Fan KM, Qiu LJ, Ma N, Du YN, Qian ZQ, Wei CL, Han J, Ren W, Shi MM, Liu ZQ.
PMID: - | DOI: 10.3389/fnins.2019.00071
Acute stress impairs recall memory through the facilitation of long-term depression (LTD) of hippocampal synaptic transmission. The endogenous opioid system (EOS) plays essential roles in stress-related emotional and physiological responses. Specifically, behavioral studies have shown that the impairment of memory retrieval induced by stressful events involves the activation of opioid receptors. However, it is unclear whether signaling mediated by μ-opioid receptors (μRs), one of the three major opioid receptors, participates in acute stress-related hippocampal LTD facilitation. Here, we examined the effects of a single elevated platform (EP) stress exposure on excitatory synaptic transmission and plasticity at the Schaffer collateral-commissural (SC) to CA1 synapses by recording electrically evoked field excitatory postsynaptic potentials and population spikes of hippocampal pyramidal neurons in anesthetized adult mice. EP stress exposure attenuated GABAergic feedforward and feedback inhibition of CA1 pyramidal neurons and facilitated low-frequency stimulation (LFS)-induced long-term depression (LTD) at SC-CA1 glutamatergic synapses. These effects were reproduced by exogenously activating μRs in unstressed mice. The specific deletion of μRs on GABAergic neurons (μRGABA) not only prevented the EP stress-induced memory impairment but also reversed the EP stress-induced attenuation of GABAergic inhibition and facilitation of LFS-LTD. Our results suggest that acute stress endogenously activates μRGABA to attenuate hippocampal GABAergic signaling, thereby facilitating LTD induction at excitatory synapses and eliciting memory impairments.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
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.
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.
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.
American Journal of Veterinary Research
Sojka, P;Smith, S;Greenacre, C;Newkirk, K;Mountain, D;
| DOI: 10.2460/ajvr.21.04.0052
OBJECTIVE To perform a qualitative analysis of the distribution of µ- and κ-opioid receptor mRNA in the forebrain and midbrain of budgerigars (Melopsittacus undulatus). SAMPLE 8 brains of male budgerigars. PROCEDURES Custom-made RNA hybridization probes (RNAscope; Advanced Cell Diagnostics Inc) were used for fluorescent in situ hybridization (FISH) assays performed on selected fresh frozen prepared sections of brain tissue to identify µ- and κ-opioid receptor mRNA. RESULTS There was κ-opioid receptor mRNA present in the nucleus dorsomedialis posterior thalami, lateral striatum, mesopallium, tractus corticohabenularis et corticoseptalis, griseum et fibrosum, stratum griseum centrale, medial striatum, and area parahippocampalis. There was µ-opioid receptor mRNA present in the stratum griseum centrale, stratum opticum, dorsomedialis posterior thalami, area parahippocampalis, medial striatum, and nidopallium intermedium. CLINICAL RELEVANCE Consistent with previous studies in pigeons and domestic chicks, κ-opioid receptors were more abundant than µ-opioid receptors in the samples of the present study. The results of this study may also help explain the hyperexcitability or lack of response that can occur with administration of pure µ-opioid receptor agonists, but not κ-opioid receptor agonists. This study was not quantitative, so further research should endeavor to compare the various regions of the brain using FISH technology.
Neurobiology of Sleep and Circadian Rhythms
Berezin, C;Bergum, N;Luchini, K;Curdts, S;Korkis, C;Vigh, J;
| DOI: 10.1016/j.nbscr.2022.100078
Circadian sleep/wake rhythms are synchronized to environmental light/dark cycles in a process known as photoentrainment. We have previously shown that activation of β-endorphin-preferring μ-opioid receptors (MORs) inhibits the light-evoked firing of intrinsically photosensitive retinal ganglion cells (ipRGCs), the sole conduits of photoentrainment. Although we have shown that β-endorphin is expressed in the adult mouse retina, the conditions under which β-endorphin is expressed are unknown. Moreover, it is unclear whether endogenous activation of the MORs expressed by ipRGCs modulates the photoentrainment of sleep/wake cycles. To elucidate this, we first measured the mRNA expression of β-endorphin's precursor, proopiomelanocortin (POMC), at various times of day by quantitative reverse-transcription PCR. POMC mRNA appears to have cyclic expression in the mouse retina. We then studied β-endorphin expression with immunohistochemistry and found that retinal β-endorphin is more highly expressed in the dark/at night. Finally, we used telemetry to measure activity, EEG and EMG in freely moving animals to compare sleep/wake cycles in wild-type and transgenic mice in which only ipRGCs lack functional MORs. Results from these experiments suggest that the MORs expressed by ipRGCs contribute to the induction and maintenance of activity in the dark phase in nocturnal mice, via the promotion of wakefulness and inhibition of slow-wave sleep. Together, these data suggest that endogenous β-endorphin activates MORs expressed by ipRGCs to modulate sleep/wake activity via the photoentrainment pathway.
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.
