A Map Through Time: Tracking Huntington’s Disease From Birth in the Brain

A new study in mouse models reveals how Huntington’s disease (HD) disrupts brain development over time, even long before symptoms appear. Using advanced sequencing tools and spatial transcriptomics, a technique that maps where in the brain genes are activated, researchers discovered early warning signs that could help explain why some brain cells are more vulnerable than others in HD.

Why this matters

We know that HD is caused by a repetition of genetic letters that spell C-A-G in the huntingtin gene. People who won’t develop HD have 35 or fewer CAGs, whereas people who go on to develop HD have 36 or more.

And while every cell carries this genetic spelling mistake, certain brain cells are hit much harder, causing them to die early. What we still don’t fully understand is why those cells are more vulnerable, or what might be happening silently in the brain long before symptoms appear to make them more vulnerable.  

In a new study, led by Dr. Leslie Thompson and Dr. Mara Burns at the University of California Irvine, the team dove into that mystery. They used a powerful combination of techniques called “spatial transcriptomics” and “single-cell sequencing”. 

Spatial transcriptomics sounds fancy (and it is!), but its name gives us clues into what it does. It spatially maps transcripts, or the short genetic messages created from DNA before they turn into protein, on a brain sample. So it can be used to show where genetic messages are on an image of the brain. The researchers used this technique to map changes across the lifetime of mice that model HD.

Single-cell sequencing looks at the genetic messages within a sample in each individual cell. Both of these techniques give a wealth of data and help create a detailed map of what’s going on inside the brain because of HD. 

Interestingly, they found some surprises! Their work suggests that changes in gene activity start from birth and evolve in a cell-type- and region-specific way, particularly affecting the striatum (central brain region that controls movement, motivation, and emotion) and cortex (outer wrinkly bit that controls things like perception, movement, and planning). These two brain regions are heavily impacted by HD. Knowing more about when and how changes happen in these brain regions can help us understand the mystery of selective vulnerability in HD.

The HD Brain’s Vulnerable Zones: Striatum and Cortex

We know that HD doesn’t affect all brain cells equally. Some types of cells, like glia cells which work to support neurons, aren’t vulnerable to death in the same way that neurons are. 

But even neurons themselves are selectively vulnerable. Some types are particularly vulnerable to death, while others remain surprisingly resilient, even in late stages. Among the most affected are medium spiny neurons (MSNs), which make up the bulk of the striatum — a brain region central to coordinating movement, motivation, and learning.

MSNs are critical “relay stations” in the brain’s circuitry, passing along dopamine signals and fine-tuning motor control. In HD, these neurons are among the first to show altered function and eventually die. The new study shows that even in newborn HD mice, MSNs begin to show abnormal gene activation, including increased levels of identity genes like Drd1 and Tac1, which later decline. This suggests the cells might be “overcompensating” early on before crashing.

Meanwhile, in the cortex, another brain region that governs higher thinking and decision-making, the researchers found reduced expression of Tcf4, a key genetic hub important for neuron development. These cortical changes start early and persist through disease progression, hinting that HD may also subtly disrupt how the cortex matures.

A New Era of Brain Mapping

Until recently, if we wanted to know which genes were activated differently by HD, most studies relied on a method called “bulk RNA sequencing”. This technique is powerful, but it has a big drawback: to measure which genes are switched on, scientists first have to grind up brain tissue. That means the genetic messages from all cell types in the sample — vulnerable and resilient neurons, glia, and even cells from blood vessels — gets mixed together. 

