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The Journal of Neuroscience : the... Jun 2022Stimulus-specific adaptation (SSA) is the reduction in responses to frequent stimuli (standards) that does not generalize to rare stimuli (deviants). We investigated the...
Stimulus-specific adaptation (SSA) is the reduction in responses to frequent stimuli (standards) that does not generalize to rare stimuli (deviants). We investigated the contribution of inhibition in auditory cortex to SSA using two-photon targeted cell-attached recordings and optogenetic manipulations in male mice. We characterized the responses of parvalbumin (PV)-, somatostatin (SST)-, and vasoactive intestinal polypeptide (VIP)-expressing interneurons of layer 2/3, and of serotonin receptor 5HT3a-expressing interneurons of layer 1. All populations showed early-onset SSA. Unexpectedly, the PV, SST, and VIP populations exhibited a substantial late component of evoked activity, often stronger for standard than for deviant stimuli. Optogenetic suppression of PV neurons facilitated pyramidal neuron responses substantially more (approximately ×10) for deviants than for standards. VIP suppression decreased responses of putative PV neurons, specifically for standard but not for deviant stimuli. Thus, the inhibitory network does not generate cortical SSA, but powerfully controls its expression by differentially affecting the responses to deviants and to standards. Stimulus-specific adaptation (SSA) reflects the growing complexity of auditory processing along the ascending auditory system. In the presence of SSA, neuronal responses depend not only on the stimulus itself but also on the history of stimulation. Strong SSA in the fast, ascending auditory pathway first occurs in cortex. Here we studied the role of the cortical inhibitory network in shaping SSA, showing that while cortical inhibition does not generate SSA, it powerfully controls its expression. We deduce that the cortical network contributes in crucial ways to the properties of SSA.
Topics: Animals; Auditory Cortex; Auditory Perception; Interneurons; Male; Mice; Parvalbumins; Pyramidal Cells; Vasoactive Intestinal Peptide
PubMed: 35477904
DOI: 10.1523/JNEUROSCI.0988-21.2022 -
Nature Chemical Biology Oct 2023Despite wide appreciation of the biological role of nitric oxide (NO) synthase (NOS) signaling, questions remain about the chemical nature of NOS-derived bioactivity....
Despite wide appreciation of the biological role of nitric oxide (NO) synthase (NOS) signaling, questions remain about the chemical nature of NOS-derived bioactivity. Here we show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase and directly activate the sGC-cGMP-PKG pathway without intermediacy of free NO. The NO-ferroheme species (with or without a protein carrier) efficiently relax isolated blood vessels and induce hypotension in rodents, which is greatly potentiated after the blockade of NOS activity. While free NO-induced relaxations are abolished by an NO scavenger and in the presence of red blood cells or blood plasma, a model compound, NO-ferroheme-myoglobin preserves its vasoactivity suggesting the physiological relevance of NO-ferroheme species. We conclude that NO-ferroheme behaves as a signaling entity in the vasculature.
Topics: Nitric Oxide; Erythrocytes; Heme; Signal Transduction
PubMed: 37710073
DOI: 10.1038/s41589-023-01411-5 -
BJA Education Jul 2021
Review
PubMed: 34178384
DOI: 10.1016/j.bjae.2021.03.002 -
Journal of Biological Rhythms Apr 2024It has been 50 years since the suprachiasmatic nucleus (SCN) was first identified as the central circadian clock and 25 years since the last overview of developments... (Review)
Review
It has been 50 years since the suprachiasmatic nucleus (SCN) was first identified as the central circadian clock and 25 years since the last overview of developments in the field was published in the . Here, we explore new mechanisms and concepts that have emerged in the subsequent 25 years. Since 1997, methodological developments, such as luminescent and fluorescent reporter techniques, have revealed intricate relationships between cellular and network-level mechanisms. In particular, specific neuropeptides such as arginine vasopressin, vasoactive intestinal peptide, and gastrin-releasing peptide have been identified as key players in the synchronization of cellular circadian rhythms within the SCN. The discovery of multiple oscillators governing behavioral and physiological rhythms has significantly advanced our understanding of the circadian clock. The interaction between neurons and glial cells has been found to play a crucial role in regulating these circadian rhythms within the SCN. Furthermore, the properties of the SCN network vary across ontogenetic stages. The application of cell type-specific genetic manipulations has revealed components of the functional input-output system of the SCN and their correlation with physiological functions. This review concludes with the high-risk effort of identifying open questions and challenges that lie ahead.
