The Slack Channel Regulates Anxiety-like Behaviors via Basolateral Amygdala Glutamatergic Projections to Ventral Hippocampus

The Journal of neuroscience : the official journal of the Society for Neuroscience

2022 Feb 22

Zhang, Q;Gao, SH;Shen, ZS;Wang, Y;Hu, SW;Duan, GB;Liu, Y;Zhong, DY;Liu, J;Sun, MH;Zhang, X;Cao, TY;Cao, JL;Tang, QY;Zhang, Z;
PMID: 35197318 | DOI: 10.1523/JNEUROSCI.2027-21.2022

Anxiety disorders are a series of mental disorders characterized by anxiety and fear, but the molecular basis of these disorders remains unclear. In the present study, we find that the global Slack KO male mice exhibit anxious behaviors whereas the Slack Y777H male mice manifest anxiolytic behaviors. The expression of Slack channels is rich in BLA glutamatergic neurons and down-regulated in chronic corticosterone-treated mice. In addition, electrophysiological data show enhanced excitability of BLA glutamatergic neurons in the Slack KO mice and decreased excitability of these neurons in the Slack Y777H mice. Furthermore, the Slack channel deletion in BLA glutamatergic neurons is sufficient to result in enhanced avoidance behaviors while Kcnt1 gene expression in the BLA or BLA-vHPC glutamatergic projections reverses anxious behaviors of the Slack KO mice. Our study identifies the role of the Slack channel in controlling anxious behaviors by decreasing the excitability of BLA-vHPC glutamatergic projections, providing a potential target for anxiolytic therapies.SIGNIFICANCE STATEMENTAnxiety disorders are a series of mental disorders characterized by anxiety and fear, but the molecular basis of these disorders remains unclear. Here, we examined the loss- and gain-of-function Slack channel mice's behaviors in elevated plus maze and open field tests and found the anxiolytic role of the Slack channel. By altering the Slack channel expression in the specific neuronal circuit, we demonstrated that the Slack channel played its anxiolytic role by decreasing the excitability of BLA-vHPC glutamatergic projections. Our data reveal the role of the Slack channel in the regulation of anxiety, which may provide a potential molecular target for anxiolytic therapies.

A prolactin-dependent sexually dimorphic mechanism of migraine chronification

Cephalalgia : an international journal of headache

2021 Sep 12

Ikegami, D;Navratilova, E;Yue, X;Moutal, A;Kopruszinski, CM;Khanna, R;Patwardhan, A;Dodick, DW;Porreca, F;
PMID: 34510920 | DOI: 10.1177/03331024211039813

Determination of possible sex differences in mechanisms promoting migraine progression and the contribution of prolactin and the prolactin long (PRLR-L) and short (PRLR-S) receptor isoforms.The majority of patients with chronic migraine and medication overuse headache are female. Prolactin is present at higher levels in women and increases migraine. Prolactin signaling at the PRLR-S selectively sensitizes nociceptors in female rodents, while expression of the PRLR-L is protective.Medication overuse headache was modeled by repeated sumatriptan administration in male and female mice. Periorbital and hindpaw cutaneous allodynia served as a surrogate of migraine-like pain. PRLR-L and PRLR-S isoforms were measured in the trigeminal ganglion with western blotting. Possible co-localization of PRLR with serotonin 5HT1B and 5HT1D receptors was determined with RNAscope. Cabergoline, a dopamine receptor agonist that inhibits circulating prolactin, was co-administered with sumatriptan. Nasal administration of CRISPR/Cas9 plasmid was used to edit expression of both PRLR isoforms.PRLR was co-localized with 5HT1B or 5HT1D receptors in the ophthalmic region of female trigeminal ganglion. A single injection of sumatriptan increased serum PRL levels in female mice. Repeated sumatriptan promoted cutaneous allodynia in both sexes but down-regulated trigeminal ganglion PRLR-L, without altering PRLR-S, only in females. Co-administration of sumatriptan with cabergoline prevented allodynia and down-regulation of PRLR-L only in females. CRISPR/Cas9 editing of both PRLR isoforms in the trigeminal ganglion prevented sumatriptan-induced periorbital allodynia in females.We identified a sexually dimorphic mechanism of migraine chronification that involves down-regulation of PRLR-L and increased signaling of circulating prolactin at PRLR-S. These studies reveal a previously unrecognized neuroendocrine mechanism linking the hypothalamus to nociceptor sensitization that increases the risk of migraine pain in females and suggest opportunities for novel sex-specific therapies including gene editing through nasal delivery of CRISPR/Cas9 constructs.

