Using a rodent stress model, researchers at the Laboratory of Thalamus Research, HUN-REN Institute of Experimental Medicine discovered a sustained increase in neural activity that persisted for several days after an exposure to a strongly stressful event in a thalamic nucleus called paraventricular thalamus (PVT). Prolonged elevation of PVT activity was paralleled by restlessness during wakefulness, disturbed behaviour before falling asleep, and prolonged sleep onset. If the PVT activity was selectively inhibited after the stress event for only one hour the sustained increase in PVT activity did not take place and the behavior of the mice remained normal after the stress event during the ensuing days.
Why is this significant?
Increased spontaneous activity that persists for days has never been described in the brain. The brain typically has robust mechanisms to reduce excessive excitatory activity. Increased excitation is always paralleled by a compensatory increase in inhibition. Even in the epileptic brains neuronal activity between the seizures is largely normal because of increased inhibition. The present data demonstrate that persistently increased activity can still take place under special circumstances in special brain regions. The data highlight a mechanism that allows to alter the state of the brain for prolonged periods after the exposure to a single salient event. The results also show that this increase in neuronal activity is reversable suggesting that the effect of a stressful event can be ameliorated possibly by natural mechanisms as well.
Why the PVT?
The heightened activity was recorded in the PVT, a uniquely organised cluster of neurons in the thalamus. This was no coincidence: the PVT acts as a "hub" where inputs from brain areas encoding stress, alertness and motivation converge before being relayed to the cortex as a fast glutamatergic neuronal message. The integrated message is projected to all major forebrain centres (amygdala, prefrontal cortex, hippocampus, nucleus accumbens) that control behavior. No other brain region is known to display similar connectional properties. Thus, PVT acts like a real bottleneck in the brainstem-forebrain communication, an integrator of stress signals.
What is the relevance for the human condition?
An earlier study of the same research group demonstrated that the organization of PVT is very similar in mice and humans. PVT contains the same cell type in both species and receives similar selective inputs from the brainstem and the hypothalamus. This shows that the brain centre specialized to transfer emotional and arousal signals to the forebrain is evolutionary highly conserved.
In the mice model the researchers exposed the animals to an ecologically relevant stressor the scent of a predator (fox) for 10 minutes. The ensuing behavioral phenotype was very similar to the symptom clusters of acute stress disorder (negative mood, avoidance, increased arousal, sleep problems). This validates the present approach as a potentially relevant animal model to study the initial changes in the brain after a significantly stressful event.
What are the implications to treat stress disorders?
A traumatic experience or a major stressful event can lead to lasting, and in some cases lifelong, changes in behaviour. Although this phenomenon is well known, its neurological underpinnings are not yet understood, and effective treatments are still lacking.
An assault in the street, an accident, a family tragedy, or an ordeal cause lasting changes in behaviour in around 20% of individuals who experience such events. Researchers distinguish between the early, acute phase (up to 30 days after the stressor) and the later phase (after 30 days, in cases of post-traumatic stress disorder, PTSD) of the disease. Symptoms are similar in both phases. One of the best-known symptoms of PTSD is the frequent recurrence of traumatic memories in inappropriate situations. In addition to these intermittent symptoms, there can be persistent ones that significantly affect mood and behaviour. Examples of such symptoms include restlessness, difficulty falling asleep, emotional instability, and withdrawal.
Many studies have investigated how the brain encodes and retrieves memories but it still remained less clear what neural mechanisms underlie the persistent emotional changes following a trauma. Researchers know that during the encoding and retrieval of memories, brief changes occur in the activity of neurons that store these memories. However, when the event is not recalled, the brain's memory trace remains in a 'dormant' state: neural activity is low and unchanged. Can brief fluctuations in activity, related to memory recalls lead to persistent emotional changes? Or the latter is governed by independent mechanisms? This is a crucial question because currently the main treatments for PTSD focus on extinguishing memories, but these approaches are not very effective.
The present data point to a mechanism that is independent of the memory trace, displays persistent changes after the stress event and is causally related to the stress induced alteration of behavior. This mechanism could pave the way for new therapies for treating stress-related issues. By modulating PVT activity, treatments could be developed that effectively address stress-induced anxiety and trauma-related disorders. A deeper understanding of these long-term neural changes could also contribute to the development of targeted therapies aimed at alleviating stress-related behavioural disorders. Finally, the researchers found that the short, one-hour long inhibition of PVT remained significantly effective even when applied five days after the stressful event. This finding extends the potential therapeutic time window in which a treatment based on these findings could be effective.
