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Chronic pain often leads to depression, increasing patient suffering and worsening prognosis. While hyperactivity of the anterior cingulate cortex (ACC) appears to be critically involved, the molecular mechanisms underlying comorbid depressive symptoms in chronic pain remain elusive. T cell lymphoma invasion and metastasis 1 (Tiam1) is a Rac1 guanine nucleotide exchange factor (GEF) that promotes dendrite, spine, and synapse development during brain development. Here, we show that Tiam1 orchestrates synaptic structural and functional plasticity in ACC neurons via actin cytoskeleton reorganization and synaptic N-methyl-D-aspartate receptor (NMDAR) stabilization. This Tiam1-coordinated synaptic plasticity underpins ACC hyperactivity and drives chronic pain-induced depressive-like behaviors. Notably, administration of low-dose ketamine, an NMDAR antagonist emerging as a promising treatment for chronic pain and depression, induces sustained antidepressant-like effects in mouse models of chronic pain by blocking Tiam1-mediated maladaptive synaptic plasticity in ACC neurons. Our results reveal Tiam1 as a critical factor in the pathophysiology of chronic pain-induced depressive-like behaviors and the sustained antidepressant-like effects of ketamine., Introduction Chronic pain and depression are frequently comorbid, and their coexistence tends to worsen the severity of both disorders (1-4). Clinical and preclinical studies have established that anterior cingulate cortex [...]

Clinical treatment of acute myeloid leukemia (AML) largely relies on intensive chemotherapy. However, the application of chemotherapy is often hindered by cardiotoxicity. Patient sequence data revealed that angiotensin II receptor type 1 (AGTR1) is a shared target between AML and cardiovascular disease (CVD). We found that inhibiting AGTR1 sensitized AML to chemotherapy and protected the heart against chemotherapy-induced cardiotoxicity in a human AML cell–transplanted mouse model. These effects were regulated by the AGTR1-Notch1 axis in AML cells and cardiomyocytes from mice. In mouse cardiomyocytes, AGTR1 was hyperactivated by AML and chemotherapy. AML leukemogenesis increased the expression of the angiotensin-converting enzyme and led to increased production of angiotensin II, the ligand of AGTR1, in an MLL-AF9–driven AML mouse model. In this model, the AGTR1-Notch1 axis regulated a variety of genes involved with cell stemness and chemotherapy resistance. AML cell stemness was reduced after Agtr1a deletion in the mouse AML cell transplant model. Mechanistically, Agtr1a deletion decreased γ-secretase formation, which is required for transmembrane Notch1 cleavage and release of the Notch1 intracellular domain into the nucleus. Using multiomics, we identified AGTR1-Notch1 signaling downstream genes and found decreased binding between these gene sequences with Notch1 and chromatin enhancers, as well as increased binding with silencers. These findings describe an AML/CVD association that may be used to improve AML treatment. Editor's summary: Chemotherapy for acute myeloid leukemia (AML) can result in cardiotoxicity. Pan et al. found that the angiotensin II receptor type 1 (AGTR1) was increased in the blood from patients with AML or with cardiovascular disease and that it could be targeted to both enhance chemotherapy and protect against cardiotoxicity in mouse models. Genetic deletion of the receptor in a human AML cell transplant mouse model and in two other genetic mouse models of AML resulted in decreased leukemic burden and increased survival. Treating mice with losartan, an AGTR1 inhibitor, both enhanced the efficacy of chemotherapy against AML and prevented cardiotoxicity associated with the chemotherapy treatment. Together, these findings demonstrate that AGTR1 may be a target for improving AML treatment. —Brandon Berry [ABSTRACT FROM AUTHOR]

