Single-cell whole-brain imaging and network analysis provide evidence of the three-stage hypothesis of addiction

SummaryThree main theories of the neurobiology of addiction have been proposed: (1) incentive salience mediated by a brainstem-striatal network, (2) habit mediated by a cortico-striato-thalamic network, and (3) hedonic allostasis mediated by an extended amygdala network. Efforts have been made to reconcile these theories within a three-stage model, but the relevance of each theory remains controversial. We tested the validity of each theory with a single dataset using unbiased single-cell whole-brain imaging and data-driven analyses of neuronal activity in a mouse model of alcohol use disorder. Abstinence in alcohol dependent mice decreased brain modularity and resulted in clustering of brain regions that correspond to each stage of the three-stage theory of addiction. Furthermore, we identified several brain regions whose activity highly predicted addiction-like behaviors and “hub” regions that may drive neural activation during abstinence. These results validate the three-stage theory of addiction and identify potential target regions for future study.

Download Full-text

Characterization of the brain functional architecture of psychostimulant withdrawal using single-cell whole brain imaging

10.1101/743799 ◽

2019 ◽

Author(s):

Adam Kimbrough ◽

Lauren C. Smith ◽

Marsida Kallupi ◽

Sierra Simpson ◽

Andres Collazo ◽

...

Keyword(s):

Single Cell ◽

Brain Imaging ◽

Drugs Of Abuse ◽

Brain Regions ◽

Functional Architecture ◽

Whole Brain ◽

Similarities And Differences ◽

Drug Dependent ◽

The Brain

AbstractNumerous brain regions have been identified as contributing to addiction-like behaviors, but unclear is the way in which these brain regions as a whole lead to addiction. The search for a final common brain pathway that is involved in addiction remains elusive. To address this question, we used male C57BL/6J mice and performed single-cell whole-brain imaging of neural activity during withdrawal from cocaine, methamphetamine, and nicotine. We used hierarchical clustering and graph theory to identify similarities and differences in brain functional architecture. Although methamphetamine and cocaine shared some network similarities, the main common neuroadaptation between these psychostimulant drugs was a dramatic decrease in modularity, with a shift from a cortical- to subcortical-driven network, including a decrease in total hub brain regions. These results demonstrate that psychostimulant withdrawal produces the drug-dependent remodeling of functional architecture of the brain and suggest that the decreased modularity of brain functional networks and not a specific set of brain regions may represent the final common pathway that leads to addiction.Significance StatementA key aspect of treating drug abuse is understanding similarities and differences of how drugs of abuse affect the brain. In the present study we examined how the brain is altered during withdrawal from psychostimulants. We found that each drug produced a unique pattern of activity in the brain, but that brains in withdrawal from cocaine and methamphetamine shared similar features. Interestingly, we found the major common link between withdrawal from all psychostimulants, when compared to controls, was a shift in the broad organization of the brain in the form of reduced modularity. Reduced modularity has been shown in several brain disorders, including traumatic brain injury, and dementia, and may be the common link between drugs of abuse.

Download Full-text

Cerebrovascular responses of the rat brain to noxious stimuli as examined by functional near-infrared whole brain imaging

Journal of Neurophysiology ◽

10.1152/jn.00050.2011 ◽

2012 ◽

Vol 107 (10) ◽

pp. 2853-2865 ◽

Cited By ~ 6

Author(s):

Ji-Wei He ◽

Fenghua Tian ◽

Hanli Liu ◽

Yuan Bo Peng

Keyword(s):

Brain Imaging ◽

Near Infrared ◽

Small Animal ◽

Nir Spectroscopy ◽

Brain Regions ◽

Anterior Cingulate ◽

Hemodynamic Changes ◽

Whole Brain ◽

Brain Hemodynamics

While near-infrared (NIR) spectroscopy has been increasingly used to detect stimulated brain activities with an advantage of dissociating regional oxy- and deoxyhemoglobin concentrations simultaneously, it has not been utilized much in pain research. Here, we investigated and demonstrated the feasibility of using this technique to obtain whole brain hemodynamics in rats and speculated on the functional relevance of the NIR-based hemodynamic signals during pain processing. NIR signals were emitted and collected using a 26-optodes array on rat's dorsal skull surface after the removal of skin. Following the subcutaneous injection of formalin (50 μl, 3%) into a hindpaw, several isolable brain regions showed hemodynamic changes, including the anterior cingulate cortex, primary/secondary somatosensory cortexes, thalamus, and periaqueductal gray ( n = 6). Time courses of hemodynamic changes in respective regions matched with the well-documented biphasic excitatory response. Surprisingly, an atypical pattern (i.e., a decrease in oxyhemoglobin concentration with a concomitant increase in deoxyhemoglobin concentration) was seen in phase II. In a separate group of rats with innocuous brush and noxious pinch of the same area ( n = 11), results confirmed that the atypical pattern occurred more likely in the presence of nociception than nonpainful stimulation, suggesting it as a physiological substrate when the brain processes pain. In conclusion, the NIR whole brain imaging provides a useful alternative to study pain in vivo using small-animal models. Our results support the notion that neurovascular response patterns depend on stimuli, bringing attention to the interpretation of vascular-based neuroimaging data in studies of pain.

