Researchers at the HUN-REN Institute have discovered that specific inhibitory neurons in the brain, called HDB-PV neurons, play a critical role in learning from negative experiences. These neurons enhance cognitive processes and are essential for attracting attention and facilitating learning in response to aversive stimuli. Credit: Issues.fr
A neuroscience study identifies specific brain neurons that are essential for learning from negative stimuli, highlighting their potential role in mental health.
We often say “I won’t do that anymore” when faced with negative feedback, side effects, or disappointing results. From these experiences we try to learn.
How does the brain facilitate this type of learning? Positive and negative reinforcement are crucial mechanisms within the brain’s valuation system. Neurons releasing the neurotransmitter dopamine mean better or worse outcomes than expected by increasing or decreasing their activity. At the same time, there is growing evidence that other parts of the brain handle “negative” and “positive” differently.
Arousal and attention in negative experiences
Negative experiences often cause a strong arousal effect, activating specific parts of the neocortex. This activation helps us focus on relevant features and learn from the experience, a concept known as “attention for aversive learning.”
Researchers from the HUN-REN Institute of Experimental Medicine, led by Balazs Hangya, explored which brain regions and neuron types are involved in aversive learning. Their study, published in Natural communicationsreveals that long-range projecting inhibitory neurons that express the protein parvalbumin (PV) in the horizontal limb of Broca’s diagonal band (HDB) play a crucial role in this process.
Axons expressing parvalbumin (yellow) contact a cholinergic neuron (cyan) in the medial septum. Credit: Panna Hegedüs. Based on Hegedüs et al., 2024, Nature Communications.
Neuron functionality and experimental results
These HDB-PV neurons, known for their rapid activity, transmit excitatory effects to the neocortex and control gamma oscillations essential for cognitive functions. Therefore, they emerged as good candidates for mediating “attention to aversive learning.” Hangya’s team showed that these neurons are indeed recruited by aversive events in experimental mice, such as an unexpected puff of air to the face that the mice strive to avoid, or the smell of a fearful predator.
The effects of aversive events
Aversive events activate a range of pathways, leading to a range of consequences in the brain. First, they promote avoidance behaviors that reduce the risk of experiencing negative impacts. Second, they improve awareness and attention by activating the relevant parts of the neocortex, thus helping the body to cope with the situation. Third, they facilitate learning to avoid or mitigate similar future scenarios.
Panna Hegedüs, the first author of the study, noted: “Learning from negative experience is an ancient and deeply rooted survival strategy. It can even negate the effects of positive reinforcement.
Overviews of optogenetics
Hangya’s team used a technology called optogenetics, which can make specific cell types, in this case HDB-PV neurons, sensitive to light. These techniques enable precise activation or suppression of neuron activity by programmed delivery of light into brain tissue via small optical fibers. They found that activation of HDB-PV neurons did not cause avoidance behavior in mice, suggesting that this pathway is not involved in active avoidance such as seeking shelter, but that it more likely mediates attention and/or aspects of learning induced by aversive stimuli.
Indeed, when optogenetically blocking neuron responses to facial air puffs, mice failed to learn discriminative predictive auditory stimuli predicting probable or improbable air puffs. This experiment demonstrated that HDB-PV neurons are necessary for learning aversive stimuli.
Neural circuits and behavioral responses
Neurons do not act in isolation but are part of complex circuits with various input and output pathways. Hangya’s team, with Gabor Nyiri and colleagues from the same institute, mapped the inputs and outputs of HDB-PV neurons. They found that these cells integrate multiple sources of aversive information, including important pathways from the hypothalamus and raphe nuclei of the brainstem. In turn, they transmit integrated information to the so-called limbic system, largely responsible for behavioral and emotional responses, including the septo-hippocampal system important for the storage and recall of episodic memories.
Additionally, inhibitory HDB-PV cells primarily target other inhibitory neurons in these regions, thus likely relieving excitatory cells of inhibition and allowing them to be more active – a ubiquitous brain mechanism called disinhibition.
Conclusion and implications for mental health
The study suggests that long-range inhibitory HDB-PV neurons are recruited by aversive stimuli to perform crucial associative learning functions by increasing cortical excitability at specific target areas, likely through disinhibition. Thus, at least for aversive stimuli, HDB-PV neurons could be the physical substrate of the concept of “attention for learning”.
“Dysregulation of positive and negative valence processing can be observed in different psychiatric disorders, including anxiety and depression. It is therefore crucial to understand how negative valence is encoded in the brain and how it contributes to learning,” concludes Hegedüs.