This study investigated the anti-arrhythmic effects from chronic intermittent hypobaric hypoxia (CIHH) and the cellular mechanisms in rats with metabolic syndrome. Male Sprague-Dawley rats were randomly distributed among the control, fructose-fed (fed with 10% fructose in the drinking water to induce metabolic syndrome), CIHH (42 days of hypobaric hypoxia treatment simulating an altitude of 5000 m a.s.l.: PB = 404 mm Hg, [PO.sub.2] = 84 mm Hg, 6 h per day), and the CIHH plus fructose (CIHH-F) groups. In anesthetized rats, the arrhythmia score was determined after 30 min of cardiac ischemia followed by 120 min of reperfusion. Action potentials (AP) were recorded from isolated ventricular papillary muscles. The arrhythmia score was much lower in CIHH-F rats than in the fructose-fed rats. Under basic conditions, AP duration (APD) was significantly shortened in fructose-fed rats, but obviously prolonged in CIHH rats compared with that of the control rats. During ischemia, the AP amplitude, the maximal rate of rise of phase 0, APD, and resting potential, were lower in the control, fructose-fed, and CIHH-F groups, but were not changed in the CIHH rats. The lower AP during ischemia did not recover after washout for the fructose-fed rats. In conclusion, CIHH protects the heart against ischemia-reperfusion induced arrhythmia in rats with metabolic syndrome. This effect of CIHH is possibly related to baseline prolongation of the AP and attenuation of AP reduction during ischemia-reperfusion. Key words: chronic intermittent hypobaric hypoxia, metabolic syndrome, ischemia-reperfusion, papillary muscle, action potential. Cette etude s'est penchee sur l'effet anti-arythmique d'une hypoxie hypobare intermittente chronique (HHIC) et ses mecanismes cellulaires chez des rats atteints du syndrome metabolique. Des rats males Sprague-Dawley ont ete repartis de maniere aleatoire en groupes controle, nourri au fructose (Fruc, nourri avec 10 % de fructose dans l'eau de consommation afin d'induire le syndrome metabolique), HHIC (42 jours d'hypoxie hypobare simulant une altitude de 5000 m : PB 404 mm Hg, [PO.sub.2] = 84 mm Hg, 6 heures par jour), et HHIC et fructose (HHIC-F). L'indice d'arythmie a ete determine chez les rats anesthesies apres 30 min d'ischemie cardiaque suivie d'une reperfusion de 120 min. Les potentiels d'action (PA) ont ete enregistres a partir des muscles ventriculaires papillaires isoles. L'indice d'arythmie etait beaucoup plus faible chez les rats du groupe HHIC-F que ceux du groupe Fruc. En condition de base, la duree du PA (DPA) etait significativement raccourcie chez les rats du groupe Fruc, mais prolongee de maniere evidente chez les rats HHIC comparativement a ceux du groupe controle. Durant l'ischemie, l'amplitude du PA, le taux maximal d'elevation de la phase 0, le DPA et le potentiel au repos etaient plus faibles chez les groupes controle, Fruc et HHIC-F, mais ils etaient inchanges chez les rats du groupe HHIC. Le PA plus faible durant l'ischemie n'etait pas retabli apres un rincage chez les rats Fruc. En conclusion, l'HHIC protege le coeur de l'arythmie induite par ischemie/reperfusion chez les rats atteints du syndrome metabolique. Cet effet de l'HHIC est possiblement relie a la prolongation de la ligne de base du PA et a l'attenuation de la reduction du PA durant l'ischemie-reperfusion. [Traduit par la Redaction] Mots-cles : hypoxie hypobare intermittente chronique, syndrome metabolique, ischemie-reperfusion, muscle papillaire, potentiel d'action., Introduction Metabolic syndrome occurs in 20% of the population worldwide (Brown et al. 2001; Liu et al. 2010; Hanci et al. 2011; Angeloni et al. 2012). The main pathological characteristics [...]

Nociceptive afferents innervate the stomach and send signals centrally to the brain and locally to stomach tissues. Nociceptive afferents can be detected with a variety of different markers. In particular, substance P (SP) is a neuropeptide and is one of the most commonly used markers for nociceptive nerves in the somatic and visceral organs. However, the topographical distribution and morphological structure of SP‐immunoreactive (SP‐IR) axons and terminals in the whole stomach have not yet been fully determined. In this study, we labeled SP‐IR axons and terminals in flat mounts of the ventral and dorsal halves of the stomach of mice. Flat‐mount stomachs, including the longitudinal and circular muscular layers and the myenteric ganglionic plexus, were processed with SP primary antibody followed by fluorescent secondary antibody and then scanned using confocal microscopy. We found that (1) SP‐IR axons and terminals formed an extensive network of fibers in the muscular layers and within the ganglia of the myenteric plexus of the whole stomach. (2) Many axons that ran in parallel with the long axes of the longitudinal and circular muscles were also immunoreactive for the vesicular acetylcholine transporter (VAChT). (3) SP‐IR axons formed very dense terminal varicosities encircling individual neurons in the myenteric plexus; many of these were VAChT immunoreactive. (4) The regional density of SP‐IR axons and terminals in the muscle and myenteric plexus varied in the following order from high to low: antrum‐pylorus, corpus, fundus, and cardia. (5) In only the longitudinal and circular muscles, the regional density of SP‐IR axon innervation from high to low were: antrum‐pylorus, corpus, cardia, and fundus. (6) The innervation patterns of SP‐IR axons and terminals in the ventral and dorsal stomach were comparable. Collectively, our data provide for the first time a map of the distribution and morphology of SP‐IR axons and terminals in the whole stomach with single‐cell/axon/synapse resolution. This work will establish an anatomical foundation for functional mapping of the SP‐IR axon innervation of the stomach and its pathological remodeling in gastrointestinal diseases. [ABSTRACT FROM AUTHOR]

