How the reward system modulates fear responses ?

  • Research
Published on October 1, 2022 Updated on October 1, 2022

on the September 21, 2022

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A research team from the Institute of Molecular and Cellular Pharmacology collaborating with researchers from IMN has demonstrated the unexpected role played by the reward system in modulating freezing, a key stage in human stress management. Their results were published in the journal Molecular Psychiatry.

Stress is a key driver of adaptation, and an organism's stress response is usually beneficial because it contributes to survival. Faced with danger, the brain orchestrates the detection and response to aversive environmental stimuli and guides the selection of the most suitable coping strategy. These innate and acquired behaviors have been shaped by natural selection and preserved in both invertebrates and vertebrates. They include passive strategies such as freezing and active responses such as fight-or-flight. The capacity to switch between these passive/active modes is essential for behavioral flexibility. Freezing is a universal response to fear characterized by a total lack of movement, apart from breathing, due to a tense body posture when a threat is encountered. Freezing is essential in stress management processes because it corresponds to a state of hypervigilance that allows for decision-making and, consequently, the choice of the most relevant behavioral strategy. Although freezing is relevant to the etiology of fear-related disorders such as post-traumatic stress disorder, panic attacks, and social phobias, the neural circuits and underlying cellular substrates remain largely unexplored. 

To address this issue, we combined ex vivo and in vivo electrophysiology approaches coupled with pharmaco- and optogenetic tools and complemented them with microscopy analyses. We used a preclinical model of exposure to an aversive stimulus and measured the immediate freezing responses. We identified new key structures that modulate this defense behavior. These brain structures link the GABAergic neurons of the lateral-dorsal tegmentum (LDTg) that project to the ventral tegmental area (VTA), a structure well known for its role in reward-related responses. Within the VTA, the GABAergic projection neurons subsequently transmit this information to the cerebral amygdala. Activation of the LDTg-VTA-Amygdala triumvirate by aversive events provides a better understanding of the brain processes involved in stress adaptation.

In particular, these results challenge the accepted view of the LDTg-VTA axis, which has historically been linked to reward and reinforcement processes.



 Left: Coronal section of the brain containing the region of the laterodorsal tegmentum nucleus (LDTg); GABAergic neurons in this structure are identifiable through restricted expression of the fluorescent protein mCherry. Center: 3D image of a mouse brain showing the neural circuit (LDTg- >VTA->Amygdala) identified in the Broussot et al. study, highlighting its role in the modulation of freezing behavior in the vigilant animal (right). 
The confocal microscopy image was published in the article. The other illustrations are royalty-free.

A non-canonical GABAergic pathway to the VTA promotes unconditioned freezing
Loïc Broussot 1, 2*, Thomas Contesse 1, 2*, Renan Costa-Campos1, 2, Christelle Glangetas3, Léa Royon 1, 2, Hugo Fofo 1, 2, Thomas Lorivel 2, François Georges 3, Sebastian P. Fernandez 1, 2, 4, and Jacques Barik 1, 2, 4.
1 Université Côte d'Azur, Nice, France.
2 Institute of Molecular & Cellular Pharmacology, CNRS UMR7275, Valbonne, France.
3 University of Bordeaux, CNRS, IMN, UMR 5293, F-33000 Bordeaux, France.
4 Co-last and co-corresponding authors.

Researcher contact
Jacques Barik - Associate Professor, Université Côte d'Azur - - 04 93 95 34 43
Sebastian Fernandez - Researcher, CNRS - - 04 93 95 34 39
 Institute of Molecular and Cellular Pharmacology (CNRS – Université Côte d'Azur).
660 route des Lucioles - 06560 Sophia Antipolis, Valbonne