Bu eser FY 2013 araştırma değişim programı arasında JSP'ler ve CNRS, JSP'ler KAKENHI Grant numarası 26860858 ve Narishige nörolojik araştırma Vakfı tarafından desteklenmiştir. Drs. Mariko Harada-Shiba ve Kyoko Shioya yararlı tartışmalar için teşekkür ederiz. Mari Furuta, Mutsumi Sakamoto, Ritsuko Maki ve Dr EMI Tanaka mükemmel teknik destek için teşekkür ederiz.

Tüm deneyler deneysel hayvan bakım ve kullanım komitesi ulusal beyin ve dolaşım Merkezi, Suita, Japonya tarafından onaylanmış protokoller uyarınca gerçekleştirilmiştir.
1. aşağıdaki hayvan ve malzemeleri MIUH ameliyat için hazırlayın
<ol><li>Gestasyonel gün 17, zamanlanmış hamile Sprague-Dawley Rat hazırlamak Yani, embriyonik gün 17 (E17). Baraj ortalama vücut ağırlıkları vardır 307.0 ± 40.7 g (yani ± SD, n = 9).</li>
	<li>Metal halkaları hazırlamak; altın kaplı çelikten yapılmış 0,24 mm iç çap.</li>
	<li>Malzemeleri masa başı olarak tüm malzemeleri hazırlayın.</li>
</ol>2. MIUH ameliyat için hazırlayın
<ol><li>Bir Isıtma yastığı sıçan yerleşim için 37 ° C'de sıcak</li>
	<li>Steril bez Isıtma yastığını yerleştirin</li>
	<li>Sıcak steril serum fizyolojik bir su banyosu içinde 37 ° C'de</li>
</ol>3. MIUH ameliyatı
<ol><li>Steril koşul altında cerrahi işlemler gerçekleştirmek. Sargılar, forseps, iğne ile % 70 etanol kullanmadan önce sterilize. Zaman zaman etanol sprey uygulanarak dezenfekte ve steril eldiven kullanın.</li>
	<li>Fareyi anestezi indüksiyon kutuya koyun. %4 isoflurane içine belgili tanımlık kutu (yaklaşık 5 dk) tanıtmak.</li>
	<li>Hayvan iyice indüksiyon kutusunda anestezi sonra Steril bez üzerine fare Isıtma yastığını sırtüstü pozisyonda yerleştirin. Bir yanıt-e doğru ayak parmağı çimdik eksikliği ile anestezi derinliği için denetleyin. 1.5-%2.0 isoflurane burun konisi ile koruyun.</li>
	<li>Pelvik Kemer bölgesi aşağı göbek karın üzerine depilatory köpük uygulayın. Birkaç dakika sonra kağıt havlu ile depilatory köpük yok etmek. Bir tıraş makinesi depilatory köpük için bir yedek olarak kullanılabilir.</li>
	<li>İyot dezenfektan çözüm cilt depilated bölgesine batırılmış gazlı bez uygulayın.</li>
	<li>Karın bölgesinin kalbinde cerrahi kesi dışında kapsayacak şekilde yuvarlak bir açılış ile cerrahi örtüsü yerleştirin. Gazlı bez gibi birkaç asmak için bir yedek olarak kullanılabilir.</li>
	<li>Cerrahi bir neşter kullanarak yaptığınız bir kesi yaklaşık 2.5 cm uzun kasık kemiğine üst kenarından alt karın üzerinde yukarı doğru göbek. O zaman, bir kesi altında kas katmanı üzerinden yapmak.</li>
	<li>Örtüsü açılış etrafında steril gazlı bez gibi birkaç yer ve gazlı bez ısıtılmış salin ile ıslak.</li>
	<li>Rahim boynuz bir kısmı--dan belgili tanımlık kesme ortaya karın yanal her iki tarafında yavaşça itin.</li>
	<li>Cerrahın elleri % 70 etanol ile dezenfekte.</li>
	<li>Yavaşça tüm rahim boynuz Karın boşluğundan el ile forseps kullanmadan çekin. Cerrahi forseps kullanarak onlar kolayca kırılgan rahim, fetus ve kan damarları güçlü ve düzensiz sıkıştırarak zarar verebilir tavsiye, değildir.</li>
	<li>Rahim boynuz üzerinde ıslak gazlı bez koyun.</li>
	<li>Diğer rahim horn için aynı yordamı gerçekleştirin.</li>
	<li>Fetusa saymak.</li>
	<li>Sık sık rahim ameliyatı sıcak ve nemli tutmak için ısıtılmış salin uygulanır.<ol>
<li>Çok fazla tuz absorbe ne zaman bebek bezi değiştirme. Çalışma düzenini sağlamak için dezenfeksiyon eldiven % 70 etanol ve iyot aletle ipuçları ile yineleyin. Non-steril parmak enstrümanın steril ipuçları uzak tutmak çok önemlidir.</li>
	</ol>
</li>
	<li>Bir stereomicroscope altında yumurtalık ve uterin arter ana arcade proksimal parçası belirleyin. Not: Ana arcade şube için plasenta ayırt etmek önemlidir. Not ne zaman rahim boynuz saygısız Cerrahi operasyon daha kolay olabilir. Bazen, bir bobin Arcade çok proksimal kısmında uygulama derin karın boşluğu içinde bulunduğu ve arterler için plasenta arcade proksimal parçası yakın çok zor, çünkü. Bu durumda, bir bobin arcade bir parçası ilk şube çatal sonra kapalı uygulanabilir.</li>
	<li>Forseps ile paralel damar damar ayrı ve aralarında boşluk olun.</li>
	<li>Dize (ipek dikiş 4.0, 5 cm uzunluğunda) arter altında bir parça yerleştirin.</li>
	<li>Böylece arter kaldırdı ve kırılgan damar ayrılmış dizenin her iki ucunu Forseps ile kaldırın.</li>
	<li>Öte yandan iyi Forseps ile microcoil kenarına tutarak, bir microcoil yanında kaldırdı arter (Şekil 2.1) yerleştirin.</li>
	<li>Kaldırdı arter, microcoil arter etrafında sarmak için microcoil ip kullanarak döndürme. Arter bobin bobin arter (Şekil 2.2) etrafında döndürmek daha etrafında döndürmek daha kolaydır.</li>
	<li>(Bobinleri 5 döner var) arter 3 veya 4 döner döner sonra bobin diğer kenarına kadar tutulan site değiştirin. Atardamarın etrafından Forseps ile sarılmış bobin kenarı tutun. Sitenin hangi öbür Sargının arter dize asansörleri değiştirin. Arter bobin etrafında döndürme böylece bobin tamamen (5 döner) arter (Şekil 2.3, 2.4) tamamladı.</li>
	<li>Dize kaldırmak.</li>
	<li>Diğer üç arterler için aynı yordamı gerçekleştirin.</li>
	<li>Sık sık uygulanan ılık salin rahim için çok önemli olduğunu unutmayın; Aksi takdirde, fetusa ölüm oranı artar ve hipotermi nöroprotektif olabilir.</li>
	<li>Yavaşça rahim boynuz karın boşluğuna dönün. Forseps ile belgili tanımlık karın duvarı kesme kenarına kaldırma bu yordamı daha kolay yapabilirsiniz.</li>
	<li>Dikiş karın kas ve sonra Dikiş dikiş (ipek dikiş 4.0) ile karın cildi. Her dikiş sonra yani kesintiye uğramış tek Dikiş dikiş bağla.</li>
	<li>İyot dezenfektan çözüm ve cerrahi kesi çevresinde batırılmış gazlı bez uygulayın.</li>
	<li>Subkutan 0,5 mg/kg vücut ağırlığı, analjezik Meloksikam yönetmek.</li>
	<li>30 dk ısıtılan bir kafes içinde kurtarma sağlar. Onay hayvanlar tam olarak uyanık ve kafes, hareket için eve kafes döndürür.</li>
</ol>

