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Novelty tuning: behavioural, electrophysiological and molecular mechanisms of novelty detection

Final Report Summary - NOVELTUNE (Novelty Tuning: behavioural, electrophysiological and molecular mechanisms of novelty detection)

The nervous system has constantly to adapt to its changing environment. Modifications in the neuronal circuitry, presumably due to synaptic plasticity, occur in response to unexpected events. It follows that novelty detection is crucial for the successful adaptation of an animal to a new environment. A cogent paradigm is that of the auditory system.

Mechanisms underlying novelty detection in auditory cortex are regulated by and may depend on modulatory neurotransmitter systems such as cholinergic, dopaminergic and serotonergic systems, and additionally may be modulated by stress response, such as glucocorticoid (GC) release following environmental changes. Also, the induction of c-Fos and mismatch negativity (MMN), share the dependence not only on neuromodulatory signalling but also on normal NMDA receptor function.

Overall, the mechanism of processing of novel, as opposed to non-novel, stimuli detection can be considered as a three-stage process in which:
(1) novelty is detected in the cortex by the conjunction of sensory information with novelty signal that is carried by the neuromodulatory systems;
(2) this conjunction leads to novelty-related electrophysiological responses such as MMN in humans and to their close correlates such as stimulus-specific adaptation (SSA) on the one hand, and to the associated induction of the expression of IEGs on the other hand;
(3) transcription factors initiate a cascade of events, including adaptive changes in mRNAs, microRNAs and alternative splicing, eventually leading to synaptic plasticity.

The specific aim of this project was to study the interactions between the behavioural, molecular and electrophysiological aspects of the processing of novel stimuli. More precisely, the objective was to understand the implication of electrophysiological responses, the induction of IEGs (c-Fos in particular), the modulation by neurotransmitters and the resulting long-term synaptic changes, which together combine to adapt the sensory responses. The approach developed here will help in generating high resolution cortical maps and in defining auditory-motor cortex areas that are jointly involved in the control of a specific behaviour. Finally, it will give a complete circle of predictions for the processing of novel versus non-novel stimuli, including the electrophysiological, behavioural and molecular effects that follow.

The project is based on an operant version of avoidance training, where the conditioned stimulus is a pure tone. Novelty is manipulated by pre-exposing animals to a tone stimulus, and then training the animals either with the same stimulus (the non-novel condition) or with a different stimulus (the novel condition) as warning signals. In the non-novel condition, it is well known that avoidance caused by re-exposing the animals to the training stimulus is reduced (latent inhibition).

Neuromodulary systems play a crucial role in cortical plasticity. In that context, the dopaminergic, cholinergic and serotonergic systems are thought to play a pivotal role in the auditory system. Perturbation of these systems is crucial to establish causation. The serotonergic neurons from the raphe are known to project directly into all cortical areas including the primary auditory cortex. Therefore, reducing or abolishing serotonin synthesis in this tissue should clarify the role of this system in auditory processing of novelty detection. The spatial inhibition of 5-HT synthesis in the neurons of the dorsal raphe in female mice of the C57/BL6 strain was carried out by an RNA interference approach targeting the TPH2 mRNA. Appropriate lentiviral vectors and shRNA constructs proved to be quite efficient.

A single stereotactic injection into the dorsal raphe inhibits serotonin production, as revealed by antibodies against TPH2 and serotonin. These findings have been confirmed by HPLC analysis. Moreover, initial electrophysiological experiments show an altered response of the primary auditory cortex neurons to the tone presentation. Further work will decipher the underlying mechanisms which implicate the serotonergic system in the creation of the novelty response.

Observations made as part of the project served as a rationale to explore the effects of the GRD1Cre genetic manipulation in different paradigms relevant to negative and cognitive symptoms of SZ such as pre-pulse inhibition, social interaction and novel object recognition. Initial findings suggest that the biological substrates underlying the behaviour abnormalities observed in SZ patients might diverge. Indeed, GRD1Cre mice appear to exhibit impairment in pre-attention processes such as MMN although they behave normally in social interaction and pre-pulse inhibition paradigm.

Further, this genetic manipulation attenuates distinctive behaviour alterations elicited by administration of non-competitive NMDA antagonists. The findings in this part of the project open new venues for discovery of previously non-perceived targets for therapeutic intervention with SZ symptoms.