Empagliflozin Disrupts a Tnfrsf12a-Mediated Feed Forward Loop That Promotes Left Ventricular Hypertrophy

Cardiovascular drugs and therapy

2021 Apr 22

Yerra, VG;Batchu, SN;Kabir, G;Advani, SL;Liu, Y;Siddiqi, FS;Connelly, KA;Advani, A;
PMID: 33886003 | DOI: 10.1007/s10557-021-07190-2

Although the cardioprotective benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors are now widely appreciated, the mechanisms underlying these benefits remain unresolved. Tumor necrosis factor receptor superfamily member 12a (Tnfrsf12a) is a receptor for tumor necrosis factor superfamily member 12 (Tnfsf12). Tnfrsf12a is highly inducible and plays a key role in the development of cardiac hypertrophy and heart failure. Here we set out to determine if SGLT2 inhibition affects the Tnfsf12/Tnfrsf12a system in the stressed myocardium. C57BL/6N mice that had undergone sham or transverse aortic constriction (TAC) surgery were treated with either the SGLT2 inhibitor empagliflozin (400 mg/kg diet; 60-65 mg/kg/day) or standard chow alone and were followed for 8 weeks. Tnfrsf12a expression in mouse hearts was assessed by in situ hybridization, qRT-PCR, and immunoblotting. Left ventricular (LV) mass, end-systolic volume, and end-diastolic volume were all increased in TAC mice and were significantly lower with empagliflozin. Myocyte hypertrophy and interstitial fibrosis in TAC hearts were similarly attenuated with empagliflozin. Tnfrsf12a expression was upregulated in mouse hearts following TAC surgery but not in the hearts of empagliflozin-treated mice. In cultured cardiomyocytes, Tnfrsf12a antagonism attenuated the increase in cardiomyocyte size that was induced by phenylephrine. Empagliflozin attenuates LV enlargement in mice with hypertrophic heart failure. This effect may be mediated, at least in part, by a reduction in loading conditions which limits upregulation of the inducible, proinflammatory, and prohypertrophic TNF superfamily receptor, Tnfrsf12a. Disruption of the Tnfsf12/Tnfrsf12a feed forward system may contribute to the cardioprotective benefits of SGLT2 inhibition.

A basomedial amygdala to intercalated cells microcircuit expressing PACAP and its receptor PAC1 regulates contextual fear

The Journal of neuroscience : the official journal of the Society for Neuroscience

2021 Feb 26

Rajbhandari, AK;Octeau, JC;Gonzalez, S;Pennington, ZT;Mohamed, F;Trott, J;Chavez, J;Ngyuen, E;Keces, N;Hong, WZ;Neve, RL;Waschek, J;Khakh, BS;Fanselow, MS;
PMID: 33637560 | DOI: 10.1523/JNEUROSCI.2564-20.2021

Trauma can cause dysfunctional fear regulation leading some people to develop disorders such as post-traumatic stress disorder (PTSD). The amygdala regulates fear, whereas PACAP (pituitary adenylate activating peptide) and PAC1 receptors are linked to PTSD symptom severity at genetic/epigenetic levels, with a strong link in females with PTSD. We discovered a PACAPergic projection from the basomedial amygdala (BMA) to the medial intercalated cells (mICCs) in adult mice. In vivo optogenetic stimulation of this pathway increased cfos expression in mICCs, decreased fear recall and increased fear extinction. Selective deletion of PAC1 receptors from the mICCs in females reduced fear acquisition, but enhanced fear generalization and reduced fear extinction in males. Optogenetic stimulation of the BMA-mICCs PACAPergic pathway produced excitatory postsynaptic currents (EPSCs) in mICC neurons, which were enhanced by the PAC1 receptor antagonist, PACAP 6-38. Our findings show that mICCs modulate contextual fear in a dynamic and sex-dependent manner via a microcircuit containing the BMA and mICCs, and in a manner that was dependent on behavioral state.SIGNIFICANCE STATEMENTTraumatic stress can affect different aspects of fear behaviors including fear learning, generalization of learned fear to novel contexts, how the fear of the original context is recalled, and how fear is reduced over time. While the amygdala has been studied for its role in regulation of different aspects of fear, the molecular circuitry of this structure is quite complex. In addition, aspects of fear can be modulated differently in males and females. Our findings show that a specific circuitry containing the neuropeptide PACAP and its receptor, PAC1, regulates various aspects of fear including acquisition, generalization, recall and extinction in a sexually dimorphic manner, characterizing a novel pathway that modulates traumatic fear.