Topics: Circadian Rhythm; Neuropeptides; Suprachiasmatic Nucleus; Vasoactive Intestinal Peptide; Gastrin-Releasing Peptide
PubMed: 38366616
DOI: 10.1177/07487304231225706 -
Medicina (Kaunas, Lithuania) May 2023Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is often associated with various other syndromes or conditions including mast cell activation (MCA),...
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is often associated with various other syndromes or conditions including mast cell activation (MCA), dysmenorrhea and endometriosis, postural tachycardia (POTS) and small fiber neuropathy (SFN). The causes of these syndromes and the reason for their frequent association are not yet fully understood. We previously published a comprehensive hypothesis of the ME/CFS pathophysiology that explains the majority of symptoms, findings and chronicity of the disease. We wondered whether some of the identified key pathomechanisms in ME/CFS are also operative in MCA, endometriosis and dysmenorrhea, POTS, decreased cerebral blood flow and SFN, and possibly may provide clues on their causes and frequent co-occurrence. Our analysis indeed provides strong arguments in favor of this assumption, and we conclude that the main pathomechanisms responsible for this association are excessive generation and spillover into the systemic circulation of inflammatory and vasoactive tissue mediators, dysfunctional β2AdR, and the mutual triggering of symptomatology and disease initiation. Overall, vascular dysfunction appears to be a strong common denominator in these linkages.
Topics: Female; Humans; Fatigue Syndrome, Chronic; Dysmenorrhea; Endometriosis; Comorbidity
PubMed: 37241210
DOI: 10.3390/medicina59050978 -
Lin Chuang Er Bi Yan Hou Tou Jing Wai... Sep 2021The role of neuroimmunomodulation in allergic diseases is a research hotspot in recent years. Allergic rhinitis(AR) is caused by overactive immune response to a...
The role of neuroimmunomodulation in allergic diseases is a research hotspot in recent years. Allergic rhinitis(AR) is caused by overactive immune response to a foreign antigen in nasal mucosa. Immune cells release inflammatory mediators(including histamine, cytokines and neurotrophins), which directly activate peripheral neurons to mediate nasal congestion, itching, sneezing, and other hyperresponsive symptoms. Upon activation, these peripheral neurons release neurotransmitters (including acetylcholine and norepinephrine) and neuropeptides(including calcitonin gene-related peptide, substance P and vasoactive intestinal peptide) that directly act on immune cells to drive allergic inflammation. Neuro-immune signaling may play a significant role in the pathophysiology of AR. Therefore, a better understanding of these cellular and molecular neuro-immune interactions may inspire the discovery of new targets and novel therapies.
Topics: Humans; Nasal Mucosa; Neuroimmunomodulation; Neuropeptides; Rhinitis, Allergic; Vasoactive Intestinal Peptide
PubMed: 34628846
DOI: 10.13201/j.issn.2096-7993.2021.09.021 -
Journal of Inflammation Research 2023Psoriasis is an autoimmune disease that is characterized by discolored, scaled patches of skin. Clinically, it is found that psychological factors often induce or... (Review)
Review
Psoriasis is an autoimmune disease that is characterized by discolored, scaled patches of skin. Clinically, it is found that psychological factors often induce or aggravate the disease. Current research suggests that the pathogenesis of psoriasis involves the nervous and immune systems. This article reviews how neuropeptides secreted by nerve fibers affect dendritic cells in psoriasis. In this review, we describe that the neuropeptides calcitonin gene-related peptide, substance P, and vasoactive intestinal peptide can act on dendritic cells and participate in the pathogenesis of psoriasis. These neuropeptides can affect the secretion of interleukin (IL)-12 and IL-23 by dendritic cells, which stimulate T helper (Th)1, Th17, and Th22 cells to produce immune responses and cause the manifestation of psoriasis. The application of neuropeptide inhibitors can improve the skin lesions of psoriasis, which has been confirmed in clinical trials. Therefore, neuroimmune response may be a new direction to develop new drug treatments and perspectives in the development of psoriasis.
