Ventral striatal islands of Calleja neurons bidirectionally mediate depression-like behaviors in mice

Abstract

The ventral striatum is a reward center implicated in the pathophysiology of depression. It contains islands of Calleja, clusters of dopamine D3 receptor-expressing granule cells, predominantly in the olfactory tubercle (OT). These OT D3 neurons regulate self-grooming, a repetitive behavior manifested in affective disorders. Here we show that chronic restraint stress (CRS) induces robust depression-like behaviors in mice and decreases excitability of OT D3 neurons. Ablation or inhibition of these neurons leads to depression-like behaviors, whereas their activation ameliorates CRS-induced depression-like behaviors. Moreover, activation of OT D3 neurons has a rewarding effect, which diminishes when grooming is blocked. Finally, we propose a model that explains how OT D3 neurons may influence dopamine release via synaptic connections with OT spiny projection neurons (SPNs) that project to midbrain dopamine neurons. Our study reveals a crucial role of OT D3 neurons in bidirectionally mediating depression-like behaviors, suggesting a potential therapeutic target.

Quantitative characterization of cell niches in spatial atlases

“…We then investigated the Corpus Callosum, Anterior Commissure and Major Island of Calleja niches more in detail. The Major Island of Calleja has been described to contain dopamine D3 receptor-expressing granule cells 129 involved in depression 130 , and to express Gad65 131 and Nos1 (Nitric Oxide Synthase 1) 132 ; accordingly, we observed spatially localized Drd3 expression 129 ( Supplementary Fig. 28 ).…”

Endogenous opioids in the olfactory tubercle and their roles in olfaction and quality of life

“…Olfactory dysfunctions can go beyond decreased QOL: they are bi-directionally associated with psychiatric disorders, including depression ( Kohli et al, 2016 ; Taquet et al, 2021 ; Hasegawa et al, 2022 ). Ablation or inhibition of D3-expressing granule cells in the OT leads to depression-like behaviors and negatively impacts dopamine release from the VTA ( Zhang et al, 2023 ). Conversely, olfactory enrichment has been shown to be a beneficial treatment strategy for depression ( Leon and Woo, 2022 ).…”

“…Granule cells are clustered from the anteromedial surface to the deep layers of the central OT, forming a continuous structure of the Islands of Calleja (ICj) ( Fallon et al, 1978 ; de Vente et al, 2001 ). The axonal targets of the granule cells are MSNs in the OT, which project their axons to the VTA, suggesting the role of granule cells in the disinhibition of dopamine release from the VTA ( Zhang et al, 2023 ). Dopamine receptor subtypes are expressed differently by these principal neurons: MSNs express D1 or D2 dopamine receptors, dwarf cells express D1 receptors, and granule cells express D3 receptors ( Le Moine and Bloch, 1995 ; Yung et al, 1995 ; Murata et al, 2015 ; Zhang et al, 2021 ).…”

“…Optogenetic activation of D1-expressing MSNs in the anteromedial OT elicits place preference, whereas activation of D2-expressing MSNs in the same site elicits place aversion ( Murata et al, 2019 ). Further, D3-expressing granule cells in the ICj are involved in grooming behavior and suppression of depression-like behaviors ( Zhang et al, 2021 , 2023 ).…”