Final Report Summary - SOMATOLEARNING (The cortical circuits of associative learning)
Associative learning tags a neutral sensory stimulus with the emotional valence of an aversive or appetitive event. One well described consequence is the enlarged representation of the conditioned stimulus (CS) in the sensory map. However, virtually nothing is known about the cortical circuitry underlying this phenomenon. Neuronal circuits in primary sensory cortices are patterned in columns, one for each sensory stimulus. Together, the cortical columns form a topographic map of our sensory body, the homunculus. This cortical map is plastic and can be modified by sensory experience and by learning. In rodents, the deflection of a whisker previously paired with a shock enlarges the representation of the conditioned whisker in the barrel cortex. What are the circuits propagating the CS inputs across cortical columns, throughout cortex? What aspects of the behavioural fear response do they control?
Our objectives are to:
(a) identify cortical circuits underlying the transformation of the cortical whisker map upon learning;
(b) investigate the cellular mechanisms of plasticity;
(c) probe the relationships between the circuit changes and the behavioural response.
Experimental work and main results
A first study was published early 2011 (Rosselet et al. Frontiers in Neural Circuit). We trained mice in a whisker-discriminative paradigm to associate the deflection of one whisker row with a mild tail shock and probed the changes in the intracortical circuits of barrel cortex using glutamate uncaging with laser scanning photostimulation (LSPS). This technique combines optics and electrophysiology to find in a slice all presynaptic cells to one neuron and examine the pattern of their connections. This technique was previously used to track the development of cortical networks. We used it for the first time to describe their plasticity linked to associative learning. We found multiple circuit alterations in cortical columns that were adjacent to the column of CS and, surprisingly, no change in the column of CS itself. Our claim is that these alterations serve the recall of memorised events by propagating the CS inputs across cortical columns, throughout barrel cortex. This effect should amplify the CS signal before it is sent to other key players of associative learning. In support of our model, we show that these circuit changes are linked to the learning performance of animals as they did not occur in mice that were trained the exact same way but did not show a behavioural fear response, and the strength of a particular projection correlated with the ability of the animal to discriminate the CS amongst other sensory stimuli.
We are currently working on another study to address our objectives. To do so, we use conditional mutants which are models of fragile X syndrome. Fragile X mental retardation (FMRP), the missing protein in fragile X, modulates synaptic plasticity, mostly acting as a break. Our strategy is to use the conditional mutant mouse to alter this break in a specific layer of barrel cortex. This trick will allow us to assess the consequences of an improper function of barrel cortex in our training paradigm and more generally to evaluate the role of primary sensory cortices in associative learning and the consequences of their impairment. A first step to validate our model was to verify that FMRP was indeed modulating the plasticity of cortical maps in adult mice. To do so, we used a simpler paradigm to enlarge the representation of whiskers by clipping all but two rows of whiskers. We then mapped with LSPS the neuronal circuits in the columns corresponding to the spared whiskers and found that plasticity was enhanced in the conditional fragile X mutant. Our ongoing study of the cellular mechanisms suggests that FMRP is acting on neurotransmitter release to 'rein' the strengthening of circuits induced by partial sensory deprivation. These results are exciting as they unveil yet another role of FMRP and give us the thumb-up to test these mice in our conditioning protocols.