Characterization of a Knock-In Mouse Line Expressing a Fusion Protein of κ Opioid Receptor Conjugated with tdTomato: 3-Dimensional Brain Imaging via CLARITY

Chen, Chongguang; Willhouse, Alex H.; Huang, Peng; Ko, Nora; Wang, Yujun; Xu, Bin; Huang, Lan; Kieffer, Brigitte L.; Barbe, Mary F.; Liu‐Chen, Lee‐Yuan

doi:10.1523/eneuro.0028-20.2020

Cited by 41 publications

(44 citation statements)

References 62 publications

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“…KOR1 is known to be involved in chronic cocaine exposure (Collins et al, 2002 ) and could complement the role of claustral D1R in acute cocaine responses (Terem et al, 2020 ). The dense expression of KOR1 in the claustrum (Chen et al, 2020 ) could be involved in delusions caused by the KOR1 agonist salvinorin-A (Patru and Reser, 2015 ). KOR1 also has been proposed to play a role in orchestrating consciousness (Stiefel et al, 2014 ).…”

Section: Other Neuromodulatorsmentioning

confidence: 99%

Changing the Cortical Conductor’s Tempo: Neuromodulation of the Claustrum

Wong

Nair

Augustine

2021

Front. Neural Circuits

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The claustrum is a thin sheet of neurons that is densely connected to many cortical regions and has been implicated in numerous high-order brain functions. Such brain functions arise from brain states that are influenced by neuromodulatory pathways from the cholinergic basal forebrain, dopaminergic substantia nigra and ventral tegmental area, and serotonergic raphe. Recent revelations that the claustrum receives dense input from these structures have inspired investigation of state-dependent control of the claustrum. Here, we review neuromodulation in the claustrum—from anatomical connectivity to behavioral manipulations—to inform future analyses of claustral function.

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Section: Other Neuromodulatorsmentioning

confidence: 99%

Changing the Cortical Conductor’s Tempo: Neuromodulation of the Claustrum

Wong

Nair

Augustine

2021

Front. Neural Circuits

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“…of kappa opioid receptor has been also observed in the claustroendopiriform complex (Slowe et al, 1999;Chen et al, 2020). Although there is no direct evidence of the involvement of opioid transmission within the DEn in a particular behavior, hallucinogenic and hyperactivity effects of several kappa agonists have been described (Chavkin et al, 2004;Ansonoff et al, 2006;Chen et al, 2020). Thus, parallel ascending projections to DEn may adapt its function to the particular situation that triggers activation of a particular peptidergic system.…”

Section: Dorsal Endopiriform Nucleusmentioning

confidence: 99%

Relaxin-3 Innervation From the Nucleus Incertus to the Parahippocampal Cortex of the Rat

et al. 2021

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Spatial learning and memory processes depend on anatomical and functional interactions between the hippocampus and the entorhinal cortex. A key neurophysiological component of these processes is hippocampal theta rhythm, which can be driven from subcortical areas including the pontine nucleus incertus (NI). The NI contains the largest population of neurons that produce and presumably release the neuropeptide, relaxin-3, which acts via the Gi/o-protein-coupled receptor, relaxin-family peptide 3 receptor (RXFP3). NI activation induces general arousal including hippocampal theta, and inactivation induces impairment of spatial memory acquisition or retrieval. The primary aim of this study was to map the NI/relaxin-3 innervation of the parahippocampal cortex (PHC), including the medial and lateral entorhinal cortex, endopiriform cortex, perirhinal, postrhinal, and ectorhinal cortex, the amygdalohippocampal transition area and posteromedial cortical amygdala. Retrograde tracer injections were placed in different parts of the medial and lateral entorhinal cortex, which produced prominent retrograde labeling in the ipsilateral NI and some labeling in the contralateral NI. Anterograde tracer injections into the NI and immunostaining for relaxin-3 produced fiber labeling in deep layers of all parahippocampal areas and some dispersed fibers in superficial layers. Double-labeling studies revealed that both hippocampal projecting and calcium-binding protein-positive (presumed GABAergic) neurons received a relaxin-3 NI innervation. Some of these fibers also displayed synaptophysin (Syn) immunoreactivity, consistent with the presence of the peptide at synapses; and relaxin-3-positive fibers containing Syn bouton-like staining were frequently observed in contact with hippocampal-projecting or calcium-binding protein-positive neuronal somata and more distal elements. Finally, in situ hybridization studies revealed that entorhinal neurons in the superficial layers, and to a lesser extent in deep layers, contain RXFP3 mRNA. Together, our data support functional actions of the NI/relaxin-3-parahippocampal innervation on processes related to memory, spatial navigation and contextual analysis.

