Injured Brain: Childhood Trauma Alters Neural Circuits Linked to Aggression and Self-Harm

Early childhood trauma can leave the brain more sensitive and dysregulated, increasing the likelihood of aggressive and self-harming behaviors. Researchers have discovered that this occurs through hyperactivity of calcium channels in the thalamus's nucleus reuniens, which affect brain circuits linked to pain and emotions. Blocking this activity reduced maladaptive behaviors in animals, revealing a potential target for new treatments.

Aggression and self-harm are two behaviors that, at first glance, seem very different, one is outward, the other inward. However, both have in common the fact that they arise as maladaptive ways of coping with intense emotional suffering. In many cases, these reactions are rooted in traumatic experiences lived in childhood, known as early life traumas.

These traumas, which include abandonment, neglect, physical or emotional abuse, and loss of attachment figures, can profoundly alter brain development, especially in the regions responsible for emotional regulation, pain perception, and impulse control.

Previous research has shown that people with a history of self-harm are up to five times more likely to exhibit aggressive or violent behavior toward others.

This suggests that, rather than being isolated phenomena, aggression and self-harm may share the same neural circuit, representing different manifestations of the same emotional and biological imbalance. This study sought to understand precisely that: which brain mechanisms explain this link and how early trauma interferes with these processes.

Calcium Channels and Their Importance in the Brain

Researchers focused their attention on a family of structures called L-type calcium channels (LTCCs), which are present in the membranes of neurons.

These channels are responsible for controlling the entry of calcium ions into nerve cells, a process essential for communication between neurons, memory formation, learning, and mood regulation.

Two main genes control these channels in the brain: Cacna1c (which encodes the Cav1.2 channel) and Cacna1d (Cav1.3). Previous studies had already shown that alterations in these channels are linked to psychiatric symptoms such as impulsivity, anxiety, aggression, and even depression.

When there is excessive activity of L-type calcium channels, the brain may overreact to social and emotional stimuli, which favors aggressive and self-harming behaviors.

Interestingly, medications that block these channels have proven effective in reducing episodes of self-harm in psychiatric patients. On the other hand, substances that increase their activity, such as the experimental compound Bay K 8644 (called “Bay K”), provoke self-mutilating behaviors and repetitive biting in laboratory animals.

These findings raised an important hypothesis: L-type calcium channels may be a central piece connecting early trauma, emotional dysfunction, and aggressive behavior.

To understand exactly where this happens in the brain, researchers focused on a little-known but crucial area: the reunien nucleus (RE), located in the thalamus, a region that functions as a relay station between different parts of the brain.

The reunien nucleus acts as an integration point between the hippocampus (related to memory and emotion) and the medial prefrontal cortex (linked to reasoning and impulse control).

The reunien nucleus helps the brain coordinate complex emotional responses, process social information, and regulate pain. It is also involved in communication between reason and emotion, that is, in the ability to understand what we feel and react in a balanced way. In people (or animals) exposed to early trauma, this delicate balance seems to break down.

In the study, scientists used mice exposed to early stress, an experimental model that mimics the effects of childhood trauma in humans. These animals showed more aggressive behaviors and a greater tendency toward self-harm.

When observing the brains of these mice, the researchers noticed that the neurons in the nucleus reuniens that produce the neurotransmitter glutamate (called vGlut2 neurons) showed exaggerated activity of L-type calcium channels. This hyperactivity left the brain in a constant state of alert, increasing sensitivity to pain and impulsivity.

When the scientists artificially activated these channels with the substance Bay K, even in mice without prior trauma, the same aggressive and self-harming behaviors emerged. However, when they blocked the function of the Cacna1c gene (which controls L-type calcium channels) specifically in the neurons of the nucleus reuniens, the mice that had suffered trauma significantly reduced these behaviors. This shows that this region, and these channels, play a fundamental role.

The study also revealed that the nucleus reuniens communicates with the ventral hippocampus (vCA1), an area strongly associated with emotion and emotional memory. This connection, called the nucleus reuniens → ventral hippocampus pathway, proved essential for aggression and self-harm behaviors.

More specifically, the researchers discovered that:

- When the nucleus reuniens sends signals to the hypothalamus, there is an increase in aggression, possibly by activating mechanisms linked to defense and survival.

- When the nucleus reuniens communicates with the basal amygdala, a greater propensity for self-harm arises, associated with the temporary relief of emotional pain.

These findings show that aggression and self-harm are not opposing responses, but rather two possible outputs of the same altered neural circuit.

Depending on how the nucleus reuniens connects with other parts of the brain, the individual may react by turning pain against themselves or against others.

In summary, the study demonstrates that childhood trauma can alter the functioning of fundamental brain circuits, making the brain more vulnerable to impulsive and destructive responses. The discovery that the nucleus reuniens and L-type calcium channels are at the center of this network opens up new therapeutic possibilities.

Medications that modulate the activity of these channels already exist and are used in other neurological conditions, such as epilepsy and hypertension. Therefore, they could, in the future, be adapted to treat people with a history of early trauma and self-destructive behaviors, helping to restore the balance between emotion and cognitive control.

This research also reinforces an important message: emotional traumas leave real physical marks on the brain. Understanding these changes is essential for developing more humane, effective, and personalized treatment approaches that consider not only visible behavior but also the biology and history of each individual.

READ MORE:

Thalamo-hippocampal pathway determines aggression and self-harm

JANE JUNG, IN-JEE YOU, and SORA SHIN 

SCIENCE ADVANCES, 5 Nov 2025, Vol 11, Issue 45

DOI: 10.1126/sciadv.ady5540

Abstract:

Aggression and self-harm are maladaptive coping strategies that often occur in individuals with a history of early life trauma (ELT), yet their underlying neural mechanisms remain unclear. Here, we identify L-type calcium channel (LTCC)–expressing thalamic nucleus reuniens (RE) as a critical component regulating both behaviors. ELT-induced excessive LTCC activity in vesicular glutamate transporter 2 (vGlut2) RE neurons and its corresponding effects on persistent neuronal activation contribute to increasing susceptibility to aggression and self-harm. Activation of vGlut2 RE neurons projecting to ventral hippocampus (vCA1), but not medial prefrontal cortex, promotes these behaviors in control mice. Furthermore, we found that RE neurons modulate two distinct subsets of vCA1 neurons, with one projecting to the hypothalamus to drive aggression and another to the basal amygdala to mediate self-harm. Our findings uncover how LTCC functions in the RE-to-vCA1 neural pathway increase the risk of aggression and self-harm, highlighting potential therapeutic targets for mitigating destructive behaviors following early adversity.