D1- and D2-dopamine receptors. Afferents to the ventral pallidum arise from both D1- and D2-MSNs, whereas the ventral mesencephalon is selectively innervated by D1-MSN. To determine the extent of collateralization of D1-MSN to these axon terminal fields we used retrograde labeling in transgenic mice expressing tdTomato selectively in D1-MSN, and found that a large majority of D1-MSN in either the shell or core subcompartments of the accumbens collateralized to both output structures. Approximately 70% of D1-MSNs projecting to the ventral pallidum collateralized to the ventral mesencephalon, whereas >90% of mesencephalic D1-MSN afferents collateralized to the ventral pallidum. In contrast, <10% of dorsal striatal D1-MSNs collateralized to both the globus pallidus and ventral mesencephalon. D1-MSN activation is required for conditioned cues to induce cocaine seeking. To determine which D1-MSN projection mediates cued cocaine seeking, we selectively transfected D1-MSNs in transgenic rats with an inhibitory Gi-coupled DREADD. Activation of the transfected Gi-DREADD with clozapine-N-oxide administered into the ventral pallidum, but not into the ventral mesencephalon, blocked cue-induced cocaine seeking. These data show that, although accumbens D1-MSNs largely collateralize to both the ventral pallidum and ventral mesencephalon, only D1-MSN innervation of the ventral pallidum is necessary for cue-induced cocaine seeking.SIGNIFICANCE STATEMENT Activity in D1 dopamine receptor-expressing neurons in the NAc is required for rodents to respond to cocaine-conditioned cues and relapse to drug seeking behaviors. The D1-expressing neurons project to both the ventral pallidum and ventral mesencephalon, and we found that a majority of the neurons that innervate the ventral pallidum also collateralize to the ventral mesencephalon. However, despite innervating both structures, only D1 innervation of the ventral pallidum mediates cue-induced cocaine seeking.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31515501,

title = {A novel role for the actin-binding protein drebrin in regulating opiate addiction},

author = {Jennifer A Martin and Craig T Werner and Swarup Mitra and Ping Zhong and Zi-Jun Wang and Pedro H Gobira and Andrew F Stewart and Jay Zhang and Kyra Erias and Justin N Siemian and Devin Hagarty and Lauren E Mueller and Rachael L Neve and Jun-Xu Li and Ramesh Chandra and Karen C Dietz and Mary Kay Lobo and Amy M Gancarz and Zhen Yan and David M Dietz},

url = {https://pubmed.ncbi.nlm.nih.gov/31515501/},

doi = {10.1038/s41467-019-12122-8},

issn = {2041-1723},

year  = {2019},

date = {2019-01-01},

urldate = {2019-01-01},

journal = {Nat Commun},

volume = {10},

number = {1},

pages = {4140},

abstract = {Persistent transcriptional and morphological events in the nucleus accumbens (NAc) and other brain reward regions contribute to the long-lasting behavioral adaptations that characterize drug addiction. Opiate exposure reduces the density of dendritic spines on medium spiny neurons of the NAc; however, the underlying transcriptional and cellular events mediating this remain unknown. We show that heroin self-administration negatively regulates the actin-binding protein drebrin in the NAc. Using virus-mediated gene transfer, we show that drebrin overexpression in the NAc is sufficient to decrease drug seeking and increase dendritic spine density, whereas drebrin knockdown potentiates these effects. We demonstrate that drebrin is transcriptionally repressed by the histone modifier HDAC2, which is relieved by pharmacological inhibition of histone deacetylases. Importantly, we demonstrate that heroin-induced adaptations occur only in the D1 subset of medium spiny neurons. These findings establish an essential role for drebrin, and upstream transcriptional regulator HDAC2, in opiate-induced plasticity in the NAc.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}