Mu-opioid receptor activation potentiates excitatory transmission at the habenulo-peduncular synapse DOI Creative Commons
Sarthak M. Singhal, Agata Szlaga, Yen-Chu Chen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Abstract The continuing opioid epidemic poses a huge burden on public health. Identifying the neurocircuitry involved and how opioids modulate their signaling is essential for developing new therapeutic strategies. medial habenula (MHb) small epithalamic structure that projects predominantly to interpeduncular nucleus (IPN) represents mu-opioid receptor (MOR) hotspot. This habenulo-peduncular (HP) circuit can regulate nicotine withdrawal; however, little known about physiological impact of MOR its function. Using MOR-reporter mice, we observed MORs are expressed in subset MHb IPN cells. Patch-clamp recordings revealed activation inhibited action potential firing + neurons induced an inhibitory outward current neurons, consistent with canonical effects MOR. We next used optogenetics stimulate axons investigate excitatory transmission at HP synapse. In contrast elsewhere, significantly potentiated evoked glutamatergic IPN. facilitatory glutamate co-release was also from cholinergic-defined synapses. potentiation mediated by persisted presence blockers GABA receptors or voltage-gated sodium channels, suggesting monosynaptic mechanism. Finally, disruption abolished faciliatory DAMGO, indicating this non-canonical effect neurotransmission synapse dependent pre-synaptic expression. Our study demonstrates somatodendritic compartments, but synapse, establishing mode which neuronal

Language: Английский

GABAB receptor-mediated potentiation of ventral medial habenula glutamatergic transmission in GABAergic and glutamatergic interpeduncular nucleus neurons DOI Creative Commons
Hannah E. Stinson, Ipe Ninan

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Abstract The medial habenula (MHb)-interpeduncular nucleus (IPN) pathway plays an important role in information transferring between the forebrain and midbrain. MHb-IPN has been implicated regulation of fear behavior nicotine addiction. synapses ventral MHb IPN show a unique property, i.e., enhancement synaptic transmission upon activation GABA B receptors. This receptor-mediated potentiation regulating memory. Although is known to contain parvalbumin (PV) somatostatin (SST) GABAergic neurons vesicular glutamate transporter 3 (VGLUT3)-expressing neurons, it unknown how receptor affects MHb-mediated glutamatergic onto these three subtypes neurons. Our studies robust connectivity from PV SST IPN, while VGLUT3 weak. receptors produces we observed modest effect Despite diminished basal causes transient conversion non-responding into active some Thus, our results strong compared VGLUT3-expressing Furthermore, differential on PV, SST, IPN.

Language: Английский

Citations

0
Complex opioid driven modulation of glutamatergic and cholinergic neurotransmission in a GABAergic brain nucleus associated with emotion, reward and addiction DOI Open Access
Ramesh Chittajallu, Anna Vlachos, Xiaoqing Yuan

et al.

Published: March 31, 2025

The medial habenula (mHb)/interpeduncular nucleus (IPN) circuitry is resident to divergent molecular, neurochemical and cellular components which, in concert, perform computations drive emotion, reward addiction behaviors. Although housing one of the most prominent mu opioid receptor (mOR) expression levels brain, remarkably little known as how they impact mHb/IPN circuit function at granular level. In this study, our systematic functional pharmacogenetic analyses demonstrate that mOR activation attenuates glutamatergic signaling whilst producing an opposing potentiation glutamatergic/cholinergic co-transmission mediated by mHb substance P cholinergic neurons, respectively. Intriguingly, latter non-canonical augmentation developmentally regulated only emerging during later postnatal stages. Further, specific potassium channels act a molecular brake on nicotinic IPN with arm neurotransmission being operational following attenuation Kv1 function. Thus, mORs play complex role controlling salience distinct afferent inputs transmitter modalities ultimately influences synaptic recruitment common downstream GABAergic neurons. Together, these observations provide framework for future investigations aimed identifying neural underpinnings maladaptive behaviors can emerge when endogenous or exogenous opioids, including potent synthetic analogs such fentanyl, modulate/hijack vulnerable stages adolescence adulthood.

