Kay Jüngling - Academia.edu (original) (raw)

Papers by Kay Jüngling

Pharmaceuticals, 2021

Background: The neuropeptide S system, consisting of the 20 amino acid neuropeptide NPS and its G... more Background: The neuropeptide S system, consisting of the 20 amino acid neuropeptide NPS and its G-protein-coupled receptor (GPCR) neuropeptide S receptor 1 (NPSR1), has been studied intensively in rodents. Although there is a lot of data retrieved from behavioral studies using pharmacology or genetic interventions, little is known about intracellular signaling cascades in neurons endogenously expressing the NPSR1. Methods: To elucidate possible G-protein-dependent signaling and effector systems, we performed whole-cell patch-clamp recordings on principal neurons of the anterior basolateral amygdala of mice. We used pharmacological interventions to characterize the NPSR1-mediated current induced by NPS application. Results: Application of NPS reliably evokes inward-directed currents in amygdalar neurons recorded in brain slice preparations of male and female mice. The NPSR1-mediated current had a reversal potential near the potassium reversal potential (EK) and was accompanied by an ...

PLOS ONE

The 30-amino acid peptide Y-P30 corresponds to the N-terminus of the primate-specific, sweat glan... more The 30-amino acid peptide Y-P30 corresponds to the N-terminus of the primate-specific, sweat gland-derived dermcidin prepropeptide. Previous work has revealed that Y-P30 enhances the interaction of pleiotrophin and syndecans-2/3, and thus represents a natural ligand to study this signaling pathway. In immature neurons, Y-P30 activates the c-Src and p42/44 ERK kinase pathway, increases the amount of F-actin in axonal growth cones, and promotes neuronal survival, cell migration and axonal elongation. The action of Y-P30 on axonal growth requires syndecan-3 and heparan sulfate side chains. Whether Y-P30 has the potential to influence dendrites and dendritic protrusions has not been explored. The latter is suggested by the observations that syndecan-2 expression increases during postnatal development, that syndecan-2 becomes enriched in dendritic spines, and that overexpression of syndecan-2 in immature neurons results in a premature morphological maturation of dendritic spines. Here, analysing rat cortical pyramidal and non-pyramidal neurons in organotypic cultures, we show that Y-P30 does not alter the development of the dendritic arborization patterns. However, Y-P30 treatment decreases the density of apical, but not basal dendritic protrusions at the expense of the filopodia. Analysis of spine morphology revealed an unchanged mushroom/stubby-to-thin spine ratio and a shortening of the longest decile of dendritic protrusions. Whole-cell recordings from cortical principal neurons in dissociated cultures grown in the presence of Y-P30 demonstrated a decrease in the frequency of glutamatergic mEPSCs. Despite these differences in protrusion morphology and synaptic transmission, the latter likely attributable to presynaptic effects, calcium event rate and amplitude recorded in pyramidal neurons in organotypic cultures were not altered by Y-P30 treatment. Together, our data suggest that Y-P30 has the capacity to decelerate spinogenesis and to promote morphological, but not synaptic, maturation of dendritic protrusions.

Journal of Psychopharmacology

Background: Nuclei located in the dorsal midline thalamus, such as the paraventricular nucleus of... more Background: Nuclei located in the dorsal midline thalamus, such as the paraventricular nucleus of the thalamus (PVT), are crucial to modulate fear and aversive behaviour. In addition, the PVT shows a dense expression of µ-opioid receptors (MORs) and could mediate the anxiolytic effects of opioids. Methods: We analysed the contribution of MORs in the dorsal midline thalamus (i.e. the PVT) to the performance of mice in a classical fear conditioning paradigm. We locally injected a specific agonist (DAMGO), an antagonist (CTAP) of MOR or saline as a control into the dorsal midline thalamus of male mice, prior to fear extinction training. We assessed freezing as a typical measure of fear and extended our analysis by evaluation of aversive, non-aversive and neutral behavioural features using compositional data analysis. Results: Pharmacological blockade of MORs through CTAP in the dorsal midline thalamus induced a fear memory extinction deficit, as evidenced by maintained freezing during ...

Neuroscience & Biobehavioral Reviews

Translational neuroscience bridges insights from specific mechanisms in rodents to complex functi... more Translational neuroscience bridges insights from specific mechanisms in rodents to complex functions in humans and is key to advance our general understanding of central nervous function. A prime example of translational research is the study of cross-species mechanisms that underlie responding to learned threats, by employing Pavlovian fear conditioning protocols in rodents and humans. Hitherto, evidence for (and critique of) these cross-species comparisons in fear conditioning research was based on theoretical viewpoints. Here, we provide a perspective to substantiate these theoretical concepts with empirical considerations of cross-species methodology. This meta-research perspective is expected to foster cross-species comparability and reproducibility to ultimately facilitate successful transfer of results from basic science into clinical applications.