<ol>
	<li>Ohshima, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mild+intrauterine+hypoperfusion+reproduces+neurodevelopmental+disorders+observed+in+prematurity.">Mild intrauterine hypoperfusion reproduces neurodevelopmental disorders observed in prematurity.</a> Sci Rep. 6, 39377 (2016).</li><li>Anderson, P., Doyle, L. W., Victorian Infant Collaborative Study, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Neurobehavioral+outcomes+of+school-age+children+born+extremely+low+birth+weight+or+very+preterm+in+the+1990s.">Neurobehavioral outcomes of school-age children born extremely low birth weight or very preterm in the 1990s.</a> JAMA. 289 (24), 3264-3272 (2003).</li><li>Levine, T. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Early+childhood+neurodevelopment+after+intrauterine+growth+restriction:+a+systematic+review.">Early childhood neurodevelopment after intrauterine growth restriction: a systematic review.</a> Pediatrics. 135 (1), 126-141 (2015).</li><li>Sucksdorff, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Preterm+Birth+and+Poor+Fetal+Growth+as+Risk+Factors+of+Attention-Deficit/+Hyperactivity+Disorder.">Preterm Birth and Poor Fetal Growth as Risk Factors of Attention-Deficit/ Hyperactivity Disorder.</a> Pediatrics. 136 (3), e599-e608 (2015).</li><li>Volpe, J. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Brain+injury+in+premature+infants:+a+complex+amalgam+of+destructive+and+developmental+disturbances.">Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances.</a> Lancet Neurol. 8 (1), 110-124 (2009).</li><li>Nardozza, L. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fetal+growth+restriction:+current+knowledge.">Fetal growth restriction: current knowledge.</a> Arch Gynecol Obstet. 295 (5), 1061-1077 (2017).</li><li>Chang, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Preterm+birth+and+the+role+of+neuroprotection.">Preterm birth and the role of neuroprotection.</a> Bmj. 350, g6661 (2015).</li><li>Coq, J. 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I., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Association+of+impaired+neuronal+migration+with+cognitive+deficits+in+extremely+preterm+infants.">Association of impaired neuronal migration with cognitive deficits in extremely preterm infants.</a> JCI Insight. 2 (10), (2017).</li><li>Delcour, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mild+musculoskeletal+and+locomotor+alterations+in+adult+rats+with+white+matter+injury+following+prenatal+ischemia.">Mild musculoskeletal and locomotor alterations in adult rats with white matter injury following prenatal ischemia.</a> Int J Dev Neurosci. 29 (6), 593-607 (2011).</li><li>Gilbert, J. S., Babcock, S. A., Granger, J. 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H., Robinson, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Postnatal+erythropoietin+treatment+mitigates+neural+cell+loss+after+systemic+prenatal+hypoxic-ischemic+injury.">Postnatal erythropoietin treatment mitigates neural cell loss after systemic prenatal hypoxic-ischemic injury.</a> J Neurosurg Pediatr. 6 (3), 206-221 (2010).</li><li>Olivier, P., Baud, O., Evrard, P., Gressens, P., Verney, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prenatal+ischemia+and+white+matter+damage+in+rats.">Prenatal ischemia and white matter damage in rats.</a> J Neuropathol Exp Neurol. 64 (11), 998-1006 (2005).</li><li>Robinson, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Developmental+changes+induced+by+graded+prenatal+systemic+hypoxic-ischemic+insults+in+rats.">Developmental changes induced by graded prenatal systemic hypoxic-ischemic insults in rats.</a> Neurobiol Dis. 18 (3), 568-581 (2005).</li><li>Rice, D., Barone, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Critical+periods+of+vulnerability+for+the+developing+nervous+system:+evidence+from+humans+and+animal+models.">Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models.</a> Environ Health Perspect. 108, 511-533 (2000).</li><li>Basilious, A., Yager, J., Fehlings, M. 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Yazarlar ifşa gerek yok.

