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From Brain to Behavior: 34 Neuron Subtypes Linked to Addiction Identified


IMAGE: Grigor’eva et al., 2020, doi: 10.1007/s10616-020-00406-7
IMAGE: Grigor’eva et al., 2020, doi: 10.1007/s10616-020-00406-7

The nucleus accumbens (NAc) is crucial to reward and addictive behaviors, containing medium spiny neurons (MSNs) that express either D1R or D2R dopamine receptors. D1R medium spiny neurons are linked to increased drug cravings, while D2R medium spiny neurons help reduce this behavior. What were once thought to be just two types, recent studies have identified several subpopulations of MSNs with distinct functions, suggesting a complex role in addiction.


Addiction is a chronic and complex condition that affects the brain and behavior, characterized by the compulsive use of substances or engagement in behaviors despite negative consequences.


It can involve substances such as drugs, alcohol, or nicotine, or behaviors such as gambling, compulsive shopping, and excessive Internet use.


The incidence of addiction is increasing in many populations, with genetic, environmental, and psychological factors influencing its development. It is estimated that around 10-15% of the world's population will experience some type of substance use disorder at some point in their lives.


Addiction alters brain function, particularly in the areas associated with reward and impulse control.

The nucleus accumbens (NAc) is a brain region that is central to drug-taking and drug-seeking behaviors. It plays a crucial role in how the brain processes rewards and addictions.


Within the NAc, there are two main types of neurons, called medium spiny neurons (MSNs), that express different types of dopamine receptors: dopamine receptor type 1 (D1R) and type 2 (D2R).


Studies in rodents have shown that addictive drugs, such as opioids, cocaine, and methamphetamine, elicit distinct responses in these two types of MSNs.


D1R-expressing medium spiny neurons are associated with increased compulsive drug intake, while D2R-expressing medium spiny neurons help decrease drug reinforcement. For example, activating D2R medium spiny neurons can reduce heroin cravings, suggesting that these neurons have opposing functions in addiction.

All drugs of abuse increase dopamine signaling in the striatum, which may differentially modulate glutamatergic activity in the two subtypes of medium spiny neurons. Source: Lobo and Nestler. https://doi.org/10.3389/fnana.2011.00041


The nucleus accumbens (NAc) is divided into two main subregions: the core and the shell. These areas play different roles in motivated behaviors, such as drug taking and seeking, and have distinct neuronal projections.


In addition, the NAc and the rest of the striatum contain two compartments, the matrix and the striosome, which also have unique functions and are interspersed throughout the striatum.

Recently, detailed transcriptomic analyses have allowed the identification of specific subpopulations of medium spiny neurons. Transcriptomic analyses are studies that examine the complete set of RNA transcribed from genes within a cell or tissue, helping to understand which genes are active and in what quantities.


They allow the identification of patterns of gene expression, differentiating cell types and their functions. This technique is crucial for investigating how different cells contribute to biological processes and diseases, such as addiction.


Matrix and striosomal medium spiny neurons have been found to have unique gene expression profiles in both rhesus monkey and human studies. In rodents, several subtypes of medium spiny neurons have been identified, suggesting that these new subpopulations may have specific functions in the context of addiction.


In addition, studies of the dorsal striatum in humans and non-human primates have revealed differences in gene expression related to sex and cell type, particularly in the context of substance use.


This suggests the need for a more detailed classification of medium spiny neuron populations to better understand their functions and roles in motivated behaviors.

In this context, a recent study from the University of Pennsylvania used a large transcriptomic dataset of single cells from the rat NAc to identify 34 distinct populations of medium spiny neurons, including novel subtypes expressing D1R and D2R.


They confirmed these findings in an independent dataset and analyzed the expression of genes related to neurotransmitter receptors, such as glutamate, GABA, and acetylcholine, to further characterize these subgroups.


Finally, integrating data from medium spiny neurons from rats, mice, and humans, the study associated these subpopulations with different substance use disorders, such as alcohol (AUD), opioid (OUD), and tobacco (TUD) use disorder.


These results highlight the complexity of MSNs in the NAc and provide a basis for future genetic interventions targeting these specific populations of neurons.



READ MORE:


A single-nucleus transcriptomic atlas of medium spiny neurons in the rat nucleus accumbens

Benjamin C. Reiner, Samar N. Chehimi, Riley Merkel, Sylvanus Toikumo, Wade H. Berrettini, Henry R. Kranzler, Sandra Sanchez-Roige, Rachel L. Kember, Heath D. Schmidt & Richard C. Crist 

Scientific Reports. volume 14, Article number: 18258 (2024) 


Abstract:


Neural processing of rewarding stimuli involves several distinct regions, including the nucleus accumbens (NAc). The majority of NAc neurons are GABAergic projection neurons known as medium spiny neurons (MSNs). MSNs are broadly defined by dopamine receptor expression, but evidence suggests that a wider array of subtypes exist. To study MSN heterogeneity, we analyzed single-nucleus RNA sequencing data from the largest available rat NAc dataset. Analysis of 48,040 NAc MSN nuclei identified major populations belonging to the striosome and matrix compartments. Integration with mouse and human data indicated consistency across species and disease-relevance scoring using genome-wide association study results revealed potentially differential roles for MSN populations in substance use disorders. Additional high-resolution clustering identified 34 transcriptomically distinct subtypes of MSNs definable by a limited number of marker genes. Together, these data demonstrate the diversity of MSNs in the NAc and provide a basis for more targeted genetic manipulation of specific populations.

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