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https://www.readbyqxmd.com/read/29649514/endogenous-neuronal-replacement-in-the-juvenile-brain-following-cerebral-ischemia
#1
Krista M Rodgers, Jared T Ahrendsen, Olivia P Patsos, Frank A Strnad, Joan C Yonchek, Richard J Traystman, Wendy B Macklin, Paco S Herson
Replacement of dead neurons following ischemia, either via enhanced endogenous neurogenesis or stem cell therapy, has long been sought. Unfortunately, while various therapies that enhance neurogenesis or stem cell therapies have proven beneficial in animal models, they have all uniformly failed to truly replace dead neurons in the ischemic core to facilitate long-term recovery. Remarkably, we observe robust repopulation of medium-spiny neurons within the ischemic core of juvenile mice following experimental stroke...
April 9, 2018: Neuroscience
https://www.readbyqxmd.com/read/29628395/hpsc-derived-striatal-cells-generated-using-a-scalable-3d-hydrogel-promote-recovery-in-a-huntington-disease-mouse-model
#2
Maroof M Adil, Thomas Gaj, Antara T Rao, Rishikesh U Kulkarni, Christina M Fuentes, Gokul N Ramadoss, Freja K Ekman, Evan W Miller, David V Schaffer
Huntington disease (HD) is an inherited, progressive neurological disorder characterized by degenerating striatal medium spiny neurons (MSNs). One promising approach for treating HD is cell replacement therapy, where lost cells are replaced by MSN progenitors derived from human pluripotent stem cells (hPSCs). While there has been remarkable progress in generating hPSC-derived MSNs, current production methods rely on two-dimensional culture systems that can include poorly defined components, limit scalability, and yield differing preclinical results...
April 3, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29626166/cascades-of-homeostatic-dysregulation-promote-incubation-of-cocaine-craving
#3
Junshi Wang, Masago Ishikawa, Yue Yang, Mami Otaka, James Y Kim, George R Gardner, Michael T Stefanik, Mike Milovanovic, Yanhua H Huang, Johannes W Hell, Marina E Wolf, Oliver M Schlüter, Yan Dong
In human drug users, cue-induced drug craving progressively intensifies after drug abstinence, promoting drug relapse. This time-dependent progression of drug craving is recapitulated in rodent models, in which rats exhibit progressive intensification of cue-induced drug seeking after withdrawal from drug self-administration, a phenomenon termed incubation of drug craving. While recent results suggest that functional alterations of the nucleus accumbens (NAc) contribute to incubation of drug craving, it remains poorly understood how NAc function evolves after drug withdrawal to progressively intensify drug seeking...
April 6, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29625216/receptor-for-advanced-glycation-end-products-rage-is-expressed-predominantly-in-medium-spiny-neurons-of-tghd-rat-striatum
#4
Dian Shi, Joshua W H Chang, Jaimin Choi, Bronwen Connor, Simon O'Carroll, Louise F B Nicholson, Joo Hyun Kim
Receptor for advanced glycation end products (RAGE) is a multi-ligand receptor involved in the pathology of several progressive neurodegenerative disorders including Huntington's disease (HD). We previously showed that the expression of RAGE and its colocalization with ligands were increased in the striatum of HD patients, increasing with grade severity, and that the pattern of RAGE expression coincided with the medio-lateral pattern of neurodegeneration. However, the exact role of RAGE in HD remains elusive...
April 3, 2018: Neuroscience
https://www.readbyqxmd.com/read/29623030/on-the-role-of-store-operated-calcium-entry-in-acute-and-chronic-neurodegenerative-diseases
#5
REVIEW
Agnese Secondo, Giacinto Bagetta, Diana Amantea
In both excitable and non-excitable cells, calcium (Ca2+ ) signals are maintained by a highly integrated process involving store-operated Ca2+ entry (SOCE), namely the opening of plasma membrane (PM) Ca2+ channels following the release of Ca2+ from intracellular stores. Upon depletion of Ca2+ store, the stromal interaction molecule (STIM) senses Ca2+ level reduction and migrates from endoplasmic reticulum (ER)-like sites to the PM where it activates the channel proteins Orai and/or the transient receptor potential channels (TRPC) prompting Ca2+ refilling...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29621490/an-optical-neuron-astrocyte-proximity-assay-at-synaptic-distance-scales
#6
J Christopher Octeau, Hua Chai, Ruotian Jiang, Shivan L Bonanno, Kelsey C Martin, Baljit S Khakh
Astrocytes are complex bushy cells that serve important functions through close contacts between their processes and synapses. However, the spatial interactions and dynamics of astrocyte processes relative to synapses have proven problematic to study in adult living brain tissue. Here, we report a genetically targeted neuron-astrocyte proximity assay (NAPA) to measure astrocyte-synapse spatial interactions within intact brain preparations and at synaptic distance scales. The method exploits resonance energy transfer between extracellularly displayed fluorescent proteins targeted to synapses and astrocyte processes...