Endogenous µ-opioid receptor activity in the lateral and capsular subdivisions of the right central nucleus of the amygdala prevents chronic postoperative pain
Journal of neuroscience research
Cooper, AH;Hedden, NS;Corder, G;Lamerand, SR;Donahue, RR;Morales-Medina, JC;Selan, L;Prasoon, P;Taylor, BK;
PMID: 33957003 | DOI: 10.1002/jnr.24846
Tissue injury induces a long-lasting latent sensitization (LS) of spinal nociceptive signaling that is kept in remission by an opposing µ-opioid receptor (MOR) constitutive activity. To test the hypothesis that supraspinal sites become engaged, we induced hindpaw inflammation, waited 3 weeks for mechanical hypersensitivity to resolve, and then injected the opioid receptor inhibitors naltrexone, CTOP or β-funaltrexamine subcutaneously, and/or into the cerebral ventricles. Intracerebroventricular injection of each inhibitor reinstated hypersensitivity and produced somatic signs of withdrawal, indicative of LS and endogenous opioid dependence, respectively. In naïve or sham controls, systemic naloxone (3 mg/kg) produced conditioned place aversion, and systemic naltrexone (3 mg/kg) increased Fos expression in the central nucleus of the amygdala (CeA). In LS animals tested 3 weeks after plantar incision, systemic naltrexone reinstated mechanical hypersensitivity and produced an even greater increase in Fos than in sham controls, particularly in the capsular subdivision of the right CeA. One third of Fos+ profiles co-expressed protein kinase C delta (PKCδ), and 35% of PKCδ neurons co-expressed tdTomato+ in Oprm1Cre ::tdTomato transgenic mice. CeA microinjection of naltrexone (1 µg) reinstated mechanical hypersensitivity only in male mice and did not produce signs of somatic withdrawal. Intra-CeA injection of the MOR-selective inhibitor CTAP (300 ng) reinstated hypersensitivity in both male and female mice. We conclude that MORs in the capsular subdivision of the right CeA prevent the transition from acute to chronic postoperative pain.
Shi MM, Fan KM, Qiao YN, Xu JH, Qiu LJ, Li X, Liu Y, Qian ZQ, Wei CL, Han J, Fan J, Tian YF, Ren W, Liu ZQ.
PMID: 31142818 | DOI: 10.1038/s41380-019-0435-z
Stressful life events induce abnormalities in emotional and cognitive behaviour. The endogenous opioid system plays an essential role in stress adaptation and coping strategies. In particular, the µ-opioid receptor (μR), one of the major opioid receptors, strongly influences memory processing in that alterations in μR signalling are associated with various neuropsychiatric disorders. However, it remains unclear whether μR signalling contributes to memory impairments induced by acute stress. Here, we utilized pharmacological methods and cell-type-selective/non-cell-type-selective μR depletion approaches combined with behavioural tests, biochemical analyses, and in vitro electrophysiological recordings to investigate the role of hippocampal μR signalling in memory-retrieval impairment induced by acute elevated platform (EP) stress in mice. Biochemical and molecular analyses revealed that hippocampal μRs were significantly activated during acute stress. Blockage of hippocampal μRs, non-selective deletion of μRs or selective deletion of μRs on GABAergic neurons (μRGABA) reversed EP-stress-induced impairment of memory retrieval, with no effect on the elevation of serum corticosterone after stress. Electrophysiological results demonstrated that stress depressed hippocampal GABAergic synaptic transmission to CA1 pyramidal neurons, thereby leading to excitation/inhibition (E/I) imbalance in a μRGABA-dependent manner. Pharmaceutically enhancing hippocampal GABAAreceptor-mediated inhibitory currents in stressed mice restored their memory retrieval, whereas inhibiting those currents in the unstressed mice mimicked the stress-induced impairment of memory retrieval. Our findings reveal a novel pathway in which endogenous opioids recruited by acute stress predominantly activate μRGABA to depress GABAergic inhibitory effects on CA1 pyramidal neurons, which subsequently alters the E/I balance in the hippocampus and results in impairment of memory retrieval.
Du, Y;Yu, K;Yan, C;Wei, C;Zheng, Q;Qiao, Y;Liu, Y;Han, J;Ren, W;Liu, Z;
PMID: 35613854 | DOI: 10.1523/ENEURO.0487-21.2022
The endogenous opioid system plays a crucial role in stress-induced analgesia. Mu-opioid receptors (MORs), one of the major opioid receptors, are expressed widely in subpopulations of cells throughout the CNS. However, the potential roles of MORs expressed in glutamatergic (MORGlut) and γ-aminobutyric acidergic (MORGABA) neurons in stress-induced analgesia remain unclear. By examining tail-flick latencies to noxious radiant heat of male mice, here we investigated the contributions of MORGABA and MORGlut to behavioral analgesia and activities of neurons projecting from periaqueductal gray (PAG) to rostral ventromedial medulla (RVM) induced by a range of time courses of forced swim exposure. The moderate but not transitory or prolonged swim exposure induced a MOR-dependent analgesia, although all of these three stresses enhanced β-endorphin release. Selective deletion of MORGABA but not MORGlut clearly attenuated analgesia and blocked the enhancement of activities of PAG-RVM neurons induced by moderate swim exposure. Under transitory swim exposure, in contrast, selective deletion of MORGlut elicited an analgesia behavior via strengthening the activities of PAG-RVM neurons. These results indicate that MOR-dependent endogenous opioid signaling participates in nociceptive modulation in a wide range, not limited to moderate, of stress intensities. Endogenous activation of MORGABA exerts analgesia, whereas MORGlut produces antianalgesia. More importantly, with an increase of stress intensities, the efficiencies of MORs on nociception shifts from balance between MORGlut and MORGABA to biasing toward MORGABA-mediated processes. Our results point to the cellular dynamic characteristics of MORs expressed in excitatory and inhibitory neurons in pain modulation under various stress intensities.