The sympathetic nerve activity is elevated in cardiovascular diseases such as hypertension. Enhanced glutamatergic inputs in the paraventricular nucleus (PVN) of the hypothalamus contribute to heightened sympathetic outflow in spontaneously hypertensive rats (SHR). We determined the role of group I metabotropic glutamate receptors (mGluR) in the PVN in the control of sympathetic vasomotor tone in hypertension. Lumbar sympathetic nerve activity (LSNA), arterial blood pressure (ABP), and heart rate (HR) were recorded in anesthetized SHR and Wistar-Kyoto (WKY) rats. Bilateral microinjection of 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), a selective mGluR5 receptor antagonist, or (S)-(+)-[alpha]-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385), a selective mGluR1 receptor antagonist, into the PVN had no significant effect on LSNA and ABP in WKY rats. Strikingly, MPEP and LY367385 dose dependently decreased LSNA, ABP, and HR in SHR. The MPEP-induced decreases in LSNA and ABP were significantly greater than those inhibited by LY367385 in SHR. Furthermore, bilateral microinjection of (S)-3,5-dihydroxyphenylglycine (S-DHPG), a selective group I mGluR agonist, into the PVN caused a similar dose-dependent increase in LSNA, ABP, and HR in both groups. S-DHPG-induced responses were attenuated by MPEP or LY367385 alone and were abolished by a combination of MPEP and LY367385 in WKY rats and SHR. In addition, microinjection of the NMDA receptor antagonist attenuated the sympathoexcitatory responses induced by S-DHPG in both WKY rats and SHR. Collectively, this study provides important new evidence that the resting sympathetic vasomotor tone is maintained by tonic activation of group I mGluRs in the PVN in hypertension. Activation of NMDA receptors are involved in the sympathoexcitatory effect of group I mGluRs in the PVN. hypothalamus; sympathetic activity doi: 10.1152/ajpregu.00195.2010.

[GABA.sub.B] receptor function is upregulated in the paraventricular nucleus (PVN) of the hypothalamus in spontaneously hypertensive rats (SHR), but it is unclear whether this upregulation occurs pre- or postsynaptically. We therefore determined pre- and postsynaptic [GABA.sub.B] receptor function in retrogradely labeled spinally projecting PVN neurons using whole cell patch-clamp recording in brain slices in SHR and Wistar-Kyoto (WKY) rats. Bath application of the [GABA.sub.B] receptor agonist baclofen significantly decreased the spontaneous firing activity of labeled PVN neurons in both SHR and WKY rats. However, the magnitude of reduction in the firing rate was significantly greater in SHR than in WKY rats. Furthermore, baclofen produced larger membrane hyperpolarization and outward currents in labeled PVN neurons in SHR than in WKY rats. The baclofen-induced current was abolished by either including G protein inhibitor GDP[beta]S in the pipette solution or bath application of the [GABA.sub.B] receptor antagonist in both SHR and WKY rats. Blocking N-methyl-D-aspartic acid receptors had no significant effect on baclofenelicited outward currents in SHR. In addition, baclofen caused significantly greater inhibition of glutamatergic excitatory postsynaptic currents (EPSCs) in labeled PVN neurons in brain slices from SHR than WKY rats. By contrast, baclofen produced significantly less inhibition of GABAergic inhibitory postsynaptic currents (IPSCs) in labeled PVN neurons in SHR than in WKY rats. Although microinjection of the [GABA.sub.B] antagonist into the PVN increases sympathetic vasomotor tone in SHR, the [GABA.sub.B] antagonist did not affect EPSCs and IPSCs of the PVN neurons in vitro. These findings suggest that postsynaptic [GABA.sub.B] receptor function is upregulated in PVN presympathetic neurons in SHR. Whereas presynaptic [GABA.sub.B] receptor control of glutamatergic synaptic inputs is enhanced, presynapfic [GABA.sub.B] receptor control of GABAergic inputs in the PVN is attenuated in SHR. Changes in both pre- and postsynaptic [GABA.sub.B] receptors in the PVN may contribute to the control of sympathetic outflow in hypertension. autonomic nervous system; synaptic transmission; hypertension; [gamma]-aminobutyric acid; baclofen