Yumurtalık ve uterin arter her iki rahim boynuzları microcoil stenoz tutarlı ve tekrarlanabilir intrauterin hipoperfüzyon tüm plasenta ve fetusa üretir. Hipoperfüzyon düzeyini halkaları farklı iç çapları ile kullanarak değiştirilebilir. Fare pups halkaları 0,24 mm iç çapında bir baraj arter stenozu gerçekleştirildikten doğuştan IUGR ve erken doğum (referans 1 ayrıntılı bilgi için bkz:) göstermektedir. Yavrular işaretler ve prematüre çocuklarda gözlenen belirtiler benzer nöroanatomik ve d...

Bebekler ile intrauterin büyüme sınırlama (IUGR) (fetal büyüme kısıtlama olarak da bilinir) (doğum ağırlığı < 10inci yüzdelik Gestasyonel yaş için), erken doğum (d. < 37 gebelik haftasından itibaren) ve/veya düşük doğum ağırlığı (< 2500 g) hesabı için yaklaşık yüzde 10'u tüm yenidoğan 2,3. Birçok bu bebeklerde serebral palsi ve gelişimsel bozukluklar (örn., dikkat-eksikliği/hiperaktivite bozukluğu (DEHB) ve öğrenme bozuklukları) 3,4,5gibi nörolojik sorunlar ile mevcut. Bu koşulların benzerlikler ve farklılıklar nedenleri ve sonuçları var. IUGR etyolojisinde multifaktöriyel ve plasental yetmezlik ile intrauterin hipoperfüzyon ilişkili anormal sigara fetus 7en yaygın nedeni olarak kabul edilir. Erken doğum etyolojisinde de multifaktöriyel ise chorioamnionitis en sık nedeni 8.
Gelişmekte olan beyin hafif intrauterin hipoperfüzyon (MIUH) etkisi belirsizdir. Şu anda mevcut hayvan modelleri intrauterin hipoperfüzyon/iskemi öncelikle şiddetli hipoperfüzyon veya Degrade hipoperfüzyon veya reperfüzyon 9,10,11olmadan derecesini içeren. Klinik ayarları'nda, ancak, MIUH durumlarında bu ağır koşullar ilgili olanlar çok daha sık olarak kabul edilir. Şu anda mevcut MIUH dikiş ligasyonu ya rahim ya da yumurtalık arter ve ikili yumurtalık arterler ve açıklık 12,13olan aort kırpma içeren bir kemirgen model içeren bir kemirgen modeli modellerdir, 14,15,16,17. Bu modeller dezavantajları biridir fetusa derin hipoperfüzyon ile gelen fetusa fetus rahim, Arteryel arcade içinde pozisyona bağlı olarak neredeyse bozulmamış perfüzyon ile arasında değişen geniş arası fetus değişkenliği ve Yumurtalık arterler. Başka bir dezavantajı bu modellerin her fetus konumunu doğumdan sonra ayırt etmek için kendi yetersizlik ise; Bu nedenle, araştırmacılar tarafından bireysel bir köpek yavrusu doğumundan sonra deneyimli intrauterin hipoperfüzyon şiddeti ayırt edemez.
Birden çok arter stenoz 1içeren MIUH bir fare modeli geliştirdik. Yumurtalık ve uterin arter etrafında 0,24 mm bir iç çapı ile metal mikro-bobin sarma stenoz, ama değil (şekil 1) kan damarlarının tıkanıklığı neden olur. Bu halkaları tüm rahim, yani, temini arterler ikili rahim ve yumurtalık arter proksimal parça embriyonik gün 17 (embriyonik haftada 20-25 insanlar 18eşdeğeridir) uygulayarak önemli ama hafif bir düşüş neden olmaktadır Plasenta ve fetusa kan akışı. Bobinler rahim besleme tüm dört arterler uygulandıktan sonra kan akımı düşüşler büyük ölçüde her plasenta ve fetus üzerinde aynıdır. Fetus ölüm oranı % 20'den az olduğunu. Belgili tanımlık pups spontan doğum via 1-2 gün önceki (embriyonik gün 21-22) normalden daha doğar. Hemen hemen tüm pups önemli ölçüde düşük doğum ağırlıkları 1sergilenmesi doğarlar. Açık dokusuna zarar olmadan 1gri ve Beyaz maddenin birim azalmıştır. Yavruların yenidoğan refleksleri, kas güçsüzlüğü ve değiştirilmiş spontan aktivite 1gecikmeli edinimi ile mevcut. Bu modeli taklit eden klinik belirti ve bulgular çocukların erken veya IUGR ile doğan; gri çocuk d. preterm sergi azaltılmış ve Beyaz maddenin birim veya beyaz madde yaralanma 6, mevcut olmadan kilometre taşları nörolojik gelişimi gecikmiş ve DEHB 3,5gibi davranışsal sorunlar takdim edeyim; IUGR çocuklarla en az nöroanatomik değişiklikler sergi ve motor ve Bilişsel gecikme 4,7gibi Engelli nörolojik gelişme riski vardır. Erken doğum ve IUGR farklı koşullar, ancak temel mekanizması, yani hakaret tam dönemlik Gestasyonel yaş önce olgunlaşmamış beyin için iki koşul paylaşmak.

