Basal ganglia activity in a mouse model of
dyskinesia
）wi Wahyu Indriani
）octor of Philosophy
）epartment of Physiological Sciences
School of １ife Science
SO０EN）AI (The Graduate University for
Advanced Studies)
B a sa l g a n g l i a a c t i v i t y i n a mou se mod el of d y sk i n esi a
D w i W a h y u I n d r i a n i
D epart ment of P hy s i ol og i c al S c i enc es , S O K E N D A I ( G r aduat e U ni v ers i t y f or A dv anc ed S t udi es ) , O k az ak i 4 4 4 - 8 5 8 5 , J apan.
I n t r od u c t i on
T he bas al g ang l i a ( B G ) are a g roup of nuc l ei l oc at ed at t he bas e of f orebrai n and r ec ei v e i nput s f rom t he c erebral c ort ex and s end out puts to t he c erebr al c ort ex v i a t he t hal amus . T hree B G pat hw ay s c onnec t i nput and out put s t ati ons : t he ‘ di rec t ’, ‘ i ndi rec t ’ and ‘ hy perdi r ec t ’ pat hw ay s ( A l ex ander and C rut c her, 1 9 9 0 ; N ambu et al . , 2 0 0 2 ) . T he di rec t pat hw ay ari s es f rom G A B A erg i c s t ri at al neurons , i nput s t at i on of t he B G, and proj ec t s monos y napt i c al l y t o t he i nt ernal s eg ment of g l obus pal l i dus ( G P i or ent opedunc ul ar nuc l eus i n rodent s ) or s ubst ant i a ni g r a pars ret i c ul at a ( S N r) . T he i ndi rec t pat hw ay ari s es f rom G A B A erg i c s t ri at al neurons and proj ec t s pol y s y napt i c al l y t o the G P i /S N r t hroug h s equent i al c onnec t i ons of t he ex t ernal s eg ment of t he g l obus pal l i dus ( G P e or G P i n rodent s ) and s ubt hal ami c nuc l eus ( S T N ) . T he hy perdi r ec t pat hw ay ari s es f rom g l ut amat erg i c neuron i n t he S T N , anot her i nput s t at i on of B G, t hat rec ei v es di rec t c ort i c al i nput s and proj ec t s t o t he G P i /S N r ( N ambu, 2 0 0 8 ) .
T he B G pl ay an i mport ant rol e i n t he ex ec ut i on of v ol unt ar y mov ement and mot or l earni ng . D y s f unc t i on of t he B G res ul t s i n i nabi l i t y t o c ont rol mov ement t hat c an be s een i n P ark i ns on’s di s eas e ( P D ) and H unt i ng t on’s di s eas e( A l bi n et al . , 1 9 8 9 ; D eL ong , 1 9 9 0 ; N ambu, 2 0 0 8 ) . P D i s a neurol og i c al di s order t hat i s c aus ed b y t he l os s of dopami nerg i c neurons i n t he s ubs t ant i a ni g r a pars c ompac t a ( S N c ) , w hi c h proj ec t t o t he s t ri at um. R educ ed dopami ne s i g nal i ng i n t he s t ri at um l eads t o t he appearanc e of i ts c ardi nal s y mpt oms , i nc l udi ng brad y k i nes i a/ak i nes i a, t remor at res t , ri g i di t y, and l os s of pos t ural ref l ex es . T hes e P D s y mpt oms c an be s uc c es s f ul l y t reat ed w i t h dopami ne s uppl ement t herapy, L - dopa ( l ev odopa) t hat i s admi ni s t rat ed