Neuropeptide S precursor knockout mice display memory and arousal deficits

European Journal of Neuroscience

Activation of neuropeptide S (NPS) signaling has been found to produce arousal, wakefulness, anxi... more Activation of neuropeptide S (NPS) signaling has been found to produce arousal, wakefulness, anxiolytic-like behaviors, and enhanced memory formation. In order to further study physiological functions of the NPS system, we generated NPS precursor knockout mice by homologous recombination in embryonic stem cells. NPSmice were viable, fertile, and anatomically normal, when compared to their wild-type and heterozygous littermates. The total number of NPS neurons-although no longer synthesizing the peptide - was not affected by the knockout, as analyzed in NPS/NPSdouble transgenic mice. Analysis of behavioral phenotypes revealed significant deficits in exploratory activity in NPSmice. NPS precursor knockout mice displayed attenuated arousal in the hole board test, visible as reduced total nose pokes and number of holes inspected, that was not confounded by increased repetitive or stereotypic behavior. Importantly, long-term memory was significantly impaired in NPSmice in the inhibitory avoidance paradigm. NPS precursor knockout mice displayed mildly increased anxiety-like behaviors in three different tests measuring responses to stress and novelty. Interestingly, heterozygous littermates often presented behavioral deficits similar to NPSmice or displayed intermediate phenotype. These observations may suggest limited ligand availability in critical neural circuits. Overall, phenotypical changes in NPSmice are similar to those observed in NPS receptor knockout mice and support earlier findings that suggest major functions of the NPS system in arousal, regulation of anxiety and stress, and memory formation.

Neuropeptid S: Ein neues Transmittersystem im Gehirn

e-Neuroforum

ZusammenfassungDas vor wenigen Jahren entdeckte Neuropeptid S stellt zusammen mit seinem Rezeptor... more ZusammenfassungDas vor wenigen Jahren entdeckte Neuropeptid S stellt zusammen mit seinem Rezeptor ein hochinteressantes System der Neuromodulation mit einzigartigem Wirkungsspektrum dar. NPS steigert zum einen Wachheit und Aufmerksamkeit. Das NPS-System wirkt zum anderen anxiolytisch (angstlösend), sowohl akut auf Ängstlichkeit als auch anhaltend auf spezifische Aspekte des Furchtgedächtnisses (Verminderung von Kontextfurcht; Verbesserung von Furchtextinktion). Die Hauptquelle von NPS im Gehirn sind NPS-positive Neurone im Hirnstamm. NPS bindet an einen in Vertebraten hochkonservierten, G-Protein gekoppelten Rezeptor, dessen Stimulation zur Mobilisierung von intrazellulärem Ca

Frontiers in cellular neuroscience, 2016

The Neuropeptide S system, consisting of the 20-amino acid peptide neuropeptide S (NPS) and its G... more The Neuropeptide S system, consisting of the 20-amino acid peptide neuropeptide S (NPS) and its G-protein coupled receptor (NPSR), modulates arousal, wakefulness, anxiety, and fear-extinction in mice. In addition, recent evidence indicates that the NPS system attenuates stress-dependent impairment of fear extinction, and that NPS-expressing neurons in close proximity to the locus coeruleus region (LC; pericoerulear, periLC) are activated by stress. Furthermore, periLC NPS neurons receive afferents from neurons of the centrolateral nucleus of the amygdala (CeL), of which a substantial population expresses the kappa opioid receptor (KOR) ligand precursor prodynorphin. This study aims to identify the effect of the dynorphinergic system on NPS neurons in the periLC via pre- and postsynaptic mechanisms. Using electrophysiological recordings in mouse brain slices, we provide evidence that NPS neurons in the periLC region are directly inhibited by dynorphin A (DynA) via activation of κ-opi...

