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.
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.
Huo, J;Du, F;Duan, K;Yin, G;Liu, X;Ma, Q;Dong, D;Sun, M;Hao, M;Su, D;Huang, T;Ke, J;Lai, S;Zhang, Z;Guo, C;Sun, Y;Cheng, L;
PMID: 36952340 | DOI: 10.1016/j.celrep.2023.112300
Mechanical allodynia (MA) represents one prevalent symptom of chronic pain. Previously we and others have identified spinal and brain circuits that transmit or modulate the initial establishment of MA. However, brain-derived descending pathways that control the laterality and duration of MA are still poorly understood. Here we report that the contralateral brain-to-spinal circuits, from Oprm1 neurons in the lateral parabrachial nucleus (lPBNOprm1), via Pdyn neurons in the dorsal medial regions of hypothalamus (dmHPdyn), to the spinal dorsal horn (SDH), act to prevent nerve injury from inducing contralateral MA and reduce the duration of bilateral MA induced by capsaicin. Ablating/silencing dmH-projecting lPBNOprm1 neurons or SDH-projecting dmHPdyn neurons, deleting Dyn peptide from dmH, or blocking spinal κ-opioid receptors all led to long-lasting bilateral MA. Conversely, activation of dmHPdyn neurons or their axonal terminals in SDH can suppress sustained bilateral MA induced by lPBN lesion.
Arthurs, JW;Bowen, AJ;Palmiter, RD;Baertsch, NA;
PMID: 36810601 | DOI: 10.1038/s41467-023-36603-z
Breathing is regulated automatically by neural circuits in the medulla to maintain homeostasis, but breathing is also modified by behavior and emotion. Mice have rapid breathing patterns that are unique to the awake state and distinct from those driven by automatic reflexes. Activation of medullary neurons that control automatic breathing does not reproduce these rapid breathing patterns. By manipulating transcriptionally defined neurons in the parabrachial nucleus, we identify a subset of neurons that express the Tac1, but not Calca, gene that exerts potent and precise conditional control of breathing in the awake, but not anesthetized, state via projections to the ventral intermediate reticular zone of the medulla. Activating these neurons drives breathing to frequencies that match the physiological maximum through mechanisms that differ from those that underlie the automatic control of breathing. We postulate that this circuit is important for the integration of breathing with state-dependent behaviors and emotions.
Vollmer, KM;Green, LM;Grant, RI;Winston, KT;Doncheck, EM;Bowen, CW;Paniccia, JE;Clarke, RE;Tiller, A;Siegler, PN;Bordieanu, B;Siemsen, BM;Denton, AR;Westphal, AM;Jhou, TC;Rinker, JA;McGinty, JF;Scofield, MD;Otis, JM;
PMID: 36369508 | DOI: 10.1038/s41467-022-34517-w
Suppression of dangerous or inappropriate reward-motivated behaviors is critical for survival, whereas therapeutic or recreational opioid use can unleash detrimental behavioral actions and addiction. Nevertheless, the neuronal systems that suppress maladaptive motivated behaviors remain unclear, and whether opioids disengage those systems is unknown. In a mouse model using two-photon calcium imaging in vivo, we identify paraventricular thalamostriatal neuronal ensembles that are inhibited upon sucrose self-administration and seeking, yet these neurons are tonically active when behavior is suppressed by a fear-provoking predator odor, a pharmacological stressor, or inhibitory learning. Electrophysiological, optogenetic, and chemogenetic experiments reveal that thalamostriatal neurons innervate accumbal parvalbumin interneurons through synapses enriched with calcium permeable AMPA receptors, and activity within this circuit is necessary and sufficient for the suppression of sucrose seeking regardless of the behavioral suppressor administered. Furthermore, systemic or intra-accumbal opioid injections rapidly dysregulate thalamostriatal ensemble dynamics, weaken thalamostriatal synaptic innervation of downstream neurons, and unleash reward-seeking behaviors in a manner that is reversed by genetic deletion of thalamic µ-opioid receptors. Overall, our findings reveal a thalamostriatal to parvalbumin interneuron circuit that is both required for the suppression of reward seeking and rapidly disengaged by opioids.