Language: Английский

Citations

0
Complex opioid driven modulation of glutamatergic and cholinergic neurotransmission in a GABAergic brain nucleus associated with emotion, reward and addiction DOI Open Access
Ramesh Chittajallu, Anna Vlachos, Xiaoqing Yuan

et al.

Published: March 31, 2025

The medial habenula (mHb)/interpeduncular nucleus (IPN) circuitry is resident to divergent molecular, neurochemical and cellular components which, in concert, perform computations drive emotion, reward addiction behaviors. Although housing one of the most prominent mu opioid receptor (mOR) expression levels brain, remarkably little known as how they impact mHb/IPN circuit function at granular level. In this study, our systematic functional pharmacogenetic analyses demonstrate that mOR activation attenuates glutamatergic signaling whilst producing an opposing potentiation glutamatergic/cholinergic co-transmission mediated by mHb substance P cholinergic neurons, respectively. Intriguingly, latter non-canonical augmentation developmentally regulated only emerging during later postnatal stages. Further, specific potassium channels act a molecular brake on nicotinic IPN with arm neurotransmission being operational following attenuation Kv1 function. Thus, mORs play complex role controlling salience distinct afferent inputs transmitter modalities ultimately influences synaptic recruitment common downstream GABAergic neurons. Together, these observations provide framework for future investigations aimed identifying neural underpinnings maladaptive behaviors can emerge when endogenous or exogenous opioids, including potent synthetic analogs such fentanyl, modulate/hijack vulnerable stages adolescence adulthood.

Language: Английский

Citations

0
Anatomical and functional organization of the interpeduncular nucleus in larval zebrafish DOI Creative Commons
You Kure Wu, Luigi Petrucco, Rubén Portugues

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 12, 2024

Abstract The habenulo-interpeduncular pathway is a highly conserved neural circuit across vertebrates, but the anatomical and functional architecture of interpeduncular nucleus (IPN) remains poorly understood. Here, we use combination immunohistochemistry, volumetric electron microscopy (EM), two-photon imaging to provide first detailed characterization internal organization IPN in larval zebrafish. We show that receives extensive projections from tegmentum, reveal strict segregation between dorsal (dIPN) ventral (vIPN) subcircuits, with minimal cross-communication. In dIPN, characterise detail inputs outputs r1π neurons, which have been recently identified as representing animal’s heading direction. vIPN, identify six distinct glomerular structures, each exhibiting specific patterns reciprocal connections projection pathways. Finally, demonstrate connectivity spontaneous activity habenular axons are shaped by local features IPN, suggesting role for interneurons modulating presynaptic dynamics. Together, these results enhance our understanding framework future investigations into both its physiology involvement behavior.

Language: Английский

Citations

0
Synaptic vesicle pool heterogeneity drives an anomalous form of synaptic plasticity DOI Creative Commons

Natalie J. Guzikowski,

Ege T. Kavalali

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(11)

Published: Feb. 29, 2024

As AI interacts with humans on an increasing array of tasks, it is important to understand how behaves. Since much programming proprietary, developing methods assessing by observing its behaviors essential. We develop a ...We administer Turing test chatbots. examine chatbots behave in suite classic behavioral games that are designed elicit characteristics such as trust, fairness, risk-aversion, cooperation, etc., well they respond ...

Language: Английский

Citations

0
Two- and three-dimensional electron microscopy techniques: powerful tools for studying the brain under physiological and pathological conditions DOI
Rafael Luján,

Marta Turegano-Lopez,

Carolina Aguado

et al.

