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Thesis title: Role of medial prefrontal cortex long-range somatostatin inhibitory projections in fear behaviour.
Marianne Aincy
Equipe Herry (Neuronal circuits of associative learning)
Neurocentre Magendie
Summary
Life threatening situations, such as the presence of a predator, have led animals to express a subset of defensive behaviours essential to survival, that have been conserved throughout evolution. In humans, various defensive reactions with high levels of complexity and variability depending on individuals and situations can be exhibited, but in animal studies we focus on a selective set of these behaviours in order to study fear learning and expression. When fear becomes maladaptive, individuals can develop fear and anxiety disorders, which is the most common psychiatric condition. Therefore, it is important in modern neurosciences to better understand the circuits and mechanisms of fear behaviour.
Decades of research have allowed the identification of the main contributors to these processes: the amygdala (AMG), the medial prefrontal cortex (mPFC) and the periaqueductal grey matter (PAG). Classically, it is considered that fear memory storage and expression depend on excitatory neurons while interneurons (IN) are supposed to be involved in the modulation of excitatory neurons firing activity in local circuits. Among these inhibitory cells, a specific subclass requires particular attention as they can connect distant brain areas: the long-range inhibitory neurons.
In the laboratory, we discovered a specific somatostatin (SST) long-range inhibitory projection from the mPFC to both the AMG and the PAG. In this context, the present work has three objectives. First, to functionally characterize both the local and long-range SST neurons locally in the mPFC and then the projecting SST terminals. Second, to describe the anatomy of the mPFC-AMG and mPFC-PAG pathways. Finally, to identify the functional role of these long-range SST neurons in fear related behaviours by manipulating their activity. To achieve these goals, we used a combination of anatomical tracings, in vitro recordings, optogenetic approaches in behaving animals submitted to associative aversive tasks.
Our results suggest that these SST inhibitory neurons project in the ventrolateral PAG, the lateral PAG, the caudal dorsolateral PAG and the basolateral AMG. The selective manipulation of the mPFC-PAG pathway indicated that these neurons are active in physiological conditions and that they might exert a disinhibitory action over PAG excitatory output neurons controlling freezing expression. Parallelly, the selective manipulation of mPFC-AMG projections indicated that these neurons are also active in physiological conditions and that they might inhibit BLA excitatory output cells, mediating downstream pathways in control of the freezing expression.
These long-range SST inhibitory projections seem to be strategically located in two essential areas of the fear circuit and could be particularly appropriate for the regulation of activated neurons and by constraining the temporal window of integration of the generated output signal. Future work should focus on the precise activity pattern of these neurons during fear expression and the specific cellular targets in the local mPFC circuit as well as in the remote PAG and AMG regions. The presented results suggest a complementary role of long-range inhibitory neurons to the already described mPFC excitatory projections directed to the PAG and the AMG in control of fear expression. These new insights provide a more complete functional understanding of possible mechanisms underlying maladaptive fear behaviours associated to human psychiatric conditions.
Keywords : In vitro electrophysiology, Fear behaviour , Optogenetics, Long-range inhibitory neurons
Publications
Aincy M, Meziane H, Humeau Y. Synaptic dysfunction in amygdala in intellectual disorder models. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2018 Jun 8;84(Pt B):392-397 doi: 10.1016/j.pnpbp.2017.07.028
Aincy M., Chaudun F., Pai T-S., Zhang Z., Kim H-R, Aime M., Girard D., Rajot D., Penninger J., Humeau Y., and Herry C. Long-range somatostatin prefrontal inhibitory neurons control fear behaviour expression. in preparation
Jury
Dr. François Georges (DR CNRS Bordeaux) : Président
Dr. Bertrand Lambolez (DR INSERM Paris) : Rapporteur
Pr. Pierre Veinante (PR CNRS Strasbourg) : Rapporteur
Dr. Bernard Poulain (DR CNRS Strasbourg) : Examinateur
Dr. Cyril Herry (DR INSERM Bordeaux) : Directeur de thèse