Expression of an alternatively spliced variant of SORL1 in neuronal dendrites is decreased in patients with Alzheimer\'s disease

Acta neuropathologica communications

2021 Mar 16

Monti, G;Kjolby, M;Jensen, AMG;Allen, M;Reiche, J;Møller, PL;Comaposada-Baró, R;Zolkowski, BE;Vieira, C;Jørgensen, MM;Holm, IE;Valdmanis, PN;Wellner, N;Vægter, CB;Lincoln, SJ;Nykjær, A;Ertekin-Taner, N;Young, JE;Nyegaard, M;Andersen, OM;
PMID: 33726851 | DOI: 10.1186/s40478-021-01140-7

SORL1 is strongly associated with both sporadic and familial forms of Alzheimer's disease (AD), but a lack of information about alternatively spliced transcripts currently limits our understanding of the role of SORL1 in AD. Here, we describe a SORL1 transcript (SORL1-38b) characterized by inclusion of a novel exon (E38b) that encodes a truncated protein. We identified E38b-containing transcripts in several brain regions, with the highest expression in the cerebellum and showed that SORL1-38b is largely located in neuronal dendrites, which is in contrast to the somatic distribution of transcripts encoding the full-length SORLA protein (SORL1-fl). SORL1-38b transcript levels were significantly reduced in AD cerebellum in three independent cohorts of postmortem brains, whereas no changes were observed for SORL1-fl. A trend of lower 38b transcript level in cerebellum was found for individuals carrying the risk variant at rs2282649 (known as SNP24), although not reaching statistical significance. These findings suggest synaptic functions for SORL1-38b in the brain, uncovering novel aspects of SORL1 that can be further explored in AD research.

Inhibition of transforming growth factor β1 signaling in resident interstitial cells attenuates profibrotic gene expression and preserves erythropoietin production during experimental kidney fibrosis in mice

Kidney international

2021 Mar 08

Fuchs, MAA;Broeker, KAE;Schrankl, J;Burzlaff, N;Willam, C;Wagner, C;Kurtz, A;
PMID: 33705825 | DOI: 10.1016/j.kint.2021.02.035

Kidney fibrosis is characterized by the development of myofibroblasts originating from resident kidney and immigrating cells. Myofibroblast formation and extracellular matrix production during kidney damage are triggered by various cytokines. Among these, transforming growth factor β1 (TGFβ1) is considered a central trigger for kidney fibrosis. We found a highly upregulated expression of TGFβ1 and TGFβ receptor 2 (TGFβ-R2) mRNAs in kidney interstitial cells in experimental fibrosis. Here, we investigated the contribution of TGFβ1 signaling in resident kidney interstitial cells to organ fibrosis using the models of adenine induced nephropathy and unilateral ureter occlusion in mice. For this purpose TGFβ1 signaling was interrupted by inducible deletion of the TGFβ-R2 gene in interstitial cells expressing the fibroblast marker platelet derived growth factor receptor-β. Expression of profibrotic genes was attenuated up to 50% in kidneys lacking TGFβ-R2 in cells positive for platelet derived growth factor receptor-β. Additionally, deletion of TGFβ-R2 prevented the decline of erythropoietin production in ureter ligated kidneys. Notably, fibrosis associated expression of α-smooth muscle actin as a myofibroblast marker and deposits of extracellular collagens were not altered in mice with targeted deletion of TGFβ-R2. Thus, our findings suggest an enhancing effect of TGFβ1 signaling in resident interstitial cells that contributes to profibrotic gene expression and the downregulation of erythropoietin production, but not to the development of myofibroblasts during kidney fibrosis.

Histamine H1 receptor deletion in cholinergic neurons induces sensorimotor gating ability deficit and social impairments in mice

Nature communications

2021 Feb 18

Cheng, L;Xu, C;Wang, L;An, D;Jiang, L;Zheng, Y;Xu, Y;Wang, Y;Wang, Y;Zhang, K;Wang, X;Zhang, X;Bao, A;Zhou, Y;Yang, J;Duan, S;Swaab, DF;Hu, W;Chen, Z;
PMID: 33602941 | DOI: 10.1038/s41467-021-21476-x

Negative symptoms in schizophrenia strongly contribute to poor functional outcomes, however its pathogenesis is still unclear. Here, we found that histamine H1 receptor (H1R) expression in basal forebrain (BF) cholinergic neurons was decreased in patients with schizophrenia having negative symptoms. Deletion of H1R gene in cholinergic neurons in mice resulted in functional deficiency of cholinergic projections from the BF to the prefrontal cortex and in the formation of sensorimotor gating deficit, social impairment and anhedonia-like behavior. These behavioral deficits can be rescued by re-expressing H1R or by chemogenetic activation of cholinergic neurons in the BF. Direct chemogenetic inhibition of BF cholinergic neurons produced such behavioral deficits and also increased the susceptibility to hyperlocomotion. Our results suggest that the H1R deficiency in BF cholinergic neurons is critical for sensorimotor gating deficit, social impairments and anhedonia-like behavior. This finding may help to understand the genetic and biochemical bases of negative symptoms in schizophrenia.

Induction of Anxiety-Like Phenotypes by Knockdown of Cannabinoid Type-1 Receptors in the Amygdala of Marmosets

Neuroscience bulletin

2023 Jun 27

Zhu, L;Zheng, D;Li, R;Shen, CJ;Cai, R;Lyu, C;Tang, B;Sun, H;Wang, X;Ding, Y;Xu, B;Jia, G;Li, X;Gao, L;Li, XM;
PMID: 37368194 | DOI: 10.1007/s12264-023-01081-2

The amygdala is an important hub for regulating emotions and is involved in the pathophysiology of many mental diseases, such as depression and anxiety. Meanwhile, the endocannabinoid system plays a crucial role in regulating emotions and mainly functions through the cannabinoid type-1 receptor (CB1R), which is strongly expressed in the amygdala of non-human primates (NHPs). However, it remains largely unknown how the CB1Rs in the amygdala of NHPs regulate mental diseases. Here, we investigated the role of CB1R by knocking down the cannabinoid receptor 1 (CNR1) gene encoding CB1R in the amygdala of adult marmosets through regional delivery of AAV-SaCas9-gRNA. We found that CB1R knockdown in the amygdala induced anxiety-like behaviors, including disrupted night sleep, agitated psychomotor activity in new environments, and reduced social desire. Moreover, marmosets with CB1R-knockdown had up-regulated plasma cortisol levels. These results indicate that the knockdown of CB1Rs in the amygdala induces anxiety-like behaviors in marmosets, and this may be the mechanism underlying the regulation of anxiety by CB1Rs in the amygdala of NHPs.

Osteocytes: New Kids on the Block for Cancer in Bone Therapy

Cancers

2023 May 07

Anloague, A;Delgado-Calle, J;
PMID: 37174109 | DOI: 10.3390/cancers15092645

The tumor microenvironment plays a central role in the onset and progression of cancer in the bone. Cancer cells, either from tumors originating in the bone or from metastatic cancer cells from other body systems, are located in specialized niches where they interact with different cells of the bone marrow. These interactions transform the bone into an ideal niche for cancer cell migration, proliferation, and survival and cause an imbalance in bone homeostasis that severely affects the integrity of the skeleton. During the last decade, preclinical studies have identified new cellular mechanisms responsible for the dependency between cancer cells and bone cells. In this review, we focus on osteocytes, long-lived cells residing in the mineral matrix that have recently been identified as key players in the spread of cancer in bone. We highlight the most recent discoveries on how osteocytes support tumor growth and promote bone disease. Additionally, we discuss how the reciprocal crosstalk between osteocytes and cancer cells provides the opportunity to develop new therapeutic strategies to treat cancer in the bone.

Autoimmune comorbidities associated with sarcoidosis: a case-control study in the All of Us research program

Rheumatology Advances in Practice

2023 Apr 12

Murphy, M;Edemobi, P;Leasure, A;Gulati, M;Miller, E;Damsky, W;Cohen, J;
| DOI: 10.1093/rap/rkad030

Objective The degree to which sarcoidosis patients are affected by autoimmune diseases is poorly understood. Prior studies of autoimmune co-morbidities in sarcoidosis have focused on populations outside the USA or have been impeded by small sample sizes and limited scope. This case-control study evaluated the association between sarcoidosis and autoimmune diseases in a large, diverse cohort based in the USA. Methods We used data from the All of Us research programme to conduct a case-control study involving patients ≥18 years old, from 2018 to the present, diagnosed with sarcoidosis. Sarcoidosis cases and age-, sex- and race-matched controls were identified in a 1:4 ratio. Autoimmune co-morbidities were compared between sarcoidosis patients and controls in univariable and multivariable analyses using logistic regression. The degree of association was measured using the odds ratio (OR). Results A total of 1408 sarcoidosis cases and 5632 controls were included in this study. Seven of 24 examined autoimmune diseases were significantly associated with sarcoidosis in our multivariable analysis (P < 0.05). The composite variable of any autoimmune disease was also significantly associated with sarcoidosis (OR = 2.29, P < 0.001). Conclusion We demonstrate an association between sarcoidosis and multiple autoimmune diseases in a large and diverse cohort based in the USA. These results underscore the need for careful screening of sarcoidosis patients for concomitant autoimmune disease.

A Spatial Atlas of Wnt Receptors in Adult Mouse Liver

The American journal of pathology

2023 Feb 10

Gayden, J;Hu, S;Joseph, PN;Delgado, E;Liu, S;Bell, A;Puig, S;Monga, SP;Freyberg, Z;
PMID: 36773785 | DOI: 10.1016/j.ajpath.2023.01.011

Hepatic zonation is critical for most metabolic functions in liver. Wnt signaling plays an important role in establishing and maintaining liver zonation. Yet, the anatomic expression of Wnt signaling components, especially all 10 Frizzled (Fzd) receptors, has not been characterized in adult liver. To address this, we quantitatively mapped the spatial expression of Fzd receptors in adult mouse liver via multiplex fluorescent in situ hybridization. Although all 10 Fzd receptors are expressed within a metabolic unit, Fzd receptors 1, 4, and 6 are the highest expressed. Although most Wnt signaling occurs in zone 3, expression of most Fzd receptors is not zonated. In contrast, Fzd receptor 6 is preferentially expressed in zone 1. We also verified that Wnt2 and Wnt9b expression is highly zonated and primarily found in zone 3. Therefore, our results suggest that zonated Wnt/β-catenin signaling at baseline is mostly due to Wnt2 and Wnt9b rather than zonation of Fzd mRNA expression. Finally, we showed that Fzd receptors and Wnts are not uniformly expressed by all hepatic cell types. Instead, there is broad distribution among both hepatocytes and nonparenchymal cells, including endothelial cells. Overall, our establishment of a definitive mRNA expression atlas, especially of Fzd receptors, opens the door to future functional characterization in healthy and diseased liver states.

Expression Profile of EBV-Derived Micro-RNA in Systemic Chronic Active EBV Disease

Blood

2022 Nov 15

Yoshimori, M;Ohashi, A;Yoshioka, K;Yokota, T;Shimizu, N;Nishio, M;Arai, A;
| DOI: 10.1182/blood-2022-169693

RESULTS: We identified highly abundant miR-BARTs in the 4 cell lines and the EBV-infected T- or NK-cells from 12 sCAEBV patient's PBMCs (age of 17 to 47 y.o). The expression of miR-BHRFs was not detected in these cells. miR-BART7-3p, miR-BART6-3p, and miR-BART5-5p were the top three expressed among the EBV-derived miRNAs. The highest miR-BART expression among all samples was miR-BART7-3p. We also confirmed the expression of miR-BART7-3p and miR-BART5-5p by _in situ_ hybridization in histological specimens of 3 patients which were observable. Two reports have demonstrated deletion in part of BART region in approximately 30% of sCAEBV cases (_Okuno et al, Nature Microbiology, 2018. Wongwiwat et al, J. Virology, 2022)_. In contrast, no deletion was detected in the region encoding miR-BARTs of EBV obtained from 10 sCAEBV patients. Finally, we examined the role of miR-BART7-3p in sCAEBV. Inhibition of miR-BART7-3p by the inhibitor did not show significant effects on cell proliferation in SNT16 and SNK10 cells. However, GO analysis showed upregulation of immune activation-related genes after miR-BART7-3p inhibition. These results suggest that miR-BART7-3p may function as an immunosuppressor in sCAEBV.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
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tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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