<table>
	<tbody>
		<tr>
			<td>Stereomicroscope</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Isoflurane anesthesia machine</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Anesthesia induction box</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Heating pad</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Diaper 30x40 cm</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Depilatory foam or shaver</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Iodine disinfectant solution</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Gauze 10x20 cm&#160;</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Surgical drape 45x45 cm with a round opening 5 cm in diameter</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Spray bottle with ethanol for disinfection</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Cotton swab</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Forceps with large blunt tips</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Forceps with angled fine tips</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Scissors</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Surgical scalpel, blade size is 27mm long (no.10, Axel, AS ONE Corporation, Osaka, Japan)</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Surgical suture needle</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Metal microcoils; inner diameter 0.24 mm, made from gold-coated steel (SAMINI Co. Ltd., Shizuoka, Japan)</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Silk suture 4-0</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Sterile saline (0.9% sodium chloride)</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Heating water bath</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Plastic syringes (50ml) and needles (18G)</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
	</tbody>
</table>

a rat model of mild intrauterine hypoperfusion with microcoil stenosis

İntrauterin hipoperfüzyon/iskemi/fetal intrauterin büyüme kısıtlama, erken doğum ve düşük doğum ağırlığı en önemli nedenlerinden biridir. Bu fenomenin en çalışmaları şiddetli intrauterin iskemi ya modelleriyle veya modelleri intrauterin hipoperfüzyon degrade derecesi ile gerçekleştirilmiş. Hiçbir çalışma üniforma hafif intrauterin hipoperfüzyon (MIUH) bir modeli içinde yapıldı. İki model MIUH çalışmaları için kullanılan: Arteryel arcade her iki tarafında dikiş ligasyonu üzerinde dayalı bir modeli ile rahim ve yumurtalık arter oluşmuş ve geçici bir modelini alan ikili yumurtalık arterler ve açıklık sahip aort kırpma. MIUH bu iki kemirgen modelleri bazı sınırlamalar var, örneğin, tüm fetus rahim boynuz konumlarına bağlı olarak MIUH için tabi tutulmaktadır. Bizim MIUH modelinde, tüm fetusa intrauterin hipoperfüzyon karşılaştırılabilir bir seviyeye tabi tutulmaktadır. MIUH rahim, yani, besleme tüm dört arterler ikili rahim ve yumurtalık arter hafif stenoz tarafından sağlanır.
Arteryel stenoz metal halkaları besleme arter sarılı tarafından akımıdır. Bizi kontrol etmek, en iyi duruma getirmek, ve çok az arası hayvan değişkenlik ve düşük mortalite azalmış kan akışını yeniden izin halkaları ile Arteryel stenoz üreten, böylece doğru değerlendirme etkinleştirme. Halkaları 0,24 mm bir iç çapı ile kullanıldığında, plasenta ve fetüsün kan akışında hafif yapıldı (yaklaşık % 30 plasenta öncesi stenoz düzeyi) düşmüştür. Bizim MIUH modeli dölü açıkça nörolojik, nöroanatomik ve davranış testi sonuçlarında uzun ömürlü değişiklikler göstermektedir.

