Yan-Ling Xu

Bio: Yan-Ling Xu is an academic researcher from University of California, Irvine. The author has contributed to research in topics: Neuropeptide S & Neuropeptide S receptor. The author has an hindex of 7, co-authored 9 publications receiving 718 citations. Previous affiliations of Yan-Ling Xu include University of California & Stanford University.

Distribution of neuropeptide S receptor mRNA and neurochemical characteristics of neuropeptide S-expressing neurons in the rat brain.

Abstract: Neuropeptide S (NPS) and its receptor (NPSR) constitute a novel neuropeptide system that is involved in regulating arousal and anxiety. The NPS precursor mRNA is highly expressed in a previously undescribed group of neurons located between the locus coeruleus (LC) and Barrington's nucleus. We report here that the majority of NPS-expressing neurons in the LC area and the principal sensory trigeminal nucleus are glutamatergic neurons, whereas many NPS-positive neurons in the lateral parabrachial nucleus coexpress corticotropin-releasing factor (CRF). In addition, we describe a comprehensive map of NPSR mRNA expression in the rat brain. High levels of expression are found in areas involved in olfactory processing, including the anterior olfactory nucleus, the endopiriform nucleus, and the piriform cortex. NPSR mRNA is expressed in several regions mediating anxiety responses, including the amygdaloid complex and the paraventricular hypothalamic nucleus. NPSR mRNA is also found in multiple key regions of sleep neurocircuitries, such as the thalamus, the hypothalamus, and the preoptic region. In addition, NPSR mRNA is strongly expressed in major output and input regions of hippocampus, including the parahippocampal regions, the lateral entorhinal cortex, and the retrosplenial agranular cortex. Multiple hypothalamic nuclei, including the dorsomedial and the ventromedial hypothalamic nucleus and the posterior arcuate nucleus, express high levels of NPSR mRNA, indicating that NPS may regulate energy homeostasis. These data suggest that the NPS system may play a key role in modulating a variety of physiological functions, especially arousal, anxiety, learning and memory, and energy balance. J. Comp. Neurol. 500:84–102, 2007. © 2006 Wiley-Liss, Inc.

Pharmacological Characterization of Human and Murine Neuropeptide S Receptor Variants

Abstract: We have recently shown that Neuropeptide S (NPS) can promote arousal and induce anxiolytic-like effects after central administration in rodents. Another study reported a number of natural polymorphisms in the human NPS receptor gene. Some of these polymorphisms were associated with increased risk of asthma and possibly other forms of atopic diseases, but the physiological consequences of the mutations remain unclear. One of the polymorphisms produces an Asn-Ile exchange in the first extracellular loop of the receptor protein, and a C-terminal splice variant of the NPS receptor was found overexpressed in human asthmatic airway tissue. We sought to study the pharmacology of the human receptor variants in comparison with the murine receptor protein. Here, we report that the N107I polymorphism in the human NPS receptor results in a gain-of-function characterized by an increase in agonist potency without changing binding affinity in NPSR Ile107. In contrast, the C-terminal splice variant of the human NPS receptor shows a pharmacological profile similar to NPSR Asn107. The mouse NPS receptor, which also carries an Ile residue at position 107, displays an intermediate pharmacological profile. Structure-activity relationship studies show that the amino terminus of NPS is critical for receptor activation. The altered pharmacology of the Ile107 isoform of the human NPS receptor implies a mechanism of enhanced NPS signaling that might have physiological significance for brain function as well as peripheral tissues that express NPS receptors.

Anatomical characterization of the neuropeptide S system in the mouse brain by in situ hybridization and immunohistochemistry.

Abstract: Neuropeptide S (NPS) is the endogenous ligand for GPR154, now referred to as neuropeptide S receptor (NPSR). Physiologically, NPS has been characterized as a modulator of arousal and has been shown to produce anxiolytic-like effects in rodents. Neuroanatomical analysis in the rat revealed that the NPS precursor mRNA is strongly expressed in the brainstem in only three distinct regions: the locus coeruleus area, the principal sensory trigeminal nucleus, and the lateral parabrachial nucleus. NPSR mRNA expression in the rat is widely distributed, with the strongest expression in the olfactory nuclei, amygdala, subiculum, and some cortical structures, as well as various thalamic and hypothalamic regions. Here we report a comprehensive map of NPS precursor and receptor mRNA expression in the mouse brain. NPS precursor mRNA is only expressed in two regions in the mouse brainstem: the Kolliker-Fuse nucleus and the pericoerulear area. Strong NPSR mRNA expression was found in the dorsal endopiriform nucleus, the intra-midline thalamic and hypothalamic regions, the basolateral amgydala, the subiculum, and various cortical regions. In order to elucidate projections from NPS-producing nuclei in the brainstem to NPSR-expressing structures throughout the brain, we performed immunohistochemical analysis in the mouse brain by using two polyclonal anti-NPS antisera. The distribution of NPS-immunopositive fibers overlaps well with NPSR mRNA expression in thalamic and hypothalamic regions. Mismatches between NPSR expression and NPS-immunoreactive fiber staining were observed in hippocampal, olfactory, and cortical regions. These data demonstrate that the distribution pattern of the central NPS system is only partially conserved between mice and rats. J. Comp. Neurol. 519:1867–1893, 2011. © 2011 Wiley-Liss, Inc.

