A molecularly defined D1 medium spiny neuron subtype negatively regulates cocaine addiction

Abstract

The striatum plays a critical role in regulating addiction-related behaviors. The conventional dichotomy model suggests that striatal D1/D2 medium spiny neurons (MSNs) positively/negatively regulate addiction-related behaviors. However, this model does not account for the neuronal heterogeneity and functional diversity of the striatum, and whether MSN subtypes beyond the pan-D1/D2 populations play distinct roles in drug addiction remains unknown. We characterized the role of a tachykinin 2 –expressing D1 MSN subtype ( Tac2 + ), present in both rodent and primate striatum, using cocaine addiction mouse models. We found that acute cocaine administration reduces Tac2 neuronal activity, and cocaine conditioning alters neuronal response related to cocaine reward contextual associations. In addition, activation/inhibition of Tac2 + neurons attenuates/promotes cocaine-induced conditioned place preference and cocaine intravenous self-administration. Furthermore, stimulation of the NAc-to-lateral hypothalamic projection of Tac2 + neurons suppresses cocaine reward behavior. Our study reveals an unconventional negative regulatory function of D1 MSNs in drug addiction that operates in a subtype- and projection-specific manner.

Integrative multi-dimensional characterization of striatal projection neuron heterogeneity in adult brain

“…Similarly, we recently connected D1R signaling to incubation of cocaine craving where mice exhibited decreased membrane excitability of D1R-expressing, but not D2R-expressing SPNs within the NAc shell after withdrawal from cocaine self-administration 120 . Likewise, different subtypes of D1R SPNs modulate cocaine reward and addiction in mouse models 121 . D2R-only SPNs were significantly associated with psychiatric traits including major depressive disorder and schizophrenia which is in line with an extensive literature connecting D2R signaling with both illnesses 4,12,122 .…”

Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need

“…However, these effects appear to be region-specific as reducing mTOR activity in the VTA mediates morphine tolerance ( 32 ). Our study and prior reports using single-cell sequencing and spatial transcriptomics have revealed considerable cellular heterogeneity within the NAc ( 57–61 ), but it remains unknown how the same component of the mTOR pathway controls divergent actions of cocaine and morphine. One possibility, implied by our results from imaging and snRNA-seq after CRISPR perturbation, is that these two types of drug rewards preferentially sensitize firing rates of distinct cell types, and that the intracellular mTOR pathway is then essential for each cell-specific drug action.…”

A molecularly distinct cell type in the midbrain regulates intermale aggression behaviors in mice

“…The induction pattern of Tac2 peptide or distributed expression of Tac2 + neurons suggest that the regulatory roles of the Tac2/NkB signaling in multiple brain functions depend on its anatomical location and neural connection. The Tac2 -expressing neuron located in the dorsomedial shell of the nucleus accumbens is previously characterized as a subtype of D1 medium spiny neurons to play a negative regulatory role in cocaine addiction (Zhao et al, 2022). In the CeA, Tac2 -expressing neurons mainly modulate consolidation of fear memory (Andero et al ., 2014; Florido et al, 2021).…”