Experiencing chronic stress or taking addictive drugs like cocaine can change your brain and behavior in similar ways, making you prone to anxiety or addiction.
Key Facts:
- Chronic stress and chronic drug abuse both impair the striatum, which can make people become rigid in their thinking and unable to update information. This can promote anxiety, addiction, OCD and other problems.
- Both stress and drugs cause epigenetic changes in the striatum. Epigenetics refers to chemical changes that alter how genes are turned on or off.
- These epigenetic changes include DNA methylation, histone modifications, and activation of jumping genes called transposons. They alter the activity of genes that control learning and habit formation.
- Studies in mice and rats show that stress and drug exposure produce converging epigenetic changes in the striatum. This suggests common mechanisms contribute to cognitive inflexibility from stress or addiction.
- Understanding these shared epigenetic effects may lead to new therapies to treat or prevent mental health disorders related to chronic stress or addiction.
Source: Trends in Neuroscience. 2022 Dec.
The Striatum Controls Habits and Decision-Making
The striatum is a structure deep inside the brain that plays critical roles in decision-making, action planning, motivation, and habit formation.
It acts like a hub integrating inputs from many other brain regions involved in emotion, movement, and cognition.
The striatum is divided into several subregions with distinct functions.
The dorsomedial striatum controls goal-directed behaviors, while the dorsolateral striatum handles habitual or automatic behaviors.
Shifting activation from dorsomedial to dorsolateral striatum is a natural part of learning routines and skills.
But in some cases, the striatum becomes impaired, leading to inflexible thinking and behaviors.
This underlies problems like drug addiction, obsessive-compulsive disorder, anxiety, and poor decision-making.
How Stress and Drugs Disrupt Striatum Function
Both chronic stress and chronic drug abuse can alter signaling in the striatum and connected brain regions.
This disrupts the delicate balance between flexible, thoughtful behaviors versus automatic habits.
Stress Exposure:
- Stress hormones including cortisol overactivate brain receptors, impairing signaling
- Increased glutamate activity alters synapse function and connections between striatum and cortex
- This impairs evaluating consequences of actions, promotes risky choices
Drug Abuse:
- Cocaine, methamphetamine increase dopamine, altering striatum signaling
- With repeated drug use, changes in receptors and synapses make drug-seeking more automatic
- Drug-induced elevation of dopamine disrupts updating of reward information
- Leads to inflexible focus on drug-taking without reassessing consequences
Both stress and drug abuse lead to converging issues like poor decision-making, compulsivity, and cognitive inflexibility regulated by the striatum.
Shared Epigenetic Changes Underlie Striatum Dysfunction
So how do stress and drugs induce these similar effects in the brain?
Studies suggest they cause overlapping epigenetic changes in the striatum that disrupt normal activity of genes involved in learning and plasticity.
Epigenetic Modifications Alter Gene Activity
“Epigenetics” refers to molecular factors and processes that regulate how genes are turned on or off inside cells.
Unlike fixed changes in the DNA sequence itself, epigenetic modifications are reversible chemical alterations to DNA or its packaging proteins.
There are three main types of epigenetic changes:
DNA Methylation:
- Adds methyl groups to DNA, typically silencing gene expression
- Done by enzymes called DNA methyltransferases
Histone Modifications:
- Histones are proteins DNA wraps around to package into chromosomes
- Adding chemical tags like acetyl groups to histones alters chromatin structure, activating or repressing genes
Transposon Activation:
- Transposons are “jumping genes” that can copy and insert themselves in new places in the genome
- Normally silenced, but environmental factors can trigger increased transposon activity
Acute versus Chronic Effects
Research finds that acute stress or limited drug use causes epigenetic changes that increase plasticity and excitability.
This helps consolidate early memories linked to the experience.
But chronic stress or drug exposure gives way to silencing epigenetic marks that impair plasticity and learning.
This prevents updating information and memories, promoting inflexible habits.
Overlapping Epigenetic Mechanisms Identified
Studies in animal models reveal that chronic stress and chronic drug abuse lead to shared epigenetic effects in the striatum:
DNA Methylation
- Hypermethylation and silencing of genes needed for plasticity and information updating
Histone Modifications
- Changes in histone proteins impair expression of learning/plasticity genes
Transposon Activation
- Stress or drugs trigger increased transposon activity, disrupting the genome
These converging epigenetic changes likely contribute to rigid thought patterns and behaviors resulting from chronic stress or addiction.
Targeting these mechanisms may lead to new treatment approaches.
DNA Methylation Effects in Learning and Addiction Genes
DNA methylation is an epigenetic mechanism that typically silences gene expression by adding methyl tags to DNA.
It plays important roles in brain function and can be increased by stress or drug exposure.
Research finds chronic stress induces DNA hypermethylation of the GDNF gene in the striatum of mice prone to stress. GDNF encodes a nerve growth factor that protects dopamine neurons.
Methylation of GDNF reduces its expression, which may increase susceptibility to dopamine-related problems.
Studies also show cocaine and methamphetamine increase DNA methylation of multiple genes involved in synaptic plasticity and excitability.
For example, increased methylation of BDNF is linked to elevated drug craving.
Chronic hypermethylation of these plasticity-related genes likely impairs the ability to update memories and environmental information.
This promotes the rigid behaviors linked to compulsion and addiction.
Activation of Mobile Genetic Elements
Transposons are DNA sequences that can move to new locations in the genome.
They are normally silenced but can be activated by stress or stimulant drugs.
Increased transposon jumping around disrupts genomic stability and gene regulation.
One transposon called LINE-1 shows increased activity in the striatum after acute stress or cocaine use in rodent models.
However, with chronic exposure LINE-1 activity goes back down while newly inserted copies remain in the genome.
These inserted LINE-1 copies could have long-term effects on gene expression by disrupting DNA.
This may be one mechanism underlying persistent effects of chronic stress or drug abuse on striatum function.
Histone Modification Changes Implicated
Histones are proteins that DNA wraps around to condense into chromosomes inside cells.
Adding or removing chemical tags to histone proteins alters their structure, loosening or tightening chromatin packing. This controls gene activity.
Studies find stress and stimulant drugs regulate histone modifications in the striatum.
Acute exposure typically increases histone acetylation, activating plasticity genes.
But chronic exposure increases deacetylation, which represses and silences genes instead.
For example, chronic cocaine exposure in mice elevates HDAC enzymes that remove acetyl groups from histones.
This reduces global histone acetylation and plasticity gene expression.
Similarly, chronic stress exposure increases HDAC1 activity at the opioid receptor gene OPRK1.
This deacetylation maintains OPRK1 expression, which may increase susceptibility to stress.
Tracking Shared Molecular Mechanisms
The above examples illustrate how chronic stress and drug abuse induce converging epigenetic changes in the striatum that promote cognitive rigidity and compulsive behaviors.
These insights may shed light on common molecular mechanisms contributing to anxiety, addiction, and related disorders.
Future studies should aim to:
- Determine if manipulating these epigenetic changes can reverse related behavioral abnormalities
- Identify additional brain regions and cell types affected by shared epigenetic dysregulation
- Uncover molecular players and signaling pathways that coordinate similar epigenetic effects of stress and drug exposure
- Examine whether prevention or reversal of epigenetic changes early on could reduce risk of later developing stress or addiction-related disorders
Overall, a deeper understanding of overlapping epigenetic pathways altered by chronic stress and drug abuse could unlock more effective therapeutic targets to treat these challenging conditions.
- References
- Study: Convergent actions of stress and stimulants via epigenetic regulation of neural circuitry
- Authors: Michael D Murphy & Elizabeth A Heller (2022)
