Periodic Reporting for period 1 - SUBNETVIS (Identifying subtype specific networks involved in sensory representation in mouse primary visual cortex)
Periodo di rendicontazione: 2020-04-01 al 2022-03-31
The mammalian brain integrates sensory information to produce relevant behaviors. Understanding how the brain encodes this sensory information has been the focus of many studies in the last decades in neuroscience. These studies have found that some brain areas are specialized in sensory processing: as an example, neurons responding to specific features of visual stimuli (such as given orientation, direction, or position) were found in the visual cerebral cortex. Interestingly, the cerebral cortex is composed of a wide diversity of molecularly, structurally, and functionally distinct neuronal subtypes. This neuronal diversity appears as an important support for sensory processing with different inhibitory subtypes showing diverse modulation of visual response by learning or locomotion. However, most studies exploring the role of inhibitory neuronal subtypes in cortical computation have been limited to a few broad ‘Families’. These few broad Families of cells represent a very poor description of the tremendous number of subtypes identified by using the gene expression of cortical inhibitory neurons: about 60 ‘transcriptomic’ inhibitory subtypes were found in mouse visual cortex. It is therefore of major importance to be able to study these fine neuronal subtypes in vivo to determine how they contribute to sensory processing.
To this aim we defined the following objectives:
1) Develop a method to study the in vivo properties of fine neuronal subtypes
2) Determine whether these diverse neuronal subtypes have diverse activity patterns in vivo
3) Describe the visual properties of these fine neuronal subtypes
4) Link these visual properties to their connectivity patterns
To this aim we defined the following objectives:
1) Develop a method to study the in vivo properties of fine neuronal subtypes
2) Determine whether these diverse neuronal subtypes have diverse activity patterns in vivo
3) Describe the visual properties of these fine neuronal subtypes
4) Link these visual properties to their connectivity patterns
We have successfully developed a reliable experimental pipeline that allows in situ subtype identification with unprecedented power. This method uses the expression of 72 different genes to assign in vivo recorded cells to a fine subtype. Using this pipeline, we recorded and molecularly identified more than 1000 inhibitory neurons in mouse primary visual cortex.
We found that the visual properties of inhibitory neurons in the primary visual cortex differed greatly between the major Families (Pvalb, Sst, Vip, Sncg and Lamp5). However, the fine subtypes composing these Families of inhibitory cells shared very similar visual responses. In sharp contrast, the modulation by the animal’s state greatly varied even between fine subtypes of the same Family. Strikingly, we found that a single axis of variability, defined using only gene expression, could predict this state modulation across all subtypes we have recorded from. This single axis also correlated with the spike properties of the subtypes as well as with their morphology. These results were collected and published online in a pre-print article (doi: https://doi.org/10.1101/2021.10.24.465600) which was presented at different international conferences (COSYNE, FENS forum, SfN annual meeting) and has just been accepted in principle for publication by the peer-reviewed journal Nature.
We are currently still exploring how the connectivity of these fine subtypes can determine their tuning properties. In particular, we are using retrograde tracing to decipher whether excitatory cells with different modulation by the animal’s arousal are connected by diverse neuronal subtypes and how this relates with their in vivo properties.
We found that the visual properties of inhibitory neurons in the primary visual cortex differed greatly between the major Families (Pvalb, Sst, Vip, Sncg and Lamp5). However, the fine subtypes composing these Families of inhibitory cells shared very similar visual responses. In sharp contrast, the modulation by the animal’s state greatly varied even between fine subtypes of the same Family. Strikingly, we found that a single axis of variability, defined using only gene expression, could predict this state modulation across all subtypes we have recorded from. This single axis also correlated with the spike properties of the subtypes as well as with their morphology. These results were collected and published online in a pre-print article (doi: https://doi.org/10.1101/2021.10.24.465600) which was presented at different international conferences (COSYNE, FENS forum, SfN annual meeting) and has just been accepted in principle for publication by the peer-reviewed journal Nature.
We are currently still exploring how the connectivity of these fine subtypes can determine their tuning properties. In particular, we are using retrograde tracing to decipher whether excitatory cells with different modulation by the animal’s arousal are connected by diverse neuronal subtypes and how this relates with their in vivo properties.
Our results provide the first large-scale in vivo functional assessment of fine inhibitory subtypes in the cerebral cortex. As such, it extends our current knowledge of the role of these subtypes far beyond the current state of the art, providing crucial information about subtype specific visual properties and state modulation. All the data were made publicly available to allow other scientists to explore this very rich dataset spanning multiple dimensions of neuronal activity and subtypes (https://doi.org/10.6084/m9.figshare.19448531.v1). The study we have published provides a framework for all future studies of the in vivo function of fine subtypes and also identifies a critical transcriptomic axis that has deep implications for cortical development and function.
More generally, subtype-specific disfunctions have been involved in several brain disorders, and fine tuning of inhibition in cortex is critical to maintain proper brain function. Our method and our results will support future studies exploring the involvement of these fine subtypes in brain disorders.
More generally, subtype-specific disfunctions have been involved in several brain disorders, and fine tuning of inhibition in cortex is critical to maintain proper brain function. Our method and our results will support future studies exploring the involvement of these fine subtypes in brain disorders.