Advanced technology in neuroscience ., Journal Year: 2024, Volume and Issue: 1(2), P. 143 - 165

Published: Nov. 27, 2024

We are in the midst of a revolution fields neuroanatomy and electron microscopy. The monumental advancements neuroscience field during last decade have led to unprecedented scientific discoveries about our brain development new technologies applications that significantly contributed such advances. Conventional transmission microscopy revolutionized neurosciences critical for determining fine morpho-functional characterization cells their connections. Electron has progressively evolved toward both more sensitive approaches unravel bidimensional subcellular localization proteins tools allow three-dimensional different nerve technological advances two- study map essential decipher complexity brain. For two-dimensional, sodium dodecyl sulfate-digested freeze-fracture replica labeling technique is with main goal chemically identifying structural components viewed replicas significant advantages over conventional immunoelectron microscopic techniques revealing organization along neuronal surface three-dimensional, volume methods can be applied studies cell organelles, just as been traditionally applied, but derived from possibility visualization analysis. greatly facilitated structure connectivity at synaptic level. Dedicated software analysis highly complex patterns three dimension evolving parallel, allowing extraction relevant information large datasets. Moreover, by applying these methodologies, pathology expected advance, potentially identification pathogenesis generating diseases. This review aims present possibilities fundamentals high-resolution ultrastructural analyses neurons These improved ability brain, thus providing insights into function.

Language: Английский

Citations

0
Complex opioid driven modulation of glutamatergic and cholinergic neurotransmission in a GABAergic brain nucleus associated with emotion, reward and addiction DOI Creative Commons
Ramesh Chittajallu, Anna Vlachos, Xiaoqing Yuan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 11, 2024

ABSTRACT The medial habenula (mHb)/interpeduncular nucleus (IPN) circuitry is resident to divergent molecular, neurochemical and cellular components which, in concert, perform computations drive emotion, reward addiction behaviors. Although housing one of the most prominent mu opioid receptor (mOR) expression levels brain, remarkably little known as how they impact mHb/IPN circuit function at granular level. In this study, our systematic functional pharmacogenetic analyses demonstrate that mOR activation attenuates glutamatergic signaling whilst producing an opposing potentiation glutamatergic/cholinergic co-transmission mediated by mHb substance P cholinergic neurons, respectively. Intriguingly, latter non-canonical augmentation developmentally regulated only emerging during later postnatal stages. Further, specific potassium channels act a molecular brake on nicotinic IPN with arm neurotransmission being operational following attenuation Kv1 function. Thus, mORs play complex role modulating salience distinct afferent inputs transmitter modalities ultimately influences synaptic recruitment common downstream GABAergic neurons. Together, these observations provide framework for future investigations aimed identifying neural underpinnings maladaptive behaviors can emerge when endogenous or exogenous opioids, including potent synthetic analogs such fentanyl, modulate hijack vulnerable stages adolescence adulthood.

Language: Английский

Citations

0
Mu-opioid receptor activation potentiates excitatory transmission at the habenulo-peduncular synapse DOI Creative Commons
Sarthak M. Singhal, Agata Szlaga, Yen-Chu Chen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Abstract The continuing opioid epidemic poses a huge burden on public health. Identifying the neurocircuitry involved and how opioids modulate their signaling is essential for developing new therapeutic strategies. medial habenula (MHb) small epithalamic structure that projects predominantly to interpeduncular nucleus (IPN) represents mu-opioid receptor (MOR) hotspot. This habenulo-peduncular (HP) circuit can regulate nicotine withdrawal; however, little known about physiological impact of MOR its function. Using MOR-reporter mice, we observed MORs are expressed in subset MHb IPN cells. Patch-clamp recordings revealed activation inhibited action potential firing + neurons induced an inhibitory outward current neurons, consistent with canonical effects MOR. We next used optogenetics stimulate axons investigate excitatory transmission at HP synapse. In contrast elsewhere, significantly potentiated evoked glutamatergic IPN. facilitatory glutamate co-release was also from cholinergic-defined synapses. potentiation mediated by persisted presence blockers GABA receptors or voltage-gated sodium channels, suggesting monosynaptic mechanism. Finally, disruption abolished faciliatory DAMGO, indicating this non-canonical effect neurotransmission synapse dependent pre-synaptic expression. Our study demonstrates somatodendritic compartments, but synapse, establishing mode which neuronal

Language: Английский

Citations

0