Yani, rahim, besleme arter ikili rahim ve yumurtalık arter herkese halkaları uygulandıktan sonra tüm fetusa hipoperfüzyon karşılaştırılabilir düzeyde tabi tutulmaktadır. Halkaları uygulamanın 0,24 mm bir iç çapı ile böylece kan akımı plasenta ve fetus için hafif bir düşüş neden bu arter hafif stenoz neden olur (şekil 3; yaklaşık %30 plasenta, ön stenoz düzeyi görmek 1 için başvuru ayrıntıları). Baraj doğan yavruların IUGR...

Watch this Scientific Journal Video about A Rat Model of Mild Intrauterine Hypoperfusion with Microcoil Stenosis at JoVE.com

A Rat Model of Mild Intrauterine Hypoperfusion with Microcoil Stenosis

Hafif intrauterin hipoperfüzyon metal halkaları embriyonik gün 17 fareler rahim ve yumurtalık arterlerde sarılı olan Artere Stent tarafından üretildi. Bu yordamı doğum öncesi hipoperfüzyon ve intrauterin büyüme kısıtlama üretti.

Microcoil stenoz ile hafif intrauterin hipoperfüzyon fare modeli

Intrauterine hypoperfusion/ischemia is one of the major causes of intrauterine/fetal growth restriction, preterm birth, and low birth weight. Most studies ...

a-rat-model-of-mild-intrauterine-hypoperfusion-with-microcoil-stenosis

Research

JoVE Journal

Neuroscience

10.2K Görüntüleme.  National Cerebral and Cardiovascular Center. Hafif intrauterin hipoperfüzyon metal halkaları embriyonik gün 17 fareler rahim ve yumurtalık arterlerde sarılı olan Artere Stent tarafından üretildi. Bu yordamı doğum öncesi hipoperfüzyon ve intrauterin büyüme kısıtlama üretti.

Video: A Rat Model of Mild Intrauterine Hypoperfusion with Microcoil Stenosis

Investigations on Alterations of Hippocampal Circuit Function Following Mild Traumatic Brain Injury

Traumatic Brain Injury (TBI) afflicts more than 1.7 million people in the United States each year and even mild TBI can lead to persistent neurological impairments 1. Two pervasive and disabling symptoms experienced by TBI survivors, memory deficits and a reduction in seizure threshold, are thought to be mediated by TBI-induced hippocampal dysfunction 2,3. In order to demonstrate how altered hippocampal circuit function adversely affects behavior after TBI in mice, we employ lateral fluid percussion injury, a commonly used animal model of TBI that recreates many features of human TBI including neuronal cell loss, gliosis, and ionic perturbation 4-6.
	Here we demonstrate a combinatorial method for investigating TBI-induced hippocampal dysfunction. Our approach incorporates multiple ex vivo physiological techniques together with animal behavior and biochemical analysis, in order to analyze post-TBI changes in the hippocampus. We begin with the experimental injury paradigm along with behavioral analysis to assess cognitive disability following TBI. Next, we feature three distinct ex vivo recording techniques: extracellular field potential recording, visualized whole-cell patch-clamping, and voltage sensitive dye recording. Finally, we demonstrate a method for regionally dissecting subregions of the hippocampus that can be useful for detailed analysis of neurochemical and metabolic alterations post-TBI.
	These methods have been used to examine the alterations in hippocampal circuitry following TBI and to probe the opposing changes in network circuit function that occur in the dentate gyrus and CA1 subregions of the hippocampus (see Figure 1). The ability to analyze the post-TBI changes in each subregion is essential to understanding the underlying mechanisms contributing to TBI-induced behavioral and cognitive deficits. 
	The multi-faceted system outlined here allows investigators to push past characterization of phenomenology induced by a disease state (in this case TBI) and determine the mechanisms responsible for the observed pathology associated with TBI.

A multi-faceted approach to investigating functional changes to hippocampal circuitry is explained. Electrophysiological techniques are described along with the injury protocol, behavioral testing and regional dissection method. The combination of these techniques can be applied in similar fashion for other brain regions and scientific questions.

Hafif Travmatik Beyin Hasarı takiben Hipokampal Devre İşlev değişimler üzerine araştırmalar

Traumatic Brain Injury (TBI) afflicts more than 1.7 million people in the United States each year and even mild TBI can lead to persistent neurological ...

