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Multimodal analysis reveals cellular diversity and divergent circuits of the zona incerta

ABSTRACT: The zona incerta (ZI) plays an important role in diverse behavioral functions and is an emerging clinical target for deep brain stimulation to treat neurological conditions. Despite their importance, the cell type composition of the ZI and the anatomical circuit organization linking specific ZI cell types to brain-wide circuits remain unclear. In this study, we used single-nucleus RNA-sequencing, spatial RNA profiling, ex vivo electrophysiology, and anatomical circuit mapping to generate a multimodal cellular atlas of the ZI and to characterize the brain-wide monosynaptic inputs to specific ZI cell types. We define four genetically distinct populations of ZI GABAergic neurons that display unique spatial distributions, specialized intrinsic electrophysiological properties, divergent efferent projections, and cell-type dependent synaptic input patterns. Finally, using fiber photometry we reveal response divergence between distinct ZI cell types in a novel behavioral assay that centers around approach-avoid conflict produced by innately appetitive and aversive stimuli. This study thus provides a foundational resource for the design and interpretation of future experiments aimed at understanding the organization and function of the ZI.

ORGANISM(S): Mus musculus

PROVIDER: GSE273853 | GEO | 2024/08/02

REPOSITORIES: GEO

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Project description:Animals perform innate behaviors that are stereotyped responses to specific evolutionarily relevant stimuli in the absence of prior learning or experience. These behaviors can be reduced to an axis of valence, whereby specific odors evoke approach and avoidance. The cortical amygdala (plCoA) mediates innate attraction and aversion to odor. However, little is known about how this brain area gives rise to behaviors of opposing motivational valence. Here, we sought to define the circuit features of plCoA that give rise to innate olfactory behaviors of valence. We characterized the physiology, gene expression, and projections of this structure, identifying a divergent, topographic organization that selectively controls innate attraction and avoidance to odor. First, we examined odor-evoked responses in these areas and found sparse encoding of odor identity, but not valence. We next considered a topographic organization and found that optogenetic stimulation of the anterior and posterior domains of plCoA elicits attraction and avoidance, respectively, suggesting a functional axis for valence. Using single cell and spatial RNA sequencing, we identified the molecular cell types in plCoA, revealing an anteroposterior gradient in cell types, whereby anterior glutamatergic neurons preferentially express Slc17a6 and posterior neurons express Slc17a7. Activation of these respective cell types recapitulates appetitive and aversive valence behaviors, and chemogenetic inhibition reveals partial necessity for valence responses to innate appetitive or aversive odors. Finally, we identified topographically organized circuits defined by projections, whereby anterior neurons preferentially project to medial amygdala, and posterior neurons preferentially project to nucleus accumbens, which are respectively sufficient and necessary for innate negative and positive olfactory valence. Together, these data advance our understanding of how the olfactory system generates stereotypic, hardwired attraction and avoidance, and supports a model whereby distinct, topographically distributed plCoA populations direct innate olfactory valence responses by signaling to divergent valence-specific targets, linking upstream olfactory identity to downstream valence behaviors, through a population code. This represents a novel circuit motif in which valence encoding is represented not by the firing properties of individual neurons, but by population level identity encoding that is routed through divergent targets to mediate distinct valence.

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Multimodal analysis reveals cellular diversity and divergent circuits of the zona incerta

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