Cruces Solis, Hugo

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Cruces Solís, H.

MPG.PuRe

Neuronal correlates of implicit learning in the mammalian midbrain

Filtering auditory information according to its relevance is critical to elicit the appropriate behavioral response. The relevance of a sound is not carried by the sound itself but rather assigned by the brain based on previous experience to the same or similar sounds. Although in experimental settings, the effects of learning on sound processing are mostly studied in the context of extensive training, in real life the value and meaning of many sounds is learned without explicit feedback (implicit auditory learning). Up to date, it is not clear at which level of the auditory pathway previous experience starts to contribute to sound processing of incoming information. The inferior colliculus (IC), located in the midbrain, is the first auditory nucleus in the auditory pathway where inputs from all ascending and several descending auditory nuclei converge. Moreover, it also receives projections from multiple non-auditory areas, which suggests that it can be modulated by multiple factors. Here, using a combination of behavioral, electrophysiological and molecular tools, I tested the hypothesis that already at the level of the IC the sensory input is influenced by implicitly learned auditory associations.
To manipulate the auditory experience of animals I used the Audiobox. The Audiobox is an automated testing chamber, where mice live 24 hours a day, allowing continuous monitoring of behavior. It consists of two compartments: a home cage and a sound - attenuated corner with water access, separated by a long corridor. To drink, mice needed to visit the corner and the individual visits were detected by a transponder previously implanted in each mouse. In a group of mice, every visit to the corner was paired with the presentation of tone pips of a specific frequency (exposed group). The control group consisted of mice that lived in the Audiobox, but were not exposed to sound in any compartment. In the exposed group, the sound was paired with a specific action in a specific area (visits to the corner), hence it was the group where an implicit association could develop. I characterized the evoked responses from multinunit activity in the IC by performing acute electrophysiological recordings in anesthetized mice. I found that, after 6-12 days of sound exposure, the amplitude of the tuning curves were higher than the control group, also there was a unspecific reorganization in frequency representation. There was also an expansion of the area that responded to the frequency used during behavior. These changes were not due to an increase in the overall excitation in the auditory pathway, since no changes in sound processing were found in the cochlear nucleus. It has been shown that collicular plasticity depends on cortical feedback. However, recordings in the IC while simultaneously inactivating the cortex revealed that no cortical feedback is needed for the maintenance of the observed changes. The electrophysiological changes were paralleled at a molecular level with an increase in the excitation/inhibition ratio in collicular synapses, as measured by immunolabeling of VGAT and Vglut2.
2. To test the effects of sound exposure alone, without implicit learning, I performed recordings in a group of animals that lived in the Audiobox, and were exposed to the same sound but in a random way. This group also showed plasticity in the IC, also in the form of tuning curves of larger amplitude. However these changes were more dominant in the dorsal cortex of the IC, an area that did not show plasticity in the exposed group. The shift in frequency representation was visible in this group but smaller than the induced in the exposed group. Additionally, it did not show an expansion of the area responsive to the exposed sound.
A key question is whether these plastics changes, induced by implicit learning, had an effect on subsequent behavioural responses or even learning. To test whether frequency discrimination at a behavioral level could be affected by the changes described in sound processing in the IC, I tested frequency discrimination acuity using pre-pulse inhibition of the acoustic startle response, whose expression strongly depends on the IC. Sound exposure decreased frequency discrimination acuity in the exposed group, but not in the random group, indicating that relevant sound exposure, unlike random, increased sound generalization. To test implicit auditory learning, I trained the animals in a two-tone discrimination sound, where the conditioned sound had been previously presented in a non-conditioned manner. The exposed group elicited latent inhibition, a delay in learning, while the random group learned the task within the first day, indicating that indeed, the exposed group had developed an association between the exposed sound and a neutral outcome, previous to conditioning. 
Together, these results strongly support the idea of a correlation between long-term collicular plasticity of sound processing and two behavioral readouts of frequency discrimination, supporting the theory that the IC is a subcortical filter of current auditory information that is adjusted by previous auditory experience. Implicit auditory learning has been related to the developing of important communication processes such as the categorization of phonemes. The work of the present thesis offers an animal model to study the neuronal correlates of implicit auditory learning and, in combination with genetic models of neurodevelopmental diseases, can contribute to the better understanding of the neuronal deficits underlying higher cognitive processes such as speech acquisition

Georg-August-University Göttingen

https://ediss.uni-goettingen.de/bitstream/11858/00-1735-0000-0028-8819-5/1/Hugo%20Cruces%20Solis%20Dissertation2.pdf

Neuronal correlates of implicit learning in the mammalian midbrain

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