When Stress Becomes Exhaustion: What the Brain’s Salience Network Reveals About Resilience

Why do some people bend under stress and recover—while others become increasingly sensitive, overwhelmed, and depleted?

A growing body of neuroscience suggests the answer is not how much stress the brain detects, but whether it still has the energy to act on that information.

A recent single-cell study published in Cell Reports (2026) offers an important clue. Instead of focusing on what “goes wrong” in stress-related conditions, the researchers asked a different question:

What does the brain actively do when stress is successfully handled?

Their answer points to a deep connection between resilience, salience, and bioenergetic capacity.

Resilience Is Not Quiet — It’s Energetically Active

Using single-nucleus RNA sequencing, the study examined how different brain regions respond to chronic social stress. One finding stood out:

Resilient brains showed more transcriptional activity—not less.

In particular, neurons in the ventral tegmental area (VTA)—a midbrain hub closely tied to motivation and salience—underwent extensive, coordinated gene expression changes.

These changes supported:

• neural communication

• synaptic plasticity

• network stability

In contrast, stress-sensitive brains showed far fewer sustained transcriptional adaptations, even though behavioral symptoms were more severe.

This is a crucial inversion of how we usually think about stress.

Vulnerability was not associated with “too much activation,” but with insufficient adaptive capacity.

The Salience Network: What the Brain Tries to Save Until the End

To understand why this matters, we need to zoom out to brain networks.

The salience network—anchored in the anterior insula, dorsal anterior cingulate cortex, and closely coupled with the VTA—has one essential job:

Decide what matters right now.

It filters internal and external signals, assigns importance, and decides where attention, effort, and energy should go. It also helps switch between other major networks, including the central executive network (CEN), which supports planning, working memory, and goal-directed behavior.

From an energetic perspective, this makes the salience network special.

• It is metabolically expensive

• It is functionally indispensable

• And it is likely one of the last integrative networks the brain tries to preserve under energy stress

As long as salience is intact, the organism can still prioritize, mobilize, and recover—even if other functions are temporarily dialed down.

When Salience Fails, Sensitivity Appears

This new study helps clarify what happens when bioenergetic stress deepens.

In resilient individuals:

• salience detection remains coupled to adaptive action

• the VTA actively supports plasticity and recovery

• stress episodes resolve

In stress-sensitive states:

• salience signaling becomes fragmented or unstable

• adaptive transcriptional programs fail to engage

• effort no longer produces proportional outcomes

Clinically, this does not look like numbness.

It looks like:

• heightened sensitivity to minor stressors

• rapid exhaustion after small demands

• paradoxical reactions to “appropriate” treatments

In other words, sensitivity is not hyper-reactivity.

It is exhaustion.

Central Executive Network: The First to Go, Not the Last

Importantly, this framework also explains why higher cognitive functions often fail early under chronic stress.

The central executive network—responsible for focus, planning, and self-control—is energetically costly but not immediately survival-critical. Under bioenergetic constraint, it is often downregulated before salience.

That’s why people under chronic stress often say:

• “I know what I should do, but I can’t do it.”

• “My motivation is there, but my capacity isn’t.”

• “Thinking feels harder than it used to.”

The problem is not lack of insight—it’s lack of energetic bandwidth.

A Different Definition of Resilience

This research supports a more mature view of resilience:

Resilience is not resistance to stress.

It is the ability to pay the energetic cost of adaptation—and still recover.

From this perspective:

• preserved salience = adaptive capacity

• blunted or unstable salience = advanced exhaustion

• stress sensitivity = a signal, not a flaw

And interventions that ignore bioenergetic limits—by stacking demands, supplements, or protocols—may unintentionally worsen the very sensitivity they aim to fix.

The Takeaway

If we want to understand chronic stress, burnout, and stress-related illness, we need to stop asking:

“Why is this system so reactive?”

and start asking:

“Does this system still have the energy to adapt?”

The brain’s salience network may be one of the clearest windows into that answer.

Minerva, A. R., McMannon, B., Lin, R., Zhukovskaya, A., Witten, I. B., & Peña, C. J. (2026). Stress resilience is associated with transcriptional remodeling in the ventral tegmental area. Cell Reports, 45, 116867. https://doi.org/10.1016/j.celrep.2025.116867