Neuroanatomy and function of the ventral claustrum-dorsal endopiriform nucleus in mice

Abstract Social behavior is regulated by a set of brain regions that integrate external stimuli with internal emotional states to generate context-appropriate behavioral responses. Dysfunctional social behavior has been implicated in many brain disorders including neurodevelopmental disorders (e.g., autism), neurological disorders (e.g., epilepsy), and neurodegenerative disorders (e.g., Alzheimer’s disease). Despite its importance, we have very limited knowledge of underlying neurobiological mechanisms about how emotion can impact neural processing to regulate social behavior. Previously, our unbiased brain mapping study identified dense oxytocin receptor (Oxtr) expression in the ventral claustrum-dorsal endopiriform nucleus (vCLA-EPd). Limited previous studies suggest that the vCLA-EPd is involved in multi-sensory processing, emotion, memory, and attention. The dysfunction of the vCLA-EPd has been implicated in many brain disorders, including Alzheimer’s disease, autism, epilepsy, and even depression. We found that vCLA-EPd Oxtr neurons are mostly excitatory neurons with extensive connections to the olfactory, limbic, and many neuromodulatory areas. Moreover, we found strong projections from vCLA-EPd Oxtr neurons to the medial prefrontal cortex (mPFC), a hub region that regulates social behavior. Importantly, our neural recording in awake and behaving mice showed that vCLA-EPd Oxtr neurons have high neural activity during resting and exploratory states, while novel social cues induced long- lasting suppression of their activity. These preliminary data led us to hypothesize that the vCLA-EPd serves as a bottom-up regulator to disinhibit the mPFC to mediate the initial social cognition. To test the hypothesis, we will carry out three complementary experiments to understand the neurobiological mechanisms of the vCLA-EPd. In Aim 1, we will investigate anterograde and mono-synaptic input connectivity of vCLA-EPd Oxtr neurons with high-resolution 3D mapping methods. In Aim 2, we will investigate the detailed molecular characteristics of vCLA- EPd Oxtr neurons by using single-cell transcriptome and spatial transcriptome methods. In Aim 3, we will test our hypothesis that bottom-up disinhibition of the mPFC by the vCLA-EPd is necessary to mediate initial social behavior by using systems neuroscience approaches and electrophysiological methods. Results from the proposal will establish foundational knowledge to understand the anatomy and function of the vCLA-EPd and will critically inform future studies to investigate the vCLA-EPd in various pathological conditions.