April 4, 2018: Neuron
https://www.readbyqxmd.com/read/29606351/a-huntingtin-knockin-pig-model-recapitulates-features-of-selective-neurodegeneration-in-huntington-s-disease
#7
Sen Yan, Zhuchi Tu, Zhaoming Liu, Nana Fan, Huiming Yang, Su Yang, Weili Yang, Yu Zhao, Zhen Ouyang, Chengdan Lai, Huaqiang Yang, Li Li, Qishuai Liu, Hui Shi, Guangqing Xu, Heng Zhao, Hongjiang Wei, Zhong Pei, Shihua Li, Liangxue Lai, Xiao-Jiang Li
Huntington's disease (HD) is characterized by preferential loss of the medium spiny neurons in the striatum. Using CRISPR/Cas9 and somatic nuclear transfer technology, we established a knockin (KI) pig model of HD that endogenously expresses full-length mutant huntingtin (HTT). By breeding this HD pig model, we have successfully obtained F1 and F2 generation KI pigs. Characterization of founder and F1 KI pigs shows consistent movement, behavioral abnormalities, and early death, which are germline transmittable...
March 23, 2018: Cell
https://www.readbyqxmd.com/read/29574227/mtor-signaling-in-the-nucleus-accumbens-mediates-behavioral-sensitization-to-methamphetamine
#8
Shin-Han Huang, Wan-Rong Wu, Li-Ming Lee, Pei-Rong Huang, Jin-Chung Chen
Chronic psychostimulant treatment in rodents readily produces behavioral sensitization, which reflects altered brain function in response to repeated drug exposure. Numerous morphological and biochemical investigations implicate altered neural plasticity in striatal medium spiny neurons (MSNs) as an essential component in behavioral sensitization. The mammalian target of the rapamycin (mTOR) signaling pathway, a key regulator of synaptic neuroplasticity, in the ventral striatum of methamphetamine (METH) -sensitized mice was investigated to determine if a link exists with the development of METH sensitization...
March 21, 2018: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/29569345/fish-oil-treatment-reduces-chronic-alcohol-exposure-induced-synaptic-changes
#9
Zhe Shi, Youna Xie, Huixia Ren, Baixuan He, Meng Wang, Jian-Bo Wan, Ti-Fei Yuan, Xiaoli Yao, Huanxing Su
Alcohol addiction is a chronic neuropsychiatric disorder that represents one of the most serious global public health problems. Yet, currently there still lacks an effective pharmacotherapy. Omega-3 polyunsaturated fatty acids (N-3 PUFAs) have exhibited beneficial effects in a variety of neurological disorders, particularly in reversing behavioral deficits and neurotoxicity induced by prenatal alcohol exposure and binge drinking. In the present study, we investigated if fish oil, which is rich in N-3 PUFAs, had beneficial effects on preventing relapse and alleviating withdrawal symptoms after chronic alcohol exposure...
March 22, 2018: Addiction Biology
https://www.readbyqxmd.com/read/29541852/neuroinflammation-in-l-dopa-induced-dyskinesia-beyond-the-immune-function
#10
REVIEW
Augusta Pisanu, Laura Boi, Giovanna Mulas, Saturnino Spiga, Sandro Fenu, Anna R Carta
Neuroinflammation is a main component of Parkinson's disease (PD) neuropathology, where unremitting reactive microglia and microglia-secreted soluble molecules such as cytokines, contribute to the neurodegenerative process as part of an aberrant immune reaction. Besides, pro-inflammatory cytokines, predominantly TNF-α, play an important neuromodulatory role in the healthy and diseased brain, being involved in neurotransmitter metabolism, synaptic scaling and brain plasticity. Recent preclinical studies have evidenced an exacerbated neuroinflammatory reaction in the striatum of parkinsonian rats that developed dyskinetic responses following L-DOPA administration...