Download Full-text

Family history of alcohol use disorder is associated with brain structural and functional changes in healthy first-degree relatives

European Psychiatry ◽

10.1016/j.eurpsy.2019.08.003 ◽

2019 ◽

Vol 62 ◽

pp. 107-115 ◽

Cited By ~ 3

Author(s):

Irina Filippi ◽

Nicolas Hoertel ◽

Eric Artiges ◽

Guillaume Airagnes ◽

Christophe Guérin-Langlois ◽

...

Keyword(s):

Family History ◽

Alcohol Use ◽

Childhood Maltreatment ◽

Alcohol Use Disorder ◽

Grey Matter ◽

Brain Regions ◽

Whole Brain ◽

Childhood Trauma Questionnaire ◽

Functional Changes ◽

History Of

Abstract Background: Neuroimaging studies of vulnerability to Alcohol Use Disorder (AUD) have identified structural and functional variations which might reflect inheritable features in alcohol-naïve relatives of AUD individuals (FH+) compared to controls having no such family history (FH-). However, prior research did not simultaneously account for childhood maltreatment, any clinically significant disorder and maternal AUD. Therefore, we mainly aimed to investigate the brain structure and reward-related neural activations (fMRI), using whole-brain analysis in FH+ young adults with no prevalent confounders. Methods: 46 FH+ and 45 FH- male and female participants had no severe childhood maltreatment exposure, neither any psychiatric disorder or AUD, nor a prenatal exposure to maternal AUD. We used a 3 T MRI coupled with a whole brain voxel-based method to compare between groups the grey matter volumes and activations in response to big versus small wins during a Monetary Incentive Delay task. The Childhood Trauma Questionnaire score was used as confounding variable in the analyses to account for the remaining variance between groups. Results: Compared to FH- controls, FH+ participants had smaller grey matter volumes in the frontal and cingulate regions as well as in the bilateral nucleus accumbens and right insula. The FH+ participants’ fMRI datasets denoted a blunted activation in the middle cingulum with respect to FH- controls’ during the processing of reward magnitude, and a greater activation in the anterior cingulum in response to anticipation of a small win. Conclusions: Family history of alcohol use disorder is linked to structural and functional variations including brain regions involved in reward processes.

Download Full-text

Whole-Brain Imaging with Single-Cell Resolution Using Chemical Cocktails and Computational Analysis

Cell ◽

10.1016/j.cell.2014.03.042 ◽

2014 ◽

Vol 157 (3) ◽

pp. 726-739 ◽

Cited By ~ 634

Author(s):

Etsuo A. Susaki ◽

Kazuki Tainaka ◽

Dimitri Perrin ◽

Fumiaki Kishino ◽

Takehiro Tawara ◽

...

Keyword(s):

Single Cell ◽

Brain Imaging ◽

Computational Analysis ◽

Whole Brain

Download Full-text

Characterization of the brain functional architecture of psychostimulant withdrawal using single-cell whole brain imaging

eNeuro ◽

10.1523/eneuro.0208-19.2021 ◽

2021 ◽

pp. ENEURO.0208-19.2021

Author(s):

Adam Kimbrough ◽

Marsida Kallupi ◽

Lauren C. Smith ◽

Sierra Simpson ◽

Andres Collazo ◽

...

Keyword(s):

Single Cell ◽

Brain Imaging ◽

Functional Architecture ◽

Whole Brain ◽

The Brain

Download Full-text

A whole-brain imaging-based systems approach to understand origin of addiction in binge-like drinking model

10.1101/2021.02.17.431586 ◽

2021 ◽

Author(s):

Marzena Stefaniuk ◽

Monika Pawłowska ◽

Klaudia Nowicka ◽

Marcin Barański ◽

Zbigniew Zielinski ◽

...

Keyword(s):

Binge Drinking ◽

Brain Imaging ◽

Systems Approach ◽

Light Sheet ◽

Brain Regions ◽

Reward Processing ◽

Functional Networks ◽

Control Group ◽

Addictive Behaviors ◽

Whole Brain

AbstractMany fundamental questions on addiction development are still unanswered. These questions are frequently difficult to address by examining a single brain structure, but can best be addressed at the systems level. Neurons create functional networks that change over time, since brain regions may work together differently in different contexts. We offer a framework for describing the nature behind alcohol binge drinking and the transition to addiction. The present study investigated whole-brain c-Fos expression following reexposure to alcohol in a model of binge-like drinking in mice in IntelliCage. We developed a dedicated image computational workflow to identify c-Fos-positive cells in three-dimensional images obtained after optical tissue clearing and whole-brain imaging in the light-sheet microscope. We analyzed functional networks and brain modularity following reexposure to alcohol. c-Fos levels in brains from animals that were reexposed to alcohol were clearly different from binge drinking animals. Structures involved in reward processing, decision making and characteristic for addictive behaviors stood out particularly. In alcohol reexposed animals differently active structures either gained or lost correlation when compared to the control group.