Nörobilim

A Protocol for Measuring Cue Reactivity in a Rat Model of Cocaine Use Disorder

Cocaine use disorder (CUD) follows a trajectory of repetitive self-administration during which previously neutral stimuli gain incentive value. Cue reactivity, the sensitivity to cues previously linked with the drug-taking experience, plays a prominent role in human craving during abstinence. Cue reactivity can be assessed as the attentional orientation toward drug-associated cues that is measurable as appetitive approach behavior in both preclinical and human studies. Herein describes an assessment of cue reactivity in rats trained to self-administer cocaine. Cocaine self-administration is paired with the presentation of discrete cues that act as conditioned reinforcers (i.e., house light, stimulus light, infusion pump sounds). Following a period of abstinence, lever presses in the cocaine self-administration context accompanied by the discrete cues previously paired with cocaine infusion are measured as cue reactivity. This model is useful to explore neurobiological mechanisms underlying cue reactivity processes as well as to assess pharmacotherapies to suppress cue reactivity and therefore, modify relapse vulnerability. Advantages of the model include its translational relevance, and its face and predictive validities.&#160;The primary limitation of the model is that the cue reactivity task can only be performed infrequently and must only be used in short duration (e.g., 1 hour), otherwise rats will begin to extinguish the pairing of the discrete cues with the cocaine stimulus. The model is extendable to any positively reinforcing stimulus paired with discrete cues; though particularly applicable to drugs of abuse, this model may hold future applications in fields such as obesity, where palatable food rewards can act as positively reinforcing stimuli.

Cue reactivity is conceptualized as sensitivity to cues linked with drug-taking experiences that contribute to craving and relapse in abstinent humans. Cue reactivity is modeled in rats by measuring attentional orientation toward drug-associated cues that results in appetitive approach behavior in a cue reactivity test following self-administration and forced abstinence.

Cue reaktivite kokain kullanımı bozukluğu bir sıçan modelinde ölçmek için bir protokol

Cocaine use disorder (CUD) follows a trajectory of repetitive self-administration during which previously neutral stimuli gain incentive value. Cue ...

A Rat Model of Central Fatigue Using a Modified Multiple Platform Method

In this article, we introduced a rat model of central fatigue using the modified multiple platform method (MMPM). The Multiple Platform box was designed as a water tank with narrow platforms on the bottom. The model rats were put into the tank and stood on the platforms for 14 h (18:00 - 8:00) per day for a consecutive 21 days, with a blank control group set for contrast. At the end of modeling, rats in the model group showed an obvious fatigued appearance. To assess the model, we performed several behavioral tests, including the open field test (OFT), the elevated plus maze (EPM) test, and the exhaustive swimming (ES) test. The results showed that anxiety, spatial cognition impairment, poor muscle performance, and declined voluntary activity presented in model rats confirm the diagnosis of&#160;central fatigue. Changes of the central neurotransmitters also verified the result. In conclusion, the model successfully simulated central fatigue, and future study with the model may help reveal the pathological mechanism of the disease.

Here, we present a protocol to introduce a rat model of central fatigue using the modified multiple platform method (MMPM).

Bir fare modeli değiştirilmiş bir kullanarak merkezi yorgunluk birden çok Platform yöntemi

In this article, we introduced a rat model of central fatigue using the modified multiple platform method (MMPM). The Multiple Platform box was designed ...

A Novel and Translational Rat Model of Concussion Combining Force and Rotation with In Vivo Cerebral Microdialysis

Persistent cognitive and motor symptoms are known consequences of concussions/mild traumatic brain injury (mTBIs) that can be partly attributable to altered neurotransmission. Indeed, cerebral microdialysis studies in rodents have demonstrated an excessive extracellular glutamate release in the hippocampus within the first 10 min following trauma. Microdialysis offers the clear advantage of in vivo neurotransmitter continuous sampling while not having to sacrifice the animal. In addition to the aforementioned technique, a closed head injury model that exerts rapid acceleration and deceleration of the head and torso is needed, as such a factor is not available in many other animal models. The Wayne State weight-drop model mimics this essential component of human craniocerebral trauma, allowing the induction of an impact on the head of an unrestrained rodent with a falling weight. Our novel and translational rat model combines cerebral microdialysis with the Wayne State weight-drop model to study, in lightly anesthetized and unrestrained adult rats, the acute changes in extracellular neurotransmitter levels following concussion. In this protocol, the microdialysis probe was inserted inside the hippocampus as region of interest, and was left inserted in the brain at impact. There is a high density of terminals and receptors in the hippocampus, making it a relevant region to document altered neurotransmission following concussion. When applied to adult Sprague-Dawley rats, our combined model induced increases in hippocampal extracellular glutamate concentrations within the first 10 min, consistent with the previously reported post-concussion symptomology. This combined weight-drop model provides a reliable tool for researchers to study early therapeutic responses to concussions in addition to repetitive brain injury, since this protocol induces a closed-head mild trauma.

Neurotransmitter alteration is a mechanism of neural dysfunction that occurs after concussion and contributes to the sometimes-catastrophic long-term consequences. This rat model combines microdialysis, allowing in vivo neurotransmitter quantification, with a weight-drop technique exerting rapid acceleration and deceleration of the head and torso, an important factor of human craniocerebral trauma.

In vivo serebral mikrodiyaliz ile kuvvet ve rotasyonu birleştiren bir yeni ve translasyonel rat modeli

Persistent cognitive and motor symptoms are known consequences of concussions/mild traumatic brain injury (mTBIs) that can be partly attributable to ...