March 14, 2018: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29540712/accumbens-dopamine-d2-receptors-increase-motivation-by-decreasing-inhibitory-transmission-to-the-ventral-pallidum
#11
Eduardo F Gallo, Jozsef Meszaros, Jeremy D Sherman, Muhammad O Chohan, Eric Teboul, Claire S Choi, Holly Moore, Jonathan A Javitch, Christoph Kellendonk
Dopamine D2 receptors (D2Rs) in the nucleus accumbens (NAc) regulate motivated behavior, but the underlying neurobiological mechanisms remain unresolved. Here, we show that selective upregulation of D2Rs in the indirect pathway of the adult NAc enhances the willingness to work for food. Mechanistic studies in brain slices reveal that D2R upregulation attenuates inhibitory transmission at two main output projections of the indirect pathway, the classical long-range projections to the ventral pallidum (VP), as well as local collaterals to direct pathway medium spiny neurons...
March 14, 2018: Nature Communications
https://www.readbyqxmd.com/read/29527566/dopamine-d2-receptors-in-dopaminergic-neurons-modulate-performance-in-a-reversal-learning-task-in-mice
#12
Jérôme Linden, Alexander S James, Colin McDaniel, J David Jentsch
Neuroimaging studies in animal models and human subjects have each revealed that relatively low striatal dopamine D2-like receptor binding potential is associated with poor impulse control and with vulnerability for addiction-related behaviors. These studies cannot, however, disambiguate the roles for various pools of D2 receptors found in the striatum (e.g., those expressed on medium spiny striato-pallidal neurons vs on dopamine-releasing nerve terminals) in these behavioral outcomes. To clarify the role of the latter pool, namely, D2 autoreceptors, we studied mice carrying a conditional DRD2 gene, with or without Cre-recombinase expressed under the transcriptional control of the dopamine transporter gene locus (autoDrd2-KO, n = 19 and controls, n = 21)...
January 2018: ENeuro
https://www.readbyqxmd.com/read/29523623/coordinated-ramping-of-dorsal-striatal-pathways-preceding-food-approach-and-consumption
#13
T D London, J A Licholai, I Szczot, M A Ali, K H LeBlanc, W C Fobbs, A V Kravitz
The striatum controls food-related actions and consumption and is linked to feeding disorders including obesity and anorexia nervosa. Two populations of neurons project from the striatum: direct pathway medium spiny neurons (dMSNs) and indirect pathway medium spiny neurons (iMSNs). The selective contribution of dMSNs and iMSNs to food-related actions and consumption remains unknown. Here, we used in vivo electrophysiology and fiber photometry in mice (of both sexes) to record both spiking activity and pathway-specific calcium activity of dorsal striatal neurons during approach to and consumption of food pellets...
March 9, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29521210/phosphodiesterase-10-inhibitors-novel-perspectives-for-psychiatric-and-neurodegenerative-drug-discovery
#14
Agnieszka Zagorska, Anna Partyka, Adam Bucki, Alicja Gawalska, Anna Czopek, Maciej Pawlowski
BACKGROUND: The phosphodiesterase 10 (PDE10) family, identified in 1999, is mainly expressed in the brain, particularly in the striatum, within the medium spiny neurons, nucleus accumbens, and olfactory tubercle. Inhibitors of PDE10 (PDE10-Is) are a conceptually rational subject for medicinal chemistry with potential use in the treatment of psychiatric and neurodegenerative diseases. OBJECTIVE: This review is based on peer-reviewed published articles, and summarizes the cellular and molecular biology of PDE10 as a rational target for psychiatric and neurodegenerative drug discovery...
March 8, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29505597/a-novel-ex-vivo-huntington-s-disease-model-for-studying-gabaergic-neurons-and-cell-grafts-by-laser-microdissection
#15
E M André, N Daviaud, L Sindji, J Cayon, R Perrot, C N Montero-Menei
Organotypic brain slice cultures have been recently used to study neurodegenerative disorders such as Parkinson's disease and Huntington's disease (HD). They preserve brain three-dimensional architecture, synaptic connectivity and brain cells microenvironment. Here, we developed an innovative model of Huntington's disease from coronal rat brain slices, that include all the areas involved in the pathology. HD-like neurodegeneration was obtained in only one week, in a single step, during organotypic slice preparation, without the use of neurotoxins...
