Gene coexpression patterns predict opiate-induced brain-state transitions

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Significance

Persistent alterations to neural circuitry may help to explain why opiate abuse liability is higher among individuals with a history of chronic exposure. In this study, we employ a unique combination of computational approaches to understand how opiate-induced reorganization of network connectivity is supported by transcriptional and structural features of the brain. We identify a persistent reduction in FOS correlation network strength following opiate dependence and determine that correlated gene expression is predictive of opiate-induced changes in network connectivity. Further, we identify brain regions that influence the transition between opiate-naïve and opiate-dependent states. These findings establish a link between gene expression and changes in brain connectivity in response to opioids.

Abstract

Opioid addiction is a chronic, relapsing disorder associated with persistent changes in brain plasticity. Reconfiguration of neuronal connectivity may explain heightened abuse liability in individuals with a history of chronic drug exposure. To characterize network-level changes in neuronal activity induced by chronic opiate exposure, we compared FOS expression in mice that are morphine-naïve, morphine-dependent, or have undergone 4 wk of withdrawal from chronic morphine exposure, relative to saline-exposed controls. Pairwise interregional correlations in FOS expression data were used to construct network models that reveal a persistent reduction in connectivity strength following opiate dependence. Further, we demonstrate that basal gene expression patterns are predictive of changes in FOS correlation networks in the morphine-dependent state. Finally, we determine that regions of the hippocampus, striatum, and midbrain are most influential in driving transitions between opiate-naïve and opiate-dependent brain states using a control theoretic approach. This study provides a framework for predicting the influence of specific therapeutic interventions on the state of the opiate-dependent brain.

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Most cited references 39

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A mesoscale connectome of the mouse brain.

Seung Wook Oh, Julie Harris, Lydia Ng … (2014)

Comprehensive knowledge of the brain's wiring diagram is fundamental for understanding how the nervous system processes information at both local and global scales. However, with the singular exception of the C. elegans microscale connectome, there are no complete connectivity data sets in other species. Here we report a brain-wide, cellular-level, mesoscale connectome for the mouse. The Allen Mouse Brain Connectivity Atlas uses enhanced green fluorescent protein (EGFP)-expressing adeno-associated viral vectors to trace axonal projections from defined regions and cell types, and high-throughput serial two-photon tomography to image the EGFP-labelled axons throughout the brain. This systematic and standardized approach allows spatial registration of individual experiments into a common three dimensional (3D) reference space, resulting in a whole-brain connectivity matrix. A computational model yields insights into connectional strength distribution, symmetry and other network properties. Virtual tractography illustrates 3D topography among interconnected regions. Cortico-thalamic pathway analysis demonstrates segregation and integration of parallel pathways. The Allen Mouse Brain Connectivity Atlas is a freely available, foundational resource for structural and functional investigations into the neural circuits that support behavioural and cognitive processes in health and disease.

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The neural basis of drug craving: an incentive-sensitization theory of addiction.

T E Robinson, K C Berridge (1993)

This paper presents a biopsychological theory of drug addiction, the 'Incentive-Sensitization Theory'. The theory addresses three fundamental questions. The first is: why do addicts crave drugs? That is, what is the psychological and neurobiological basis of drug craving? The second is: why does drug craving persist even after long periods of abstinence? The third is whether 'wanting' drugs (drug craving) is attributable to 'liking' drugs (to the subjective pleasurable effects of drugs)? The theory posits the following. (1) Addictive drugs share the ability to enhance mesotelencephalic dopamine neurotransmission. (2) One psychological function of this neural system is to attribute 'incentive salience' to the perception and mental representation of events associated with activation of the system. Incentive salience is a psychological process that transforms the perception of stimuli, imbuing them with salience, making them attractive, 'wanted', incentive stimuli. (3) In some individuals the repeated use of addictive drugs produces incremental neuroadaptations in this neural system, rendering it increasingly and perhaps permanently, hypersensitive ('sensitized') to drugs and drug-associated stimuli. The sensitization of dopamine systems is gated by associative learning, which causes excessive incentive salience to be attributed to the act of drug taking and to stimuli associated with drug taking. It is specifically the sensitization of incentive salience, therefore, that transforms ordinary 'wanting' into excessive drug craving. (4) It is further proposed that sensitization of the neural systems responsible for incentive salience ('for wanting') can occur independently of changes in neural systems that mediate the subjective pleasurable effects of drugs (drug 'liking') and of neural systems that mediate withdrawal. Thus, sensitization of incentive salience can produce addictive behavior (compulsive drug seeking and drug taking) even if the expectation of drug pleasure or the aversive properties of withdrawal are diminished and even in the face of strong disincentives, including the loss of reputation, job, home and family. We review evidence for this view of addiction and discuss its implications for understanding the psychology and neurobiology of addiction.

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Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.

G Di Chiara, A. Imperato (1988)

The effect of various drugs on the extracellular concentration of dopamine in two terminal dopaminergic areas, the nucleus accumbens septi (a limbic area) and the dorsal caudate nucleus (a subcortical motor area), was studied in freely moving rats by using brain dialysis. Drugs abused by humans (e.g., opiates, ethanol, nicotine, amphetamine, and cocaine) increased extracellular dopamine concentrations in both areas, but especially in the accumbens, and elicited hypermotility at low doses. On the other hand, drugs with aversive properties (e.g., agonists of kappa opioid receptors, U-50,488, tifluadom, and bremazocine) reduced dopamine release in the accumbens and in the caudate and elicited hypomotility. Haloperidol, a neuroleptic drug, increased extracellular dopamine concentrations, but this effect was not preferential for the accumbens and was associated with hypomotility and sedation. Drugs not abused by humans [e.g., imipramine (an antidepressant), atropine (an antimuscarinic drug), and diphenhydramine (an antihistamine)] failed to modify synaptic dopamine concentrations. These results provide biochemical evidence for the hypothesis that stimulation of dopamine transmission in the limbic system might be a fundamental property of drugs that are abused.

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc. Natl. Acad. Sci. U.S.A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 11 August 2020

Publication date (Electronic): 21 July 2020

Publication date PMC-release: 21 July 2020

Volume: 117

Issue: 32

Pages: 19556-19565

Affiliations

[1] ^aDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104;

[2] ^bDepartment of Bioengineering, University of Pennsylvania , Philadelphia, PA 19104;

[3] ^cDepartment of Neurology, University of Pennsylvania , Philadelphia, PA 19104;

[4] ^dDepartment of Psychiatry, University of Pennsylvania , Philadelphia, PA 19104;

[5] ^eDepartment of Electrical & Systems Engineering, University of Pennsylvania , Philadelphia, PA 19104;

[6] ^fDepartment of Physics & Astronomy, University of Pennsylvania , Philadelphia, PA 19104;

[7] ^gDepartment of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH Aachen University , 52074 Aachen, Germany;

[8] ^hDepartment of Mechanical Engineering, University of California, Riverside , CA 92521;

[9] ⁱSanta Fe Institute , Santa Fe, NM 87501

Author notes

¹To whom correspondence may be addressed. Email: blendy@ 123456pennmedicine.upenn.edu .

Edited by Olaf Sporns, Indiana University, Bloomington, IN, and accepted by Editorial Board Member Michael S. Gazzaniga June 24, 2020 (received for review February 25, 2020)

Author contributions: J.K.B. and J.A.B. designed research; J.K.B., K.D.M., and C.W. performed research; E.J.C., F.P., and D.S.B. contributed new reagents/analytic tools; J.K.B. analyzed data; and J.K.B. and J.A.B. wrote the paper.