SY28-4CROSS-TALK of Corticotropin Releasing Hormone Receptor Subtype 1 with Dopamine D1 Receptor: Functional Relevance in Alcohol Dependence

Alcohol and Alcoholism, 2015

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 13, 2015

The amygdala is a key region for the processing of information underlying fear, anxiety, and fear... more The amygdala is a key region for the processing of information underlying fear, anxiety, and fear extinction. Within the local neuronal networks of the amygdala, a population of inhibitory, intercalated neurons (ITCs) modulates the flow of information among various nuclei of amygdala, including the basal nucleus (BA) and the centromedial nucleus (CeM) of the amygdala. These ITCs have been shown to be important during fear extinction and are target of a variety of neurotransmitters and neuropeptides. Here we provide evidence that the activation of μ-opioid receptors (MORs) by the specific agonist DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin) hyperpolarizes medially located ITCs (mITCs) in acute brain slices of mice. Moreover, we use whole-cell patch-clamp recordings in combination with local electrical stimulation or glutamate uncaging to analyze the effect of MOR activation on local microcircuits. We show that the GABAergic transmission between mITCs and CeM neurons is attenuated by...

Neuroforum

Das vor wenigen Jahren entdeckte Neuropeptid S stellt zusammen mit seinem Rezeptor ein hochintere... more Das vor wenigen Jahren entdeckte Neuropeptid S stellt zusammen mit seinem Rezeptor ein hochinteressantes System der Neuromodulation mit einzigartigem Wirkungsspektrum dar. NPS steigert zum einen Wachheit und Aufmerksamkeit. Das NPS-System wirkt zum anderen anxiolytisch (angstlösend), sowohl akut auf Ängstlichkeit als auch anhaltend auf spezifische Aspekte des Furchtgedächtnisses (Verminderung von Kontextfurcht; Verbesserung von Furchtextinktion). Die Hauptquelle von NPS im Gehirn sind NPS-positive Neurone im Hirnstamm. NPS bindet an einen in Vertebraten hochkonservierten, G-Protein gekoppelten Rezeptor, dessen Stimulation zur Mobilisierung von intrazellulärem Ca2+ und Aktivierung von Proteinkinasen führt. In synaptischen Schaltkreisen der Amygdala, die für die Expression von Furcht sowie die Bildung und die Expression des Furchtgedächtnisses relevant sind, führen diese Wirkungen zu einer gesteigerten Freisetzung des exzitatorischen Transmitters Glutamat, vor allem in synaptischen Ve...

Molekulare Mechanismen von Synaptogeneseprozessen : (Funktion klassischer Cadherine an glutamatergen Synapsen neuronal differenzierter ES-Zellen der Maus)

Klassische Cadherine, Adhäsionsmoleküle an Synapsen im ZNS, erfüllen durch ihren Aufbau, ihre Lok... more Klassische Cadherine, Adhäsionsmoleküle an Synapsen im ZNS, erfüllen durch ihren Aufbau, ihre Lokalisation und ihre Interaktionseigenschaften die von R. Sperry im Rahmen der Chemoaffinitäts-Hypothese für Erkennungsmoleküle postulierten Kriterien zur Zielfindung und Synapsenbildung im zentralen Nervensystem. Elektrophysiologische Analysen von N- und E-Cadherin defizienten Synapsen haben gezeigt, dass die Abwesenheit dieser Moleküle zu einer Beeinträchtigung der Transmitterfreisetzung und zu einer starken Veränderung der Kurzzeitplastizität an glutamatergen Synapsen führt. Insbesondere N-Cadherin scheint an glutamatergen Synapsen eine stabilisierende Funktion zu übernehmen, die eine effiziente Nachlieferung fusionskompetenter Vesikel in der präsynaptischen Terminalie in Phasen erhöhter Aktivität gewährleistet.

The Role of Electrical Synapses in a Rat Model of Absence Epilepsy: CA2+ Modulates the Interaction Between Neurons of the Thalamic Reticular Nucleus

Increased GABAergic Efficacy of Central Amygdala Projections to Neuropeptide S Neurons in the Brainstem During Fear Memory Retrieval

Neuropsychopharmacology, 2015

The canonical view on the central amygdala has evolved from a simple output station towards a hig... more The canonical view on the central amygdala has evolved from a simple output station towards a highly organized microcircuitry, in which types of GABAergic neurons in centrolateral (CeL) and centromedial (CeM) subnuclei regulate fear expression and generalization. How these specific neuronal populations are connected to extra-amygdaloid target regions remains largely unknown. Here we show in mice that a subpopulation of GABAergic CeL and CeM neurons projects monosynaptically to brainstem neurons expressing neuropeptide S (NPS). The CeL neurons are PKCδ-negative and are activated during conditioned fear. During fear memory retrieval, the efficacy of this GABAergic influence on NPS neurons is enhanced. Moreover, a large proportion of these neurons (~50%) contain prodynorphin and somatostatin, two neuropeptides inhibiting NPS neurons. We conclude that CeL and CeM neurons inhibit NPS neurons in the brainstem by GABA release and that efficacy of this connection is strengthened upon fear memory retrieval. Thereby, this pathway provides a possible feedback mechanism between amygdala and brainstem routes involved in fear and stress coping.Neuropsychopharmacology advance online publication, 20 May 2015; doi:10.1038/npp.2015.125.

