Unraveling the cell type specific underpinnings that shape collicular mediated visual behaviors

Cell types are the building blocks of living organisms, and the brain has the most extensive variety of them. Yet, how (or to what extent) different neuronal cell populations contribute to bringing about behavior remains an open question. The work presented in my thesis aims to advance the understanding of the relationship between specific neuronal cell types, the behaviors they evoke, and the related brain-wide activity. In the first part, I focus on the functional connectivity supported by different neuronal cell types and the behaviors they trigger while optogenetically activated. In the second part, I assess the necessity of two different cell types for a behavioral repertoire in response to various threat-mimicking visual stimuli.

As a general approach, I use the mouse superior colliculus and its involvement in visually guided behaviors as a model. The superior colliculus is a midbrain structure crucial in mediating various motor actions by directing visual attention toward or away from ethologically relevant stimuli (such as food, potential partner, or predator). The collicular-dependent behaviors are highly stereotyped and conserved across species. More importantly, there is strong evidence for a relationship between morphologically distinct and genetically targetable collicular cell types and diverse innate behaviors. These features make the superior colliculus a good model for studying cell types as structural and functional channels that support and facilitate quick and reliable sensory-motor transformations.

In the first part of my thesis, I focus on answering how specific genetically-targeted cell types of the superior colliculus broadcast behaviorally relevant information across the brain and form brain-wide functional networks. To do that, in a collaborative work, we first demonstrated that optogenetic activation of four different cell populations triggers distinct behaviors. Subsequently, we combined functional ultrasound imaging (fUSI) with optogenetics to reveal the network of 264 brain regions functionally activated by these collicular cell types. Furthermore, stimulating each neuronal group activated distinct sets of brain nuclei. This included areas previously not thought to mediate defensive behaviors, for example, the posterior paralaminar nuclei of the thalamus (PPnT), which we showed to play a role in suppressing habituation. Neuronal recordings with high-density Neuropixels probes showed that (1) patterns of spiking activity and fUSI signals correlate well in space and (2) neurons in downstream nuclei preferentially respond to innately threatening visual stimuli. This work provides insight into the functional organization of the networks that govern innate behaviors (ranging from orienting through different levels of stopping to directed escape) and demonstrates an experimental approach to explore the neuronal activity of the whole brain downstream of targeted cell types.

In the second part of my thesis, I focus on the role of two collicular cell types in responding to natural, ethologically relevant visual stimuli. Specifically, I investigated how changes in the saliency of different visual stimuli influence behavioral responses and how these responses are supported by the activity of different cell types in the superior colliculus. To do that, I designed various threat saliency scenarios by manipulating parameters like the size or contrast of two sets of visual stimuli resembling cruising or approaching predators. I demonstrated that (1) the strength of responses to these stimuli increased with the perceived threat intensity; (2) the stimuli previously considered ethologically neutral evoked defensive responses like stopping or hiding in a safe space and (3) these responses appear to be differentially modulated by the activity of two genetically-targetable and morphologically distinct collicular cell types: wide- and narrow-field neurons. Freely-moving behavioral experiments in combination with chemogenetic inhibition of these neuronal populations resulted in a set of impairments of how animals react to potentially dangerous visual stimuli, characterized by a significant drop in their defensive behavior repertoire. More specifically, I demonstrated that inhibition of collicular wide-field neurons significantly decreases the ability of an animal to respond to any stimuli adequately. In contrast, inhibition of narrow-filed neurons resulted in less pronounced behavioral responses to a subset of stimuli. These results highlight the importance of different cell types in the brain and suggest functional specialization in assessing threats. It remains to be discovered how the neural activity facilitated by these cell types engages local neural activity and global brain-wide dynamics to evoke appropriate behavior. 

Overall, this work stresses the importance of cell types as functional building blocks in the brain and provides insight into how they can facilitate information transfer across the brain to guide behavior.