Neuropeptide S as a novel arousal promoting peptide transmitter

Abstract: Behavioral arousal requires integration of multiple neurotransmitter and neuromodulatory systems. Identifying these systems is the key to not only a better understanding of the neurobiology of sleep/wakefulness but may also lead to the discovery of potential therapeutic targets for various sleep disorders. We review here a novel arousal promoting neuropeptide system, neuropeptide S (NPS) and its receptor. Pharmacologically, NPS activates NPS receptors at low nanomolar concentration to increase concentrations of intracellular Ca(2+). Anatomically, both NPS precursor and receptor mRNAs are found predominately in the central nervous system. NPS precursor mRNA is expressed only in several discrete regions located mainly in the brainstem. In particular, it is highly expressed in a previously undescribed group of neurons localized between locus coeruleus and Barrington's nucleus. NPS receptor mRNA is widely distributed in many brain areas with high expression levels in cortex, hypothalamus, amygdala and multiple midline thalamic nuclei. Functionally, central administration of NPS increases locomotor activity in both naive and habituated mice. It also significantly increases wakefulness and decreases paradoxical (rapid eye movement) sleep and slow wave sleep in rats. In addition, NPS suppresses anxiety-like behaviors in mice exposed to different behavioral paradigms measuring responses to novelty or stress. These studies indicate that the NPS system is a newly discovered transmitter system that regulates vigilance and emotional states. NPS appears to possess a unique pharmacological profile in producing both anxiolytic-like and hypervigilant effects.

Neuropeptide S and Its Receptor: A Newly Deorphanized G Protein–Coupled Receptor System

Abstract: Neuropeptide S (NPS) is a recently discovered bioactive peptide that has shed new light on the neurobiology of sleep/wakefulness regulation and anxiety-like behavior. NPS can potently promote arousal and suppress all stages of sleep. This effect might be modulated by NPS receptors expressed in thalamic centers that are relays for transmitting arousing stimuli originating from the brainstem to the cortex. The peptide precursor is expressed most prominently in a novel nucleus located directly adjacent to the nora-drenergic locus coeruleus, a brain structure with well-defined functions in arousal, stress, and anxiety. NPS was also found to induce anxiolytic-like behavior in a battery of four different tests of innate responses to stress. This unique pharmacological profile of NPS offers significant potential for developing new drugs for the treatment of sleep and/or anxiety disorders.

Control of Sleep and Wakefulness

Abstract: This review summarizes the brain mechanisms controlling sleep and wakefulness. Wakefulness promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple interacting neurotransmitter systems in the brain stem, hypothalamus, and basal forebrain converge onto common effector systems in the thalamus and cortex. Sleep results from the inhibition of wake-promoting systems by homeostatic sleep factors such as adenosine and nitric oxide and GABAergic neurons in the preoptic area of the hypothalamus, resulting in large-amplitude, slow EEG oscillations. Local, activity-dependent factors modulate the amplitude and frequency of cortical slow oscillations. Non-rapid-eye-movement (NREM) sleep results in conservation of brain energy and facilitates memory consolidation through the modulation of synaptic weights. Rapid-eye-movement (REM) sleep results from the interaction of brain stem cholinergic, aminergic, and GABAergic neurons which control the activity of glutamatergic reticular formation neurons leading to REM sleep phenomena such as muscle atonia, REMs, dreaming, and cortical activation. Strong activation of limbic regions during REM sleep suggests a role in regulation of emotion. Genetic studies suggest that brain mechanisms controlling waking and NREM sleep are strongly conserved throughout evolution, underscoring their enormous importance for brain function. Sleep disruption interferes with the normal restorative functions of NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes in emotional reactivity, and cognitive impairments in attention, memory, and decision making.

Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease

Abstract: Sleep and circadian rhythm disruption are frequently observed in patients with psychiatric disorders and neurodegenerative disease. The abnormal sleep that is experienced by these patients is largely assumed to be the product of medication or some other influence that is not well defined. However, normal brain function and the generation of sleep are linked by common neurotransmitter systems and regulatory pathways. Disruption of sleep alters sleep-wake timing, destabilizes physiology and promotes a range of pathologies (from cognitive to metabolic defects) that are rarely considered to be associated with abnormal sleep. We propose that brain disorders and abnormal sleep have a common mechanistic origin and that many co-morbid pathologies that are found in brain disease arise from a destabilization of sleep mechanisms. The stabilization of sleep may be a means by which to reduce the symptoms of--and permit early intervention of--psychiatric and neurodegenerative disease.

Amygdala pain mechanisms.

Abstract: A limbic brain area, the amygdala plays a key role in emotional responses and affective states and disorders such as learned fear, anxiety, and depression. The amygdala has also emerged as an important brain center for the emotional–affective dimension of pain and for pain modulation. Hyperactivity in the laterocapsular division of the central nucleus of the amygdala (CeLC, also termed the “nociceptive amygdala”) accounts for pain-related emotional responses and anxiety-like behavior. Abnormally enhanced output from the CeLC is the consequence of an imbalance between excitatory and inhibitory mechanisms. Impaired inhibitory control mediated by a cluster of GABAergic interneurons in the intercalated cell masses (ITC) allows the development of glutamate- and neuropeptide-driven synaptic plasticity of excitatory inputs from the brainstem (parabrachial area) and from the lateral–basolateral amygdala network (LA-BLA, site of integration of polymodal sensory information). BLA hyperactivity also generates abnormally enhanced feedforward inhibition of principal cells in the medial prefrontal cortex (mPFC), a limbic cortical area that is strongly interconnected with the amygdala. Pain-related mPFC deactivation results in cognitive deficits and failure to engage cortically driven ITC-mediated inhibitory control of amygdala processing. Impaired cortical control allows the uncontrolled persistence of amygdala pain mechanisms.