The Journal of physiology, 2012

Long-lasting changes of synaptic efficacy are thought to be a prerequisite for memory formation a... more Long-lasting changes of synaptic efficacy are thought to be a prerequisite for memory formation and maintenance. In the basolateral complex of the amygdala (BLA), one of the main regions for fear and extinction learning of the brain, various forms of long-term potentiation (LTP) have been described for excitatory glutamatergic synapses. In contrast, little is known about the mechanisms of LTP at inhibitory GABAergic synapses. Here we provide evidence that (1) LTP at inhibitory GABAergic synapses (LTP(i)) between inhibitory interneurons and principal neurons (PNs) can be induced by theta-burst stimulation (TBS), (2) this LTP(i) is prevented by AMPA- or NMDA-receptor antagonists, and (3) this LTP(i) is abolished by the NO synthase (NOS) inhibitor L-NAME or the NO scavenger PTIO, and thus is critically dependent on nitric oxide (NO) signalling. These findings are corroborated by immunocytochemical stainings for neuronal (n) NOS, which revealed the existence of nNOS-positive neurons and...

PLOS ONE, 2015

The neuropeptide S (NPS) system was discovered as a novel neurotransmitter system a decade ago an... more The neuropeptide S (NPS) system was discovered as a novel neurotransmitter system a decade ago and has since been identified as a key player in the modulation of fear and anxiety. Genetic variations of the human NPS receptor (NPSR1) have been associated with pathologies like panic disorders. However, details on the molecular fundamentals of NPSR1 activity in neurons remained elusive. We expressed NPSR1 in primary hippocampal cultures. Using single-cell calcium imaging we found that NPSR1 stimulation induced calcium mobilization from the endoplasmic reticulum via activation of IP 3 and ryanodine receptors. Store-operated calcium channels were activated in a downstream process mediating entry of extracellular calcium. We provide the first detailed analysis of NPSR1 activity and the underlying intracellular pathways with respect to calcium mobilization in neurons.

The Journal of Physiology, 2012

• Neuropeptide S (NPS) and its cognate receptor represent a recently discovered transmitter syste... more • Neuropeptide S (NPS) and its cognate receptor represent a recently discovered transmitter system in the brain modulating anxiety-and stress-related behaviour. • Using a transgenic NPS-EGFP-expressing mouse line, the present study shows that NPS-expressing neurons are situated in close proximity to corticotropin-releasing factor (CRF)-containing fibres at the locus coeruleus in the brain stem and express the CRF receptor 1 (CRF1). • CRF depolarizes NPS neurons via activation of the CRF1 receptor through two different ionic mechanisms (a decrease in potassium and an increase in cation conductance) involving the cAMP signalling pathway. • After acute immobilization stress, NPS neurons display an increased expression of c-fos. • This study identifies a mechanism by which stress-related CRF release might activate NPS neurons in the brain stem, thereby triggering NPS release in target areas such as the amygdala, and functioning as a negative feedback control to buffer stress responsiveness.

Journal of Neuroscience, 2006

The cell adhesion molecule N-cadherin has been proposed to regulate synapse formation in mammalia... more The cell adhesion molecule N-cadherin has been proposed to regulate synapse formation in mammalian central neurons. This is based on its synaptic localization enabling alignment of presynaptic and postsynaptic specializations by an adhesion mechanism. However, a potential role of N-cadherin in regulating synaptic transmission has remained elusive. In this paper, a functional analysis of N-cadherin knockout synapses was enabled by in vitro neuronal differentiation of mouse embryonic stem cells circumventing the early embryonic lethality of mice genetically null for N-cadherin. In our in vitro system, initial synapse formation was not altered in the absence of N-cadherin, which might be attributable to compensatory mechanisms. Here, we demonstrate that N-cadherin is required for regulating presynaptic function at glutamatergic synapses. An impairment in the availability of vesicles for exocytosis became apparent selectively during high activity. Short-term plasticity was strongly altered with synaptic depression enhanced in the absence of N-cadherin. Most intriguingly, facilitation was converted to depression under specific stimulation conditions. This indicates an important role of N-cadherin in the control of short-term plasticity. To analyze, whether N-cadherin regulates presynaptic function by a transsynaptic mechanism, we studied chimeric cultures consisting of wild-type neocortical neurons and ES cell-derived neurons. With N-cadherin absent only postsynaptically, we observed a similar increase in short-term synaptic depression as found in its complete absence. This indicates a retrograde control of short-term plasticity by N-cadherin. In summary, our results revealed an unexpected involvement of a synaptic adhesion molecule in the regulation of short-term plasticity at glutamatergic synapses.

