Cooperation between a team of French researchers from Inserm's "Neurocentre Magendie, Bordeaux" Research Unit 862 directed by Cyril Herry and a team of Swiss researchers from the Friedrich Miescher Institute of Biomedical Research directed by Andreas Lüthi at that institute has shown, for the first time, that the cortex, which is the largest zone of the brain and which is generally associated with high cognitive functions, is also a key zone for emotional learning.
The study, initiated by the Swiss researchers and published in Nature, constitutes ground-breaking work in exploring emotions in the brain.
Anxiety disorders constitute a complex family of pathologies affecting about 10% of adults. Patients suffering from such disorders fear certain situations or objects to exaggerated extents totally out of proportion to the real danger they present. The amygdala, a deep-brain structure, plays a key part in processing fear and anxiety. Its functioning can be disrupted by anxiety disorders.
Although researchers are well acquainted with the neurons of the amygdala and with the part those neurons play in expressing fear, their knowledge of the involvement of other regions of the brain remains limited. And yet, there can be no fear without sensory stimulation: before we become afraid, we hear, we see, we smell, we taste, or we feel something that triggers the fear. This sensory signal is, in particular, processed in the cortex, the largest region of the brain.
For the first time, these French and Swiss scientists have succeeded in visualising the path of a sensory stimulus in the brain during fear learning, and in identifying the underlying neuronal circuits.
What happens in the brain?
During the experiments conducted by the researchers, mice learnt to associate a sound with an unpleasant stimulus so that the sound itself became unpleasant for the animal.
The researchers used two-photon calcium imaging to visualise the activity of the neurons in the brain during this learning process. This imaging technique involves injecting a chemical indicator that is then absorbed by the neurons. When the neurons are stimulated, the calcium ions penetrate into the cells, where they increase the brightness of the indicator, which can then be detected under a scanning microscope.
Under normal conditions, the neurons of the auditory cortex are highly inhibited. During fear learning, a "disinhibitory" microcircuit in the cortex is activated: thus, for a short time window during the learning process, the release of acetylcholine in the cortex makes it possible to activate this microcircuit and to disinhibit the excitatory projection cells of the cortex. Thus, when the animal perceives a sound during fear learning, that sound is processed much more intensely than under normal conditions, thereby facilitating formation of memory. All of these stages have been visualised by means of the techniques developed by the researchers.
In order to confirm their discoveries, the researchers used another highly innovative recent technique (optogenetics) to disrupt the disinhibition selectively during the learning process. When they tested the memories of their mice (i.e. the association between the sound and the unpleasant stimulus), the next day they observed a severe deterioration in memory, directly showing that the phenomenon of cortical disinhibition is essential to the process of learning fear.
The discovery of this cortical disinhibitory microcircuit opens up interesting clinical prospects, and researchers can now imagine, in very specific situations, how to prevent a traumatism from establishing itself and from becoming pathological.
The above story is based on materials provided by INSERM (Institut national de la santé et de la recherche médicale). Note: Materials may be edited for content and length.
- Johannes J. Letzkus, Steffen B. E. Wolff, Elisabeth M. M. Meyer, Philip Tovote, Julien Courtin, Cyril Herry, Andreas Lüthi. A disinhibitory microcircuit for associative fear learning in the auditory cortex. Nature, 2011; DOI: 10.1038/nature10674
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