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“…For example, the LHb receives significant inputs from pro-dynorphin expressing brain regions with high levels of KOR expression such as lateral hypothalamus, amygdala, and nucleus accumbens (NAc), dorsal striatum, and globus pallidus internal (also referred to as the entopeduncular nucleus in rodents) [23,26,[34][35][36][37][38]. KOR expression has also been reported in the LHb in addition to mu opioid receptors (MOR) and delta opioid receptors (DOR) [39,40], also raising the possibility of postsynaptic modulation of LHb neurons by Dyn/KOR signaling in addition to presynaptic effects through inputs projecting to the LHb. Therefore, the LHb is poised to be not only a potent regulator of affective disorders and addiction, but also a possible hotspot for Dyn/KOR regulation of motivation, stress and mood.…”

Section: Introductionmentioning

confidence: 99%

Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula

Simmons

Shepard

Gouty

et al. 2020

Preprint

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The lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of dopamine (DA)-mediated reward circuitry. Specifically, increased activity of the LHb is associated with drug addiction, schizophrenia and stress-related disorders such as depression, anxiety and posttraumatic stress disorder. Dynorphin (Dyn)/Kappa opioid receptor (KOR) signaling is a mediator of stress response in reward circuitry. Previously, we have shown that maternal deprivation (MD), a severe early life stress, increases LHb intrinsic excitability while blunting the response of LHb neurons to extra hypothalamic corticotropin-releasing factor (CRF) signaling, another stress mediator. CRF pathways also interact with Dyn/KOR signaling. Surprisingly, there has been little study of direct KOR regulation of the LHb despite its distinct role in stress, reward and aversion processing. To test the functional role of Dyn-KOR signaling in the LHb, we utilized ex-vivo electrophysiology combined with pharmacological tools in rat LHb slices. We show that activation of KORs by a KOR agonist (U50,488) exerts differential effects on the excitability of two distinct subpopulations of LHb neurons that differ in their expression of hyperpolarization-activated cation currents (HCN, Ih). Specifically, KOR stimulation increases neuronal excitability in LHb neurons with large Ih currents (Ih+) while decreases neuronal excitability in small/negative Ih (Ih-) neurons. Additionally, we found that an intact fast-synaptic transmission is required for the effects of U50,488 on the excitability of both Ih- and Ih+ LHb neuronal subpopulations. Consistently, KOR activation also altered both glutamatergic and GABAergic synaptic transmission. While stimulation of presynaptic KORs uniformly suppressed glutamate release onto LHb neurons, we found that U50, 488 either increased or decreased GABA release. We also found that MD significantly increased immunolabeled Dyn (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreased mRNA levels of KORs in LHb tissues compared to those from non-maternally deprived (non-MD) control rats. While total p38 MAPK (a downstream signaling pathway driven by KOR activation) expression was elevated in the LHb of MD rats compared to non-MD controls, we found that application of KOR-specific agonist, U50,488, onto LHb slices was still able to alter phosphorylated p38 MAPK (ph-p38) expression in MD rats similar to non-MD controls. Moreover, we found that the U50,488-mediated increase in LHb neuronal firing observed in non-MD rats was absent following MD. Altogether, this is the first demonstration of the existence of the functional Dyn/KOR signaling in the LHb that can be modulated in response to severe early life stressors such as MD.

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Characterization of a Knock-In Mouse Line Expressing a Fusion Protein of κ Opioid Receptor Conjugated with tdTomato: 3-Dimensional Brain Imaging via CLARITY

Cited by 41 publications

References 62 publications

Changing the Cortical Conductor’s Tempo: Neuromodulation of the Claustrum

Changing the Cortical Conductor’s Tempo: Neuromodulation of the Claustrum

Relaxin-3 Innervation From the Nucleus Incertus to the Parahippocampal Cortex of the Rat

Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula

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