Functionally distinct POMC-expressing neuron subpopulations in hypothalamus revealed by intersectional targeting
Biglari, N;Gaziano, I;Schumacher, J;Radermacher, J;Paeger, L;Klemm, P;Chen, W;Corneliussen, S;Wunderlich, CM;Sue, M;Vollmar, S;Klöckener, T;Sotelo-Hitschfeld, T;Abbasloo, A;Edenhofer, F;Reimann, F;Gribble, FM;Fenselau, H;Kloppenburg, P;Wunderlich, FT;Brüning, JC;
PMID: 34002087 | DOI: 10.1038/s41593-021-00854-0
Pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus represent key regulators of metabolic homeostasis. Electrophysiological and single-cell sequencing experiments have revealed a remarkable degree of heterogeneity of these neurons. However, the exact molecular basis and functional consequences of this heterogeneity have not yet been addressed. Here, we have developed new mouse models in which intersectional Cre/Dre-dependent recombination allowed for successful labeling, translational profiling and functional characterization of distinct POMC neurons expressing the leptin receptor (Lepr) and glucagon like peptide 1 receptor (Glp1r). Our experiments reveal that POMCLepr+ and POMCGlp1r+ neurons represent largely nonoverlapping subpopulations with distinct basic electrophysiological properties. They exhibit a specific anatomical distribution within the arcuate nucleus and differentially express receptors for energy-state communicating hormones and neurotransmitters. Finally, we identify a differential ability of these subpopulations to suppress feeding. Collectively, we reveal a notably distinct functional microarchitecture of critical metabolism-regulatory neurons.
A Spatiomolecular Map of the Striatum
Antje M�rtin, Daniela Calvigioni, Ourania Tzortzi, Janos Fuzik, Emi lW�rnberg, Konstantinos Meletis
| DOI: 10.1016/j.celrep.2019.11.096
The striatum is organized into two major outputs formed by striatal projection neuron (SPN) subtypes with distinct molecular identities. In addition, histochemical division into patch and matrix compartments represents an additional spatial organization, proposed to mirror a motor-motivation regionalization. To map the molecular diversity of patch versus matrix SPNs, we genetically labeled mu opioid receptor (Oprm1) expressing neurons and performed single-nucleus RNA sequencing. This allowed us to establish molecular definitions of patch, matrix, and exopatch SPNs, as well as identification of Col11a1+ striatonigral SPNs. At the tissue level, mapping the expression of candidate markers reveals organization of spatial domains, which are conserved in the non-human primate brain. The spatial markers are cell-type independent and instead represent a spatial code found across all SPNs within a spatial domain. The spatiomolecular map establishes a formal system for targeting and studying striatal subregions and SPNs subtypes, beyond the classical striatonigral and striatopallidal division
Mengaziol, J;Dunn, AD;Salimando, G;Wooldridge, L;Crues-Muncunill, J;Eacret, D;Chen, C;Bland, K;Liu-Chen, LY;Ehrlich, ME;Corder, G;Blendy, JA;
PMID: 36534642 | DOI: 10.1371/journal.pone.0270317
Key targets of both the therapeutic and abused properties of opioids are μ-opioid receptors (MORs). Despite years of research investigating the biochemistry and signal transduction pathways associated with MOR activation, we do not fully understand the cellular mechanisms underlying opioid addiction. Given that addictive opioids such as morphine, oxycodone, heroin, and fentanyl all activate MORs, and current therapies such as naloxone and buprenorphine block this activation, the availability of tools to mechanistically investigate opioid-mediated cellular and behavioral phenotypes are necessary. Therefore, we derived, validated, and applied a novel MOR-specific Cre mouse line, inserting a T2A cleavable peptide sequence and the Cre coding sequence into the MOR 3'UTR. Importantly, this line shows specificity and fidelity of MOR expression throughout the brain and with respect to function, there were no differences in behavioral responses to morphine when compared to wild type mice, nor are there any alterations in Oprm1 gene expression or receptor density. To assess Cre recombinase activity, MOR-Cre mice were crossed with the floxed GFP-reporters, RosaLSLSun1-sfGFP or RosaLSL-GFP-L10a. The latter allowed for cell type specific RNA sequencing via TRAP (Translating Ribosome Affinity Purification) of striatal MOR+ neurons following opioid withdrawal. The breadth of utility of this new tool will greatly facilitate the study of opioid biology under varying conditions.
Ochandarena, NE;Niehaus, J;Tassou, A;Scherrer, G;
PMID: 37271281 | DOI: 10.1016/j.neuropharm.2023.109597
Opioids are potent analgesics broadly used for pain management; however, they can produce dangerous side effects including addiction and respiratory depression. These harmful effects have led to an epidemic of opioid abuse and overdose deaths, creating an urgent need for the development of both safer pain medications and treatments for opioid use disorders. Both the analgesic and addictive properties of opioids are mediated by the mu opioid receptor (MOR), making resolution of the cell types and neural circuits responsible for each of the effects of opioids a critical research goal. Single-cell RNA sequencing (scRNA-seq) technology is enabling the identification of MOR-expressing cell types throughout the nervous system, creating new opportunities for mapping distinct opioid effects onto newly discovered cell types. Here, we describe molecularly defined MOR-expressing neuronal cell types throughout the peripheral and central nervous systems and their potential contributions to opioid analgesia and addiction.