Advanced Diffusion Imaging in The Hippocampus of Rats with Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) is the most common type of acquired brain injury. Since patients with traumatic brain injury show a tremendous variability and heterogeneity (age, gender, type of trauma, other possible pathologies, etc.), animal models play a key role in unraveling factors that are limitations in clinical research. They provide a standardized and controlled setting to investigate the biological mechanisms of injury and repair following TBI. However, not all animal models mimic the diffuse and subtle nature of mTBI effectively. For example, the commonly used controlled cortical impact (CCI) and lateral fluid percussion injury (LFPI) models make use of a craniotomy to expose the brain and induce widespread focal trauma, which are not commonly seen in mTBI. Therefore, these experimental models are not valid to mimic mTBI. Thus, an appropriate model should be used to investigate mTBI. The Marmarou weight drop model for rats induces similar microstructural alterations and cognitive impairments as seen in patients who sustain mild trauma; therefore, this model was selected for this protocol. Conventional computed tomography and magnetic resonance imaging (MRI) scans commonly show no damage following a mild injury, because mTBI induces often only subtle and diffuse injuries. With diffusion weighted MRI, it is possible to investigate microstructural properties of brain tissue, which can provide more insight into the microscopic alterations following mild trauma. Therefore, the goal of this study is to obtain quantitative information of a selected region-of-interest (i.e., hippocampus) to follow up disease progression after obtaining a mild and diffuse brain injury.

The overall goal of this procedure is to obtain quantitative microstructural information of the hippocampus in a rat with mild traumatic brain injury. This is done using an advanced diffusion-weighted magnetic resonance imaging protocol and region-of-interest based analysis of parametric diffusion maps.

Hafif Travmatik Beyin Hasarı Olan Sıçanların Hipokampuslarında İleri Difüzyon Görüntüleme

Mild traumatic brain injury (mTBI) is the most common type of acquired brain injury. Since patients with traumatic brain injury show a tremendous ...

Applying the RatWalker System for Gait Analysis in a Genetic Rat Model of Parkinson's Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta. Gait abnormalities, including decreased arm swing, slower walking speed, and shorter steps are common in PD patients and appear early in the course of disease. Thus, the quantification of motor patterns in animal models of PD will be important for phenotypic characterization during disease course and upon therapeutic treatment. Most cases of PD are idiopathic; however, the identification of hereditary forms of PD uncovered gene mutations and variants, such as loss-of-function mutations in Pink1 and Parkin, two proteins involved in mitochondrial quality control that could be harnessed to create animal models. While mice are resistant to neurodegeneration upon loss of Pink1 and Parkin (single and combined deletion), in rats, Pink1 but not Parkin deficiency leads to nigral DA neuron loss and motor impairment. Here, we report the utility of FTIR imaging to uncover gait changes in freely walking young (2 months of age) male rats with combined loss of Pink1 and Parkin prior to the development of gross visually apparent motor abnormality as these rats age (observed at 4-6 months), characterized by hindlimb dragging as previously reported in Pink1 knockout (KO) rats.

Here we describe the RatWalker system, built by redesigning the MouseWalker apparatus to accommodate for the increased size and weight of rats. This system uses frustrated total internal reflection (FTIR), high-speed video capture, and open-access analysis software to track and quantify gait parameters.

Parkinson Hastalığının Genetik Sıçan Modelinde Yürüme Analizi için RatWalker Sisteminin Uygulanması

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the loss of dopaminergic (DA) neurons in the substantia nigra pars ...

Establishment of a Rat Model of Superior Sagittal-Sinus Occlusion via a Thread-Embolism Method

The mechanisms contributing to the natural onset of cerebral venous sinus thrombosis (CVST) are mostly unknown, and a variety of uncontrollable factors are involved in the course of the disease, resulting in great limitations in clinical research. Therefore, the establishment of stable CVST animal models that can standardize a variety of uncontrollable confounding factors have helped to circumvent shortcomings in clinical research. In recent decades, a variety of CVST animal models have been constructed, but the results based on these models have been inconsistent and incomplete. Hence, in order to further explore the pathophysiological mechanisms of CVST, it is necessary to establish a novel and highly compatible animal model, which has important practical value and scientific significance for the diagnosis and treatment of CVST. In the present study, a novel Sprague-Dawley (SD) rat model of superior sagittal sinus (SSS) thrombosis was established via a thread-embolization method, and the stability and reliability of the model were verified. Additionally, we evaluated changes in cerebral venous blood flow in rats after the formation of CVST. Collectively, the SD-rat SSS-thrombosis model represents a novel CVST animal model that is easily established, minimizes trauma, yields good stability, and allows for accurately controlling ischemic timing and location.

Here, we establish a novel Sprague-Dawley (SD) rat model of superior sagittal sinus (SSS) thrombosis via a thread-embolization method, and the stability and reliability of the model were verified.

İplik Embolisi Yöntemi ile Üstün Sagittal-Sinüs Oklüzyonunun Sıçan Modelinin Kurulması

The mechanisms contributing to the natural onset of cerebral venous sinus thrombosis (CVST) are mostly unknown, and a variety of uncontrollable factors ...

