🧠 neuroscience

Prenatal THC exposure disrupts mitochondrial respiratory gene programs and delays medium spiny neuron maturation in the nucleus accumbens

This study demonstrates that prenatal THC exposure in rats disrupts mitochondrial respiratory gene programs and delays medium spiny neuron maturation in the nucleus accumbens through coordinated transcriptional and epigenetic alterations, thereby impairing the development of reward circuitry.

Original authors: Chen, Z., Chen, W., Lee, Y. S., Jones, W., Goetzl, L., Thomas, J. D., Dong, Y., Wang, C.

Published 2026-04-28

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CC BY 4.0

Original authors: Chen, Z., Chen, W., Lee, Y. S., Jones, W., Goetzl, L., Thomas, J. D., Dong, Y., Wang, C.

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ⚕️ This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer

Imagine the developing brain as a bustling, high-tech city under construction. In this city, the Nucleus Accumbens (NAc) is the "Reward District," a special neighborhood responsible for how we feel pleasure and motivation. The workers building this district are called Medium Spiny Neurons (MSNs); think of them as the master electricians and architects who wire up the city's lights and power grid.

This study looks at what happens when a pregnant mother is exposed to THC (the main active ingredient in cannabis). The researchers found that this exposure throws a wrench into the construction of the Reward District, specifically by messing with the city's power plants.

Here is the breakdown of what happened, using simple analogies:

1. The Power Plants Go Dark

Inside every cell, there are tiny power plants called mitochondria. Their job is to burn fuel to create energy (like a generator).

What the study found: When the developing brain was exposed to THC before birth, the instructions (genes) for building and running these power plants were silenced.
The result: By the time the baby rats were about a month old (Postnatal Day 24), the power plants in the Reward District were running on low battery. They couldn't generate enough energy to do their job properly.

2. The Construction Crew Gets Confused

Building a complex city requires a delicate balance: you need energy to build, and you need to manage the tools and materials (proteins) you use.

The connection: The study found that because the power plants were failing, the "construction crew" (the neurons) also got confused. The systems that manage the supply of building materials (ribosomes) and the systems that recycle old or broken tools (proteasomes) were thrown off balance.
The result: The neurons couldn't mature properly. They were like electricians who arrived at the job site but were too tired and disorganized to finish wiring the buildings. The "Reward District" remained in an immature state.

3. The Blueprint Was Tampered With

You might wonder, why did the power plants stop working?

The mechanism: The study looked at the "blueprints" (DNA) and found that the chemical locks on the pages were changed. Specifically, the switches that tell the cell to turn on the power plant genes (controlled by factors like NRF1 and YY2) were stuck in the "off" position.
The result: Even though the instructions were there, the cell couldn't read them, so it never built the necessary machinery.

4. A Second Shock Made It Worse

The researchers gave the young rats a sudden, one-time dose of THC when they were already a month old.

The result: This didn't just cause a temporary glitch; it made the existing power failure even worse and pushed the maturation of the neurons even further back. It was like trying to fix a broken generator while someone kept kicking the fuel tank.

The Bottom Line

In simple terms, this paper shows that prenatal THC exposure doesn't just "scramble" the brain randomly. It specifically targets the energy systems of the brain's reward center. By shutting down the power plants and confusing the cell's supply chain, it prevents the brain's "reward neurons" from growing up and finishing their job. This explains, at a molecular level, why the brain's reward circuitry might develop differently after exposure to cannabis before birth.

Technical Summary: Prenatal THC Exposure and NAc Neurodevelopment

1. Problem Statement
Prenatal cannabis exposure (PCE) is a growing public health concern linked to adverse neurodevelopmental outcomes. However, the specific molecular mechanisms by which PCE disrupts the development of the brain's reward circuitry—particularly the nucleus accumbens (NAc)—remain poorly understood. There is a critical gap in knowledge regarding how prenatal $\Delta^9$ -tetrahydrocannabinol (THC) exposure alters transcriptional and epigenomic landscapes during critical developmental windows, specifically concerning mitochondrial function and neuronal maturation.

2. Methodology
The study employed a rat model to investigate the molecular consequences of prenatal THC exposure. The researchers utilized a multi-omics approach to characterize cellular and molecular changes:

Experimental Design: Rats were exposed to THC prenatally. Offspring were analyzed at postnatal day 24 (P24), a critical period for NAc maturation.
Single-Cell/Nucleus Sequencing:
- snRNA-seq (Single-nucleus RNA sequencing): Used to profile transcriptomic changes across different cell types in the NAc.
- snATAC-seq (Single-nucleus Assay for Transposase-Accessible Chromatin sequencing): Used to map chromatin accessibility and identify epigenomic alterations.
Acute Challenge: A subset of PCE offspring received an acute THC challenge at P24 to assess the resilience and exacerbation of molecular deficits.
Target Analysis: Special focus was placed on Medium Spiny Neurons (MSNs), the primary neuronal population in the NAc.

3. Key Contributions
This research provides the first comprehensive transcriptional and epigenomic framework linking prenatal THC exposure to specific metabolic and developmental disruptions in the NAc. Key contributions include:

Defining the mitochondrial respiratory gene program as a primary target of PCE.
Establishing a mechanistic link between mitochondrial dysfunction and delayed neuronal maturation in MSNs.
Identifying specific transcription factors (NRF1 and YY2) and their binding motifs as key epigenomic regulators disrupted by PCE.
Demonstrating that PCE creates a "primed" state where the developing brain is more vulnerable to acute THC challenges later in life.

4. Key Results

Suppression of Oxidative Phosphorylation: PCE significantly downregulated genes associated with mitochondrial oxidative phosphorylation in the NAc at P24. This indicates a fundamental impairment in mitochondrial respiration capacity.
Coupled Disruption of Protein Homeostasis: The mitochondrial dysfunction was not isolated; it was accompanied by coordinated alterations in ribosomal and proteasomal pathways. This suggests a systemic failure in protein synthesis and degradation (proteostasis) within MSNs, hindering their maturation.
Epigenomic Alterations: snATAC-seq revealed reduced or altered chromatin accessibility at promoter regions enriched with NRF1 (a master regulator of mitochondrial biogenesis) and YY2 binding motifs. This confirms that the transcriptional suppression is driven by epigenetic remodeling.
Exacerbation by Acute Challenge: When PCE offspring were subjected to an acute THC challenge at P24, the mitochondrial dysfunction and delays in MSN maturation were significantly worsened compared to controls, suggesting a cumulative toxic effect.

5. Significance
These findings offer a novel mechanistic insight into how PCE alters reward circuitry development. By pinpointing mitochondrial dysfunction as a central driver, the study suggests that the adverse neurodevelopmental outcomes of PCE may stem from an energy deficit and proteostatic imbalance that prevents MSNs from maturing correctly. The identification of NRF1 and YY2 as epigenomic targets provides potential biomarkers for early detection and therapeutic targets for mitigating the long-term effects of prenatal cannabis exposure on the developing brain.