The Bed Nucleus of the Stria Terminalis: between Stress and Reward
December 18, 2014
The main goal of my PhD was to identify the adaptive neuronal mechanisms developing in the reward circuit and in the circuit implicated in the regulation of stress responses. More specifically, we have studied the function of the bed nucleus of the stria terminalis (BNST) in both circuits. My hypothesis was that, the BNST belongs to interconnected circuits in which it integrates contextual (from ventral hippocampus) and emotional informations (from medial prefrontal cortex).
Thus, BNST diffuses these informations in order to regulate the basal innate level of anxiety and stress centers responses induced after acute stress exposure, but also to adapt the activity of dopaminergic neurons of the ventral tegmental area (VTA) that can promote or prevent a behavioral task associated with a rewarding or aversive stimulus.
To test this hypothesis, we decided to develop several research projects using electrophysiological, anatomical and behavioral approaches. Firstly, we focused our interest on the stress circuit in which the BNST is a key structure which participates in regulating the responses of stress centers after acute stress exposure. By using in vivo electrophysiology approach in anesthetized mice, we have shown that after acute restraint stress, BNST neurons adapt their plastic responses induced by the tetanic stimulation of the medial prefrontal cortex: switch from long term depression (LTD) under control condition to long term potentiation (LTP) after acute stress condition.
Furthermore, we demonstrated that both LTD and LTP are endocannabinoid dependent by using genetic modified mice for the type 1 endocannabinoid receptors and local pharmacological approach in the BNST. In a second step, we studied the function of the ventral subiculum (vSUB) in the regulation of BNST neurons and the impact of the vSUB-BNST pathway activation on the other glutamatergic ILCx-BNST pathway. In a first set of experiments, we showed that a same single BNST neuron could integrate informations from both vSUB and the infralimbic cortex. By using high frequency stimulation (HFS) protocols, we induced in vivo NMDA-dependent LTP in the vSUB-BNST pathway whereas the same protocol led to LTD in the same BNST neurons in the ILCx-BNST pathway.
Moreover, we noted after a single application of HFS protocol in the vSUB induced a long term decrease of the basal innate level of anxiety in rats. Lastly, we presented the BNST as a key excitatory relay between the vSUB and the VTA.
Here, we have shown that in vivo HFS protocols in the vSUB potentiate the activity of dopaminergic (DA) neurons of the VTA. However, the vSUB does not directly project to the VTA. We observed that a HFS protocol in the vSUB first induce NMDA-dependent LTP in BNST neurons that project to the VTA, which is necessary to promote the potentiation of VTA DA neurons. In the last step, we demonstrated in vivo that the potentiation of VTA DA neurons increases the locomotor response to cocaine challenge.
All together, these projects allow us to confirm and detail the major function of the BNST in the regulation of stress and anxiety and also in the motivational circuit (Figure1: Conclusion scheme).
• Stress Switches Cannabinoid Type-1 (CB1) Receptor-Dependent Plasticity from LTD to LTP in the Bed Nucleus of the Stria Terminalis. Christelle Glangetas, Delphine Girard, Laurent Groc, Giovanni Marsicano, Francis Chaouloff, François Georges. Journal of Neuroscience December 2013
• Ventral Tegmental Area Cannabinoid Type-1 Receptors Control Voluntary Exercise Performance. Dubreucq S, Durand A, Matias I, Bénard G, Richard E, Soria-Gomez E, Glangetas C, Groc L, Wadleigh A, Massa F, Bartsch D, Marsicano G, Georges F, Chaouloff F. Biological Psychiatry – December 2012
Dernière mise à jour le 03.12.2014
Président (Bordeaux, France)
Rapporteur (Kingston, Canada)
Rapporteur (Paris, France)
José Miguel Pêgo
Examinateur (Braga, Portugal)
Examinateur (Bordeaux, France)
Examinateur (Bilbao, Spain)
Directeur de thèse IINS (Bordeaux)
IINS-CNRS UMR 5297
Team: Development and adaptation of neuronal circuits