The FASEB Journal, 2003

The pluripotency and high proliferative capacity of embryonic stem (ES) cells (1-3) makes them an... more The pluripotency and high proliferative capacity of embryonic stem (ES) cells (1-3) makes them an attractive source of different cell types for biomedical research and cell replacement therapies. A major prerequisite for these applications is the availability of a homogeneous population of the desired cell type. However, ES cell-derived material contains, for example, undifferentiated cells, which can cause tumor formation after transplantation into the brain (4). To avoid such unwanted side effects, effective purification of distinct types of cells needs to be developed. Here, we describe an immunoisolation procedure to purify neurons from in vitro differentiated mouse ES cells using an antibody against the neuronal cell adhesion molecule L1 (5, 6). Our procedure yields a pure population of differentiated neurons, which are electrically excitable and form excitatory, glutamatergic, and inhibitory GABAergic synapses. The ability to highly purify ES cell-derived neurons will boost their molecular characterization and the further exploration of their therapeutic potential.

PLoS ONE, 2013

Synapse elimination and pruning of axon collaterals are crucial developmental events in the refin... more Synapse elimination and pruning of axon collaterals are crucial developmental events in the refinement of neuronal circuits. While a control of synapse formation by adhesion molecules is well established, the involvement of adhesion molecules in developmental synapse loss is poorly characterized. To investigate the consequences of mis-match expression of a homophilic synaptic adhesion molecule, we analysed an asymmetric, exclusively postsynaptic expression of N-cadherin. This was induced by transfecting individual neurons in cultures of N-cadherin knockout mouse neurons with a N-cadherin expression vector. 2 days after transfection, patch-clamp analysis of AMPA receptor-mediated miniature postsynaptic currents revealed an impaired synaptic function without a reduction in the number of presynaptic vesicle clusters. Longterm asymmetric expression of N-cadherin for 8 days subsequently led to synapse elimination as indicated by a loss of colocalization of presynaptic vesicles and postsynaptic PSD95 protein. We further studied long-term asymmetric N-cadherin expression by conditional, Cre-induced knockout of N-cadherin in individual neurons in cultures of N-cadherin expressing cortical mouse neurons. This resulted in a strong retraction of axonal processes in individual neurons that lacked N-cadherin protein. Moreover, an in vivo asymmetric expression of N-cadherin in the developmentally transient cortico-tectal projection was indicated by in-situ hybridization with layer V neurons lacking N-cadherin expression. Thus, mis-match expression of Ncadherin might contribute to selective synaptic connectivity.

Neuropsychopharmacology, 2012

Stressful and traumatic events can create aversive memories, which are a predisposing factor for ... more Stressful and traumatic events can create aversive memories, which are a predisposing factor for anxiety disorders. The amygdala is critical for transforming such stressful events into anxiety, and the recently discovered neuropeptide S transmitter system represents a promising candidate apt to control these interactions. Here we test the hypothesis that neuropeptide S can regulate stress-induced hyperexcitability in the amygdala, and thereby can interact with stress-induced alterations of fear memory. Mice underwent acute immobilization stress (IS), and neuropeptide S and a receptor antagonist were locally injected into the lateral amygdala (LA) during stress exposure. Ten days later, anxiety-like behavior, fear acquisition, fear memory retrieval, and extinction were tested. Furthermore, patch-clamp recordings were performed in amygdala slices prepared ex vivo to identify synaptic substrates of stress-induced alterations in fear responsiveness. (1) IS increased anxiety-like behavior, and enhanced conditioned fear responses during extinction 10 days after stress, (2) neuropeptide S in the amygdala prevented, while an antagonist aggravated, these stress-induced changes of aversive behaviors, (3) excitatory synaptic activity in LA projection neurons was increased on fear conditioning and returned to preconditioning values on fear extinction, and (4) stress resulted in sustained high levels of excitatory synaptic activity during fear extinction, whereas neuropeptide S supported the return of synaptic activity during fear extinction to levels typical of non-stressed animals. Together these results suggest that the neuropeptide S system is capable of interfering with mechanisms in the amygdala that transform stressful events into anxiety and impaired fear extinction.