Bulk RNA-seq is a bit like taking all the conversations in a city, recording them at once, and mixing them into a single audio track. You’ll hear the overall noise, but you can’t tell whether it came from a teacher in a classroom, a busker on the street, or a child in a playground. To get around this, the researchers in this study used two novel approaches:

• Spatial transcriptomics: This method is a big step forward because it measures gene activity while keeping the tissue slices intact. It’s like taking a bird’s-eye photo of the brain with colored spots showing which neighborhoods are “loud” or “quiet” in their genetic activity. The resolution doesn’t capture signals from each individual cell, but can from groups of dozens of cells. Critically, it preserves the “where” information that bulk methods erase.
• Single-nucleus RNA sequencing (aka, snRNA-seq): Here, scientists zoom in much closer. Instead of working with whole brain slices, they isolate individual cells and read out their genetic activity one by one. This reveals who is speaking in the city of the brain — neurons, astrocytes, microglia, or oligodendrocytes — and what each type of cell is saying. But the downside is that this method loses the spatial context: you know who is talking, but not where they are in the city.

By combining these two methods on a timeline of the HD mouse lifetime, the team got the best of both worlds: the “where” from spatial transcriptomics, and the “who” from single-cell sequencing. This allowed them to build a spatial map across time of how HD unfolds. With it, they linked gene changes to specific cell types and brain regions across three stages: birth, early symptoms, and late disease. This approach offers more nuance than previous techniques and opens new possibilities for understanding complex diseases, like HD.

Key findings

• Reorganization from the very start: Even at birth, HD mice already show altered gene activity. In the striatum, mitochondrial genes (those controlling energy production) were disrupted. In the cortex, a gene called Tcf4, crucial for brain development, was reduced. This may affect how cortical neurons organize and connect.
• Changes over time: MSNs showed early increases in identity genes that help define this specific type of neuron. Over time, this trend seems to change, and identity gene levels decrease. The researchers identified other changes that could contribute to MSN impairment, like mitochondrial deficits, seeming to originate in the striatum prior to overt symptom onset and spreading to other brain regions.
• Communication breakdown: By examining cell-cell signaling pathways, the team found time-dependent changes in neuropeptide Y (NPY) signaling, which may be involved in balancing energy use and neuron health.

Looking Ahead: New Paths for Understanding and Intervention

This study doesn’t just provide a snapshot of the HD brain, it offers a time-lapse map of how things changes as HD advances. By combining spatial and single-cell data, it shows Huntington’s early influence, perhaps beginning as early as birth and building slowly over time.

It’s important to note though, that even changes identified at birth don’t mean the brain can’t compensate. Clearly it can! People with the gene for HD generally live entirely healthy lives for decades. What it could mean is that these early, subtle changes may be setting these cells up for sensitivity later on that makes them more vulnerable to death. So while they can stave off molecular insults across those decades, over time it becomes too much. 

These insights offer several takeaways for the HD community:

• Therapeutic timing: If early gene changes contribute to vulnerability, treatments aimed at stabilizing brain development could be valuable, even before symptoms appear.
• Targeted strategies: Understanding which cells change first, and how, could help develop more precise therapies. Some changes may begin early but are balanced by the brain’s own mechanisms for compensation. Studying these natural defenses could reveal new ways to fight back from the start.
• Biomarker development: Patterns like mitochondrial stress or Tcf4 downregulation may one day help identify disease onset more accurately.

Most importantly, this work highlights the growing importance of big-data brain mapping tools, helping researchers move beyond bulk averages to truly understand what’s happening in individual cells, in real tissue, across time. While this study was done in a mouse model, it lays crucial groundwork for understanding the earliest molecular ripples of HD in the human brain, and how we might one day intervene before the map changes.

Summary 

• Advanced mapping tools: Combining spatial transcriptomics and single-cell sequencing reveals both where and which cells are altered in HD.
• Early beginnings: Gene activity changes start from birth in HD mice, particularly in the striatum and cortex, the brain’s most affected regions.
• Dynamic shifts over time: Neurons in vulnerable regions show early over-activation of identity genes that later decline as disease progresses.
• Energy and communication faults: Mitochondrial and neuropeptide signalling pathways are disrupted, affecting neuron health.
• A blueprint for early intervention: These findings highlight that subtle, early-life changes may shape later vulnerability, guiding future prevention and therapy strategies.

Learn More

Original research article, “Distinct molecular patterns in R6/2 HD mouse brain: Insights from spatiotemporal transcriptomics” (open access).