Download Full-text

Conceptual disorganization and redistribution of resting state cortical hubs in untreated first episode psychosis: A 7T MRI study

10.31234/osf.io/rzvby ◽

2020 ◽

Author(s):

Avyarthana Dey ◽

Kara Dempster ◽

Michael Mackinley ◽

Peter Jeon ◽

Tushar Das ◽

...

Keyword(s):

Negative Symptoms ◽

Superior Temporal Gyrus ◽

Brain Regions ◽

First Episode Psychosis ◽

Cortical Reorganization ◽

First Episode ◽

Formal Thought Disorder ◽

Whole Brain ◽

Episode Psychosis ◽

Positive And Negative Symptoms

Background:Network level dysconnectivity has been studied in positive and negative symptoms of schizophrenia. Conceptual disorganization (CD) is a symptom subtype which predicts impaired real-world functioning in psychosis. Systematic reviews have reported aberrant connectivity in formal thought disorder, a construct related to CD. However, no studies have investigated whole-brain functional correlates of CD in psychosis. We sought to investigate brain regions explaining the severity of CD in patients with first-episode psychosis (FEPs) compared with healthy controls (HCs).Methods:We computed whole-brain binarized degree centrality maps of 31 FEPs, 25 HCs and characterized the patterns of network connectivity in the two groups. In FEPs, we related these findings to the severity of CD. We also studied the effect of positive and negative symptoms on altered network connectivity.Results:Compared to HCs, reduced hubness of a right superior temporal gyrus (rSTG) cluster was observed in the FEPs. In patients exhibiting high CD, increased hubness of a medial superior parietal (mSPL) cluster was observed, compared to patients exhibiting low CD. These two regions were strongly correlated with CD scores but not with other symptom scores.Discussion:Our observations are congruent with previous findings of reduced but not increased hubness. We observed increased hubness of mSPL suggesting that cortical reorganization occurs to provide alternate routes for information transfer.Conclusion:These findings provide insight into the underlying neural processes mediating the presentation of symptoms in untreated FEP. A longitudinal tracking of the symptom course will be useful to assess the mechanisms underlying these compensatory changes.

Download Full-text

Progress on Whole Brain Imaging Methods at The Level of Optical Microscopy*

PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS ◽

10.3724/sp.j.1206.2012.00237 ◽

2012 ◽

Vol 39 (6) ◽

pp. 498-504

Author(s):

An-An LI ◽

Hui GONG

Keyword(s):

Optical Microscopy ◽

Brain Imaging ◽

Whole Brain ◽

Imaging Methods

Download Full-text

Chemical sectioning fluorescence tomography: high-throughput, high-contrast, multicolor, whole-brain imaging at subcellular resolution

Cell Reports ◽

10.1016/j.celrep.2021.108709 ◽

2021 ◽

Vol 34 (5) ◽

pp. 108709

Author(s):

Xiaojun Wang ◽

Hanqing Xiong ◽

Yurong Liu ◽

Tao Yang ◽

Anan Li ◽

...

Keyword(s):

Brain Imaging ◽

High Throughput ◽

High Contrast ◽

Whole Brain ◽

Fluorescence Tomography ◽

Subcellular Resolution

Download Full-text

Brain-specific inhibition of mTORC1 eliminates side effects resulting from mTORC1 blockade in the periphery and reduces alcohol intake in mice

Nature Communications ◽

10.1038/s41467-021-24567-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yann Ehinger ◽

Ziyang Zhang ◽

Khanhky Phamluong ◽

Drishti Soneja ◽

Kevan M. Shokat ◽

...

Keyword(s):

Side Effects ◽

Inhibitory Action ◽

Alcohol Use Disorder ◽

Alcohol Intake ◽

Therapeutic Agents ◽

Adverse Side Effects ◽

Mtorc1 Activation ◽

Potential Use ◽

Heavy Alcohol Intake ◽

Alcohol Dependent

AbstractAlcohol Use Disorder (AUD) affects a large portion of the population. Unfortunately, efficacious medications to treat the disease are limited. Studies in rodents suggest that mTORC1 plays a crucial role in mechanisms underlying phenotypes such as heavy alcohol intake, habit, and relapse. Thus, mTORC1 inhibitors, which are used in the clinic, are promising therapeutic agents to treat AUD. However, chronic inhibition of mTORC1 in the periphery produces undesirable side effects, which limit their potential use for the treatment of AUD. To overcome these limitations, we designed a binary drug strategy in which male mice were treated with the mTORC1 inhibitor RapaLink-1 together with a small molecule (RapaBlock) to protect mTORC1 activity in the periphery. We show that whereas RapaLink-1 administration blocked mTORC1 activation in the liver, RapaBlock abolished the inhibitory action of Rapalink-1. RapaBlock also prevented the adverse side effects produced by chronic inhibition of mTORC1. Importantly, co-administration of RapaLink-1 and RapaBlock inhibited alcohol-dependent mTORC1 activation in the nucleus accumbens and attenuated alcohol seeking and drinking.

Download Full-text