Post by: Amanda McFarlan
What's the science?
It is not well understood how the brain is able to filter complex sensory inputs and decide what is most important, or ‘salient’. Recent studies have shown that the thalamus, a hub for sensory information (among other functions) in the brain, may contribute to this filtering process. The paraventricular thalamus (PVT), one of the subnuclei in the thalamus, is of particular interest. This region of the thalamus is a relay station connecting the brainstem (which provides information related to internal bodily states) to limbic brain regions involved in learning in a variety of emotional contexts. The PVT is connected to several higher-level brain areas, including the frontal and insular cortices and innervates the amygdala (which is involved in processing salience in an emotional context) and therefore could play an important role in encoding the relevance of stimuli. This week in Science, Zhu and colleagues explored the role of PVT neurons in determining the salience of behaviourally relevant stimuli and their contribution to associative learning.
How did they do it?
In mice, the authors tested several behavioural paradigms using Pavlovian conditioning (see experiment described below), optogenetics and calcium imaging to determine the role of PVT neurons in encoding salient stimuli. First, they performed stereotaxic injections of a virus expressing a genetically encoded calcium indicator (AAV-GCaMP6m) in PVT neurons. After a minimum two-week recovery period from surgery, they used fiber photometry to record calcium signals in head-fixed mice across days of associative learning. The mice, either water-restricted or sated (not water-restricted), were trained to pair an odor (‘conditioned stimulus’ in Pavlovian conditioning) with an outcome (unconditioned stimulus). There were three possible outcomes: rewarding (5 µl or 15 µL of water), neutral (nothing) or aversive (puff of air or tail shock). In the associative learning paradigm, mice were presented with the odor for 1s, followed by a 2s-delay period and then the outcome. In a subsequent experiment, PVT neurons were transfected with a virus expressing a light-gated ion channel that inhibits neuronal activity (to determine the effects of PVT inactivation during associative learning). In this experiment, PVT neurons were optogenetically inhibited in water-restricted mice during associative learning at three possible time points: the odor cue + 2-s delay period, the outcome (water) or between trials (intertrial interval).
What did they find?
The authors determined that the initial exposure to an unfamiliar odor evoked a robust response in PVT neurons that rapidly diminished as the mice became habituated to that cue. In the first associative learning paradigm, water-restricted mice were trained to pair an odor with a rewarding or aversive cue of varying intensity or a neutral cue. They found that PVT neurons responded to both the odor and outcomes in rewarding and aversive trials and that the magnitude of the response was graded to reflect the intensity of the reward. For example, PVT neurons showed greater activity in response to 15 µL of water versus 5 µL, and to a tail shock versus a puff of air. Together, these findings suggest that PVT neurons can encode a variety of stimuli (i.e. novel, rewarding, aversive) and their behavioural relevance. In the second associative learning paradigm, water-restricted and sated mice were trained to pair an odor cue with a water reward. The authors determined that the odor cue evoked robust anticipatory licking in thirsty mice but not sated mice.
Consistent with these findings, the activity of PVT neurons, as measured by calcium signals, was suppressed in sated compared to thirsty mice. Notably, PVT neurons had a greater response when sated mice were presented with an aversive cue (an air puff in the eye) compared to thirsty mice. This indicates that the aversive cue (air puff) became more salient when homeostatic needs had been satisfied. These findings suggest that PVT activity reflects the dynamic nature of stimulus salience after contextual changes. Finally, optogenetically inhibiting PVT neurons while delivering the odor cue or reward cue during training greatly decreased the number of anticipatory licks in water-restricted mice. In contrast, inhibiting PVT neurons between trials had no effect on the number of licks. Taken together, these findings indicate that the PVT is important for the formation but not expression of conditioned reward-seeking behaviour.
What's the impact?
This is the first study to show that the PVT encodes information about salient stimuli, including novel, rewarding and aversive stimuli, in a context-specific manner. The PVT has an important role in determining the salience of a stimulus, although how this salience information is communicated throughout the rest of the brain remains unknown. Elucidating the neural mechanisms involved in identifying salient stimuli and its impact on associative learning may provide insight into new therapies for the treatment of disorders like addiction.
Zhu et al. Dynamic salience processing in paraventricular thalamus gates associative learning. Science (2018). Access the original scientific publication here.