A main objective of the Animal Models Core is to provide a broad range of behavioral models of stimulant and opiate addiction in mice and rats to support the PPG's overall goal to establish molecular, cellular, and circuit mechanisms of addiction. Such models include several routine behavioral assays as well as more sophisticated self-administration, self-stimulation, and cognition paradigms. The imperative to employ this broad behavioral battery is that it is difficult to infer something about such a complex behavioral syndrome as addiction from a single model or even a limited number of models. The Core then utilizes these behavioral resources in two main ways. First, the Core provides microdissections of brain reward regions from carefully defined mouse models for molecular characterization in each Project and in the Chromatin and Gene Analysis Core. Second, the Core works with each of the four Projects to generate causal evidence that directly links specific molecular, cellular, and circuit-level adaptations to particular behavioral abnormalities that define a state of addiction. The Core accomplishes this goal by providing a range of genetic mutant mice as well as a large number of vectors for viral-mediated gene transfer, all of which are extensively validated by the Core. The mice and vectors are often generated initially to meet the specific needs of an individual Project, but then are provided to other Projects to broaden their application and thereby promote PPG integration. This Core has led the field in generating mutant mice and viral vectors, which make it possible to selectively manipulate a given gene of interest within a particular neuronal cell type or brain region of adult animals, thus avoiding confounds with more traditional approaches. Finally, the Core provides advanced optogenetic tools to Project investigators to directly implicate altered neuronal and circuit function to addiction-related behavioral abnormalities. By consolidating this behavioral, mouse mutagenesis, viral vector, and optogenetic work within a centralized Core, we ensure rigorous control over the data and facilitate comparisons and contrasts of experimental results across the individual Projects. This consolidation also makes financial sense, since we concentrate and maximize efficient use of the required expertise.

Public Health Relevance

Addiction remains one of the world's greatest public health problems, yet its pathophysiology remains incompletely understood and available treatments for addictions to various drugs of abuse are inadequately effective for most people. We believe that the most effective way of eventually developing definitive treatments and cures for addiction rests in part in a better understanding of its underlying neurobiology.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
2P01DA008227-22A1
Application #
8609279
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (40))
Project Start
Project End
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
22
Fiscal Year
2014
Total Cost
$340,240
Indirect Cost
$129,352
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Ayata, Pinar; Badimon, Ana; Strasburger, Hayley J et al. (2018) Epigenetic regulation of brain region-specific microglia clearance activity. Nat Neurosci 21:1049-1060
Walker, Deena M; Nestler, Eric J (2018) Neuroepigenetics and addiction. Handb Clin Neurol 148:747-765
Li, Xuan; Carreria, Maria B; Witonsky, Kailyn R et al. (2018) Role of Dorsal Striatum Histone Deacetylase 5 in Incubation of Methamphetamine Craving. Biol Psychiatry 84:213-222
Anderson, Ethan M; Larson, Erin B; Guzman, Daniel et al. (2018) Overexpression of the Histone Dimethyltransferase G9a in Nucleus Accumbens Shell Increases Cocaine Self-Administration, Stress-Induced Reinstatement, and Anxiety. J Neurosci 38:803-813
Walker, Deena M; Cates, Hannah M; Loh, Yong-Hwee E et al. (2018) Cocaine Self-administration Alters Transcriptome-wide Responses in the Brain's Reward Circuitry. Biol Psychiatry 84:867-880
Cahill, Michael E; Browne, Caleb J; Wang, Junshi et al. (2018) Withdrawal from repeated morphine administration augments expression of the RhoA network in the nucleus accumbens to control synaptic structure. J Neurochem 147:84-98
Cates, Hannah M; Li, Xuan; Purushothaman, Immanuel et al. (2018) Genome-wide transcriptional profiling of central amygdala and orbitofrontal cortex during incubation of methamphetamine craving. Neuropsychopharmacology 43:2426-2434
Gaspari, Sevasti; Purushothaman, Immanuel; Cogliani, Valeria et al. (2018) Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/?-catenin pathway. Proc Natl Acad Sci U S A 115:E2085-E2094
Miller, M L; Ren, Y; Szutorisz, H et al. (2018) Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability. Mol Psychiatry 23:1328-1335
Monteggia, Lisa M; Heimer, Hakon; Nestler, Eric J (2018) Meeting Report: Can We Make Animal Models of Human Mental Illness? Biol Psychiatry 84:542-545

Showing the most recent 10 out of 312 publications