A major open question in neuroscience is how perception is generated in the brain. Perception allows us to make meaning of our sensations, and is drastically effected in psychiatric disorders like schizophrenia. Auditory disturbances are prevailing, suggesting that the auditory system could be particularly affected. An influencing hypothesis states that perceptual disturbances are produced when the brain overweights priors, learnt “top-down” information that is necessary to evaluate incoming sensory signals. Yet, we have little knowledge of where and how top-down information is processed in sensory systems. In this project, we will combine in vivo calcium imaging with optogenetics in mice to elucidate how top-down information is causally encoded in auditory cortex during learning and memory to mediate physiological and pathological perception. Our results will illuminate our understanding of how sensations are transformed into perceptions in thalamo-cortical circuits.

A central goal of neuroscience is to understand the mechanisms that enable sensory perception, an active process that depends on our previous experiences and behavioural demands. In this framework, information that is captured by our sensory organs, that flows to sensory cortex in a “bottom-up” stream, needs to integrate with internal “top-down” information, to form an accurate representation of the world 1.

This fundamental brain function is affected in major neuropsychiatric disorders. While a main open question is how accurate and disturbed perception are determined, a central hypothesis states that it depends on the balance between “bottom-up” and “top-down” information. Directly addressing this question has remained challenging, largely because we have little knowledge of where and how “top-down” information is encoded in the brain. Therefore, this project aims to elucidate the function of “top-down” inputs to sensory cortex.

As opposed to the first-order sensory thalamus that conveys bottom-up information to sensory cortex, recent evidence from others and us indicate that the little explored higher-order (HO) thalamo-cortical pathways are relevant for internal top-down information across sensory modalities 1. We have recently found that the HO auditory thalamus conveys information related to aversive memories to secondary auditory cortex 2.

Conversely, a dysfunction of HO sensory thalamic nuclei has been related to cognitive deficits such as inattention and schizophrenia. Schizophrenia manifests in most cases with auditory perceptual disturbances, suggesting that alterations in the auditory HO system may be a cause.

In this research project, we will test the hypothesis that the HO-auditory thalamus sends to auditory cortex top-down signals that are critical for learning a sensory percept, and affected in pathological conditions related to schizophrenia.

To test our hypothesis, our first aim will be to define the diversity of signals that the HO-auditory thalamus transmits to auditory cortex during a discriminative perceptual decision making task. For this, we will use our lab’s development of in vivo 2-photon calcium imaging of long-range axons to investigate what top-down information is conveyed by the HO-auditory thalamus to auditory cortex during learning and memory in this task.

Our second aim is to test whether and how these top-down signals affect discriminative associative learning and perceptual discrimination. To do this, we will inhibit the thalamic synaptic activity in cortex with optogenetics at specific instances during the task and quantify how behaviour is affected.

Our third aim is to determine how these top-down signals affect encoding in auditory cortex. For this we will combine in vivo optogenetic manipulations with calcium imaging recordings of cortical neurons.

We will compare physiological and pathological conditions by employing mouse models of neuropsychiatric disorders.

Together, this research will uncover how top-down information is encoded during complex behaviours to generate perception. We will in turn determine how HO thalamic inputs to cortex affect cortical function and behaviour, as well as identify features affected in pathological conditions associated to neuropsychiatric disorders.

1. Pardi, M. B., Schroeder, A. & Letzkus, J. J. Probing top-down information in neocortical layer 1. Trends Neurosci. (2022). doi:https://doi.org/10.1016/j.tins.2022.11.001

2. Pardi, M. B. et al. A thalamocortical top-down circuit for associative memory. Science. 370, 844–848 (2020).