Increased sympathetic outflow contributes to the pathogenesis of hypertension. However, the mechanisms of increased sympathetic drive in hypertension remain unclear. We examined the tonic GABAergic inhibition in control of the excitability of paraventricular (PVN) presympathetic neurons in spontaneously hypertensive rats (SHR) and norrnotensive controls, including Sprague-Dawley (SD) and Wistar-Kyoto (WKY) rats. Whole cell patch-clamp recordings were performed on retrogradely labeled PVN neurons projecting to the rostral ventrolateral medulla (RVLM) in brain slices. The basal firing rate of PVN neurons was significantly decreased in 13-wk-old SD and WKY rats but increased in 13-wk-old SHR, compared with their respective 6-wk-old controls. The [GABA.sub.A] antagonist bicuculline consistently increased the firing of PVN neurons in normotensive controls. Surprisingly, bicuculline either decreased the firing or had no effect in 59.3% of labeled cells in 13-wk-old SHR. In contrast, the [GABA.sub.B] antagonist CGP-55845 had no effect on the firing of PVN neurons in normotensive controls but significantly increased the firing of 75% of cells studied in 13-wk-old SHR. Furthermore, the evoked [GABA.sub.A] current decreased significantly in labeled PVN neurons of 13-wk-old SHR compared with that in normotensive controls. Both the frequency and amplitude of GABAergic spontaneously inhibitory postsynaptic currents were also reduced in 13-wk-old SHR. This study demonstrates an unexpected functional change in [GABA.sub.A] and [GABA.sub.B] receptors in regulation of the firing activity of PVN-RVLM neurons in SHR. This change in [GABA.sub.A] receptor function and GABAergic inputs to PVN output neurons may contribute to increased sympathetic outflow in hypertension. brain slices; patch clamp; [gamma]-aminobutyric acid; hypothalamus; synaptic transmission

Aims Elevated sympathetic outflow is associated with primary hypertension. However, the mechanisms involved in heightened sympathetic outflow in hypertension are unclear. The central amygdala (CeA) regulates autonomic components of emotions through projections to the brainstem. The neuronal Kv7 channel is a non-inactivating voltage-dependent K+ channel encoded by KCNQ2/3 genes involved in stabilizing the neuronal membrane potential and regulating neuronal excitability. In this study, we investigated if altered Kv7 channel activity in the CeA contributes to heightened sympathetic outflow in hypertension. Methods and results The mRNA and protein expression levels of Kv7.2/Kv7.3 in the CeA were significantly reduced in spontaneously hypertensive rats (SHRs) compared with Wistar–Kyoto (WKY) rats. Lowering blood pressure with coeliac ganglionectomy in SHRs did not alter Kv7.2 and Kv7.3 channel expression levels in the CeA. Fluospheres were injected into the rostral ventrolateral medulla (RVLM) to retrogradely label CeA neurons projecting to the RVLM (CeA–RVLM neurons). Kv7 channel currents recorded from CeA–RVLM neurons in brain slices were much smaller in SHRs than in WKY rats. Furthermore, the basal firing activity of CeA–RVLM neurons was significantly greater in SHRs than in WKY rats. Bath application of specific Kv7 channel blocker 10, 10-bis (4-pyridinylmethyl)-9(10H)-anthracnose (XE-991) increased the excitability of CeA–RVLM neurons in WKY rats, but not in SHRs. Microinjection of XE-991 into the CeA increased arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA), while microinjection of Kv7 channel opener QO-58 decreased ABP and RSNA, in anaesthetized WKY rats but not SHRs. Conclusions Our findings suggest that diminished Kv7 channel activity in the CeA contributes to elevated sympathetic outflow in primary hypertension. This novel information provides new mechanistic insight into the pathogenesis of neurogenic hypertension. [ABSTRACT FROM AUTHOR]