A Rat Model of EcoHIV Brain Infection

It has been well studied that the EcoHIV infected mouse model is of significant utility in investigating HIV associated neurological complications. Establishment of the EcoHIV infected rat model for studies of drug abuse and neurocognitive disorders, would be beneficial in the study of neuroHIV and HIV-1 associated neurocognitive disorders (HAND). In the present study, we demonstrate the successful creation of a rat model of active HIV infection using chimeric HIV (EcoHIV). First, the lentiviral construct of EcoHIV was packaged in cultured 293 FT cells for 48 hours. Then, the conditional medium was concentrated and titered. Next, we performed bilateral stereotaxic injections of the EcoHIV-EGFP into F344/N rat brain tissue. One week after infection, EGFP fluorescence signals were detected in the infected brain tissue, indicating that EcoHIV successfully induces an active HIV infection in rats. In addition, immunostaining for the microglial cell marker, Iba1, was performed. The results indicated that microglia were the predominant cell type harboring EcoHIV. Furthermore, EcoHIV rats exhibited alterations in temporal processing, a potential underlying neurobehavioral mechanism of HAND as well as synaptic dysfunction eight weeks after infection. Collectively, the present study extends the EcoHIV model of HIV-1 infection to the rat offering a valuable biological system to study HIV-1 viral reservoirs in the brain as well as HAND and associated comorbidities such as drug abuse.

Here, we present a protocol to establish a new rat model of active HIV infection using chimeric HIV (EcoHIV), which is critical for enhancing our understanding of HIV-1 viral reservoirs in the brain and offering a system to study HIV-associated neurocognitive disorders and associated comorbidities (i.e., drug abuse).

EcoHIV Beyin Enfeksiyonunun Bir Sıçan Modeli

It has been well studied that the EcoHIV infected mouse model is of significant utility in investigating HIV associated neurological complications. ...

Induction and Assessment of Levodopa-induced Dyskinesias in a Rat Model of Parkinson's Disease

Levodopa (L-DOPA) remains the gold-standard therapy used to treat Parkinson&#39;s disease (PD) motor symptoms. However, unwanted involuntary movements known as L-DOPA-induced dyskinesias (LIDs) develop with prolonged use of this dopamine precursor.&#160;It is estimated that the incidence of LIDs escalates to approximately 90% of individuals with PD within 10&#8211;15 years of treatment. Understanding the mechanisms of this malady and developing both novel and effective anti-dyskinesia treatments requires consistent and accurate modeling for pre-clinical testing of therapeutic interventions. A detailed method for reliable induction and comprehensive rating of LIDs following 6-OHDA-induced nigral lesioning in a rat model of PD is presented here. Dependable LID assessment in rats provides a powerful tool that can be readily utilized across laboratories to test emerging therapies focused on reducing or eliminating this common treatment-induced burden for individuals with PD.

This article describes methods to induce and evaluate levodopa-induced dyskinesias in a rat model of Parkinson&#39;s disease. The protocol offers detailed information regarding the intensity and frequency of a range of dyskinetic behaviors, both dystonic and hyperkinetic, providing a reliable tool to test treatments targeting this unmet medical need.

Parkinson Hastalığının Sıçan Modelinde Levodopa Kaynaklı Diskinezilerin İndüksiyonu ve Değerlendirilmesi

Levodopa (L-DOPA) remains the gold-standard therapy used to treat Parkinson&#39;s disease (PD) motor symptoms. However, unwanted involuntary movements ...

Electromagnetic Controlled Closed-Head Model of Mild Traumatic Brain Injury in Mice

Highly reproducible animal models of traumatic brain injury (TBI), with well-defined pathologies, are needed for testing therapeutic interventions and understanding the mechanisms of how a TBI alters brain function. The availability of multiple animal models of TBI is necessary to model the different aspects and severities of TBI seen in people. This manuscript describes the use of a midline closed head injury (CHI) to develop a mouse model of mild TBI. The model is considered mild because it does not produce structural brain lesions based on neuroimaging or gross neuronal loss. However, a single impact creates enough pathology that cognitive impairment is measurable at least 1 month after injury. A step-by-step protocol to induce a CHI in mice using a stereotaxically guided electromagnetic impactor is defined in the paper. The benefits of the mild midline CHI model include the reproducibility of the injury-induced changes with low mortality. The model has been temporally characterized up to 1 year after the injury for neuroimaging, neurochemical, neuropathological, and behavioral changes. The model is complementary to open skull models of controlled cortical impact using the same impactor device. Thus, labs can model both mild diffuse TBI and focal moderate-to-severe TBI with the same impactor.

The protocol describes mild traumatic brain injury in a mouse model. In particular, a step-by-step protocol to induce a mild midline closed head injury and the characterization of the animal model is fully explained.

Farelerde Hafif Travmatik Beyin Hasarının Elektromanyetik Kontrollü Kapalı Kafa Modeli

Highly reproducible animal models of traumatic brain injury (TBI), with well-defined pathologies, are needed for testing therapeutic interventions and ...