Inhibition of dorsal raphe GABAergic neurons blocks hyperalgesia during heroin withdrawal

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2023 Jun 03

Alvarez-Bagnarol, Y;García, R;Vendruscolo, LF;Morales, M;
PMID: 37270620 | DOI: 10.1038/s41386-023-01620-5

Opioid withdrawal signs, such as hyperalgesia, are manifestations of opioid use disorder that may contribute to opioid seeking and taking. We have previously identified an association between dorsal raphe (DR) neurons and the expression of hyperalgesia during spontaneous heroin withdrawal. Here, we found that chemogenetic inhibition of DR neurons decreased hyperalgesia during spontaneous heroin withdrawal in male and female C57/B6 mice. By neuroanatomy, we identified three major subtypes of DR neurons expressing μ-opioid receptors (MOR) that were activated in hyperalgesia during spontaneous withdrawal, those expressing vesicular GABA transporter (VGaT), glutamate transporter 3 (VGluT3), or co-expressing VGluT3 and tryptophan hydroxylase (TPH). In contrast, we identified a small population of DR-MOR neurons expressing solely TPH, which were not activated in hyperalgesia during spontaneous withdrawal. Collectively, these findings indicate a role of the DR in hyperalgesia during spontaneous heroin withdrawal mediated, in part, by the activation of local MOR-GABAergic, MOR-glutamatergic and MOR-co-releasing glutamatergic-serotonergic neurons. We found that specific chemogenetic inhibition of DR-VGaT neurons blocked hyperalgesia during spontaneous heroin withdrawal in male and female mice. Collectively, these findings indicate that DR-GABAergic neurons play a role in the expression of hyperalgesia during spontaneous heroin withdrawal.

Targeting thalamic circuits rescues motor and mood deficits in PD mice

Nature

2022 Jun 08

Zhang, Y;Roy, DS;Zhu, Y;Chen, Y;Aida, T;Hou, Y;Shen, C;Lea, NE;Schroeder, ME;Skaggs, KM;Sullivan, HA;Fischer, KB;Callaway, EM;Wickersham, IR;Dai, J;Li, XM;Lu, Z;Feng, G;
PMID: 35676479 | DOI: 10.1038/s41586-022-04806-x

Although bradykinesia, tremor and rigidity are the hallmark motor defects in patients with Parkinson's disease (PD), patients also experience motor learning impairments and non-motor symptoms such as depression1. The neural circuit basis for these different symptoms of PD are not well understood. Although current treatments are effective for locomotion deficits in PD2,3, therapeutic strategies targeting motor learning deficits and non-motor symptoms are lacking4-6. Here we found that distinct parafascicular (PF) thalamic subpopulations project to caudate putamen (CPu), subthalamic nucleus (STN) and nucleus accumbens (NAc). Whereas PF→CPu and PF→STN circuits are critical for locomotion and motor learning, respectively, inhibition of the PF→NAc circuit induced a depression-like state. Whereas chemogenetically manipulating CPu-projecting PF neurons led to a long-term restoration of locomotion, optogenetic long-term potentiation (LTP) at PF→STN synapses restored motor learning behaviour in an acute mouse model of PD. Furthermore, activation of NAc-projecting PF neurons rescued depression-like phenotypes. Further, we identified nicotinic acetylcholine receptors capable of modulating PF circuits to rescue different PD phenotypes. Thus, targeting PF thalamic circuits may be an effective strategy for treating motor and non-motor deficits in PD.

Specific Connectivity and Unique Molecular Identity of MET Receptor Tyrosine Kinase Expressing Serotonergic Neurons in the Caudal Dorsal Raphe Nuclei

ACS Chem Neurosci.

2017 May 01

Kast RJ, Wu HH, Williams P, Gaspar P, Levitt P.
PMID: 28375615 | DOI: 10.1021/acschemneuro.7b00020

Molecular characterization of neurons across brain regions has revealed new taxonomies for understanding functional diversity even among classically defined neuronal populations. Neuronal diversity has become evident within the brain serotonin (5-HT) system, which is far more complex than previously appreciated. However, until now it has been difficult to define subpopulations of 5-HT neurons based on molecular phenotypes. We demonstrate that the MET receptor tyrosine kinase (MET) is specifically expressed in a subset of 5-HT neurons within the caudal part of the dorsal raphe nuclei (DRC) that is encompassed by the classic B6 serotonin cell group. Mapping from embryonic day 16 through adulthood reveals that MET is expressed almost exclusively in the DRC as a condensed, paired nucleus, with an additional sparse set of MET+ neurons scattered within the median raphe. Retrograde tracing experiments reveal that MET-expressing 5-HT neurons provide substantial serotonergic input to the ventricular/subventricular region that contains forebrain stem cells, but do not innervate the dorsal hippocampus or entorhinal cortex. Conditional anterograde tracing experiments show that 5-HT neurons in the DRC/B6 target additional forebrain structures such as the medial and lateral septum and the ventral hippocampus. Molecular neuroanatomical analysis identifies 14 genes that are enriched in DRC neurons, including 4 neurotransmitter/neuropeptide receptors and 2 potassium channels. These analyses will lead to future studies determining the specific roles that 5-HTMET+ neurons contribute to the broader set of functions regulated by the serotonergic system.

	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
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tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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