PubMed: 36636251
DOI: 10.2147/JIR.S397079 -
Translational Stroke Research Feb 2023Therapeutic induction of collateral flow as a means to salvage tissue and improve outcome from acute ischemic stroke is a promising approach in the era in which... (Review)
Review
Therapeutic induction of collateral flow as a means to salvage tissue and improve outcome from acute ischemic stroke is a promising approach in the era in which endovascular therapy is no longer time-dependent but collateral-dependent. The importance of collateral flow enhancement as a therapeutic for acute ischemic stroke extends beyond those patients with large amounts of salvageable tissue. It also has the potential to extend the time window for reperfusion therapies in patients who are ineligible for endovascular thrombectomy. In addition, collateral enhancement may be an important adjuvant to neuroprotective agents by providing a more robust vascular route for which treatments can gain access to at risk tissue. However, our understanding of collateral hemodynamics, including under comorbid conditions that are highly prevalent in the stroke population, has hindered the efficacy of collateral flow augmentation for improving stroke outcome in the clinical setting. This review will discuss our current understanding of pial collateral function and hemodynamics, including vasoactivity that is critical for enhancing penumbral perfusion. In addition, mechanisms by which collateral flow can be increased during acute ischemic stroke to limit ischemic injury, that may be different depending on the state of the brain and vasculature prior to stroke, will also be reviewed.
Topics: Humans; Ischemic Stroke; Brain Ischemia; Stroke; Brain; Thrombectomy; Collateral Circulation; Cerebrovascular Circulation
PubMed: 35416577
DOI: 10.1007/s12975-022-01019-2 -
Current Opinion in Endocrinology,... Apr 2021To discuss recent advances of vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP) receptors in pharmacology, cell biology, and... (Review)
Review
Pituitary adenylate cyclase-activating polypeptide/vasoactive intestinal peptide [Part 1]: biology, pharmacology, and new insights into their cellular basis of action/signaling which are providing new therapeutic targets.
PURPOSE OF REVIEW
To discuss recent advances of vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP) receptors in pharmacology, cell biology, and intracellular signaling in cancer.
RECENT FINDINGS
Recent studies provide new insights into the pharmacology, cell biology of the VIP/PACAP system and show they play important roles in a number of human cancers, as well as in tumor growth/differentiation and are providing an increased understanding of their signaling cascade that is suggesting new treatment targets/approaches.
SUMMARY
Recent insights from studies of VIP/PACAP and their receptors in both central nervous system disorders and inflammatory disorders suggest possible new treatment approaches. Elucidation of the exact roles of VIP/PACAP in these disorders and development of new therapeutic approaches involving these peptides have been limited by lack of specific pharmacological tools, and exact signaling mechanisms involved, mediating their effects. Reviewed here are recent insights from the elucidation of structural basis for VIP/PACAP receptor activation as well as the signaling cascades mediating their cellular effects (using results primarily from the study of their effects in cancer) that will likely lead to novel targets and treatment approaches in these diseases.
Topics: Biology; Humans; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Receptors, Vasoactive Intestinal Peptide; Receptors, Vasoactive Intestinal Polypeptide, Type I; Vasoactive Intestinal Peptide
PubMed: 33449573
DOI: 10.1097/MED.0000000000000617 -
Experimental Eye Research Mar 2023We have previously reported that porcine retinal veins can be contracted by vasoactive factors such as endothelin-1, but it is still unknown which cells play the major...
We have previously reported that porcine retinal veins can be contracted by vasoactive factors such as endothelin-1, but it is still unknown which cells play the major role in such contraction responses. This study seeks to confirm whether retinal vein endothelial cells play a significant role in the endothelin-1 induced contraction of porcine retinal veins. This is a novel study which provides confirmation of the endothelial cells' ability to contract retinal veins using a live vessel preparation. Retinal veins were isolated from porcine retina and cannulated for perfusion. The vessels were exposed to extraluminal delivery of endothelin-1 (10 M) and change in vessel diameter recorded automatically every 2 s. A phase contrast objective lens was also used to capture images of the endothelial cell morphometries. The length, width, area, and perimeter were assessed. In addition, vein histology and immuno-labeling for contractile proteins was performed. With 10 M endothelin-1 contractions to 63.6% of baseline were seen. The polygonal shape of the endothelial cells under normal tone became spindle-like after contraction. The area, width, perimeter and length were significantly reduced by 54.8%, 48.1%, 28.5% and 10.5% respectively. Three contractile proteins, myosin, calponin and alpha-SMA were found in retinal vein endothelial cells. Retinal vein endothelial cells contain contractile proteins and can be contracted by endothelin-1 administration. Such contractile capability may be important in regulating retinal perfusion but could also be a factor in the pathogenesis of retinal vascular diseases such as retinal vein occlusion. As far as we are aware, this is the first study on living isolated veins to confirm that endothelial cells contribute to the endothelin-1 induced contraction.
Topics: Swine; Animals; Retinal Vein; Endothelin-1; Endothelial Cells; Retinal Artery; Endothelium, Vascular; Contractile Proteins; Muscle Contraction; Endothelins
PubMed: 36657697
DOI: 10.1016/j.exer.2023.109386