2018: PloS One
https://www.readbyqxmd.com/read/29500819/camp-producing-chemogenetic-activation-of-indirect-pathway-striatal-projection-neurons-and-the-downstream-effects-on-the-globus-pallidus-and-subthalamic-nucleus-in-freely-moving-mice
#16
Safa Bouabid, Fu-Ming Zhou
The indirect pathway striatal medium spiny projection neurons (iMSNs) are critical to motor and cognitive brain functions. These neurons express a high level of cAMP-increasing adenosine A2a receptors (A2aRs). However, the potential effects of cAMP production on iMSN spiking activity have not been established, and recording identified iMSNs in freely moving animals is challenging. Here we show that in the transgenic mice expressing cAMP-producing G protein Gs -coupled designer receptor exclusively activated by designer drug (Gs-DREADD) in iMSNs, the baseline spike firing in MSNs is normal, indicating DREADD expression does not affect the normal physiology of these neurons...
March 3, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29498008/histamine-excites-striatal-dopamine-d1-and-d2-receptor-expressing-neurons-via-postsynaptic-h1-and-h2-receptors
#17
Qian-Xing Zhuang, Han-Ting Xu, Xu-Juan Lu, Bin Li, Wing-Ho Yung, Jian-Jun Wang, Jing-Ning Zhu
The central histaminergic nervous system, originating from the tuberomammillary nucleus (TMN) of the hypothalamus, widely innervates almost the whole brain, including the basal ganglia. Intriguingly, the histaminergic system is altered in parkinsonian patients. Yet, little is known about the effect and mechanisms of histamine on different types of neurons in the basal ganglia circuitry. Here, by using anterograde tracing, immunostaining, patch clamp recording, and single-cell qPCR techniques, we investigate the histaminergic afferents in the striatum, the major input structure of the basal ganglia, as well as the effect of histamine on the striatal GABAergic medium spiny projection neurons (MSNs)...
March 1, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29491258/discovery-of-2-e-2-7-fluoro-3-methylquinoxalin-2-yl-vinyl-6-pyrrolidin-1-yl-n-tetrahydro-2h-pyran-4-yl-pyrimidin-4-amine-hydrochloride-as-a-highly-selective-pde10a-inhibitor
#18
Yoichi Kadoh, Haruko Miyoshi, Takehiko Matsumura, Yoshihito Tanaka, Mitsuya Hongu, Mayumi Kimura, Kei Takedomi, Kenji Omori, Jun Kotera, Takashi Sasaki, Tamaki Kobayashi, Hiroyuki Taniguchi, Yumi Watanabe, Koki Kojima, Toshiaki Sakamoto, Toshiyuki Himiyama, Eiji Kawanishi
Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5...
2018: Chemical & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29491012/cell-specific-deletion-of-pgc-1%C3%AE-from-medium-spiny-neurons-causes-transcriptional-alterations-and-age-related-motor-impairment
#19
L J McMeekin, Y Li, S N Fox, G C Rowe, D K Crossman, J J Day, Y Li, P J Detloff, R M Cowell
Multiple lines of evidence indicate that a reduction in the expression and function of the transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator-1α (PGC-1α) is associated with neurodegeneration in diseases such as Huntington Disease (HD). Polymorphisms in the PGC-1α gene modify HD progression, and PGC-1α expression is reduced in striatal medium spiny neurons (MSNs) of HD patients and mouse models. However, neither the MSN-specific function of PGC-1α nor the contribution of PGC-1α deficiency to motor dysfunction is known...
February 28, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29487381/mglur5-antagonism-inhibits-cocaine-reinforcement-and-relapse-by-elevation-of-extracellular-glutamate-in-the-nucleus-accumbens-via-a-cb1-receptor-mechanism
#20
Xia Li, Xiao-Qing Peng, Chloe J Jordan, Jie Li, Guo-Hua Bi, Yi He, Hong-Ju Yang, Hai-Ying Zhang, Eliot L Gardner, Zheng-Xiong Xi
Metabotropic glutamate receptor 5 (mGluR5) antagonism inhibits cocaine self-administration and reinstatement of drug-seeking behavior. However, the cellular and molecular mechanisms underlying this action are poorly understood. Here we report a presynaptic glutamate/cannabinoid mechanism that may underlie this action. Systemic or intra-nucleus accumbens (NAc) administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) dose-dependently reduced cocaine (and sucrose) self-administration and cocaine-induced reinstatement of drug-seeking behavior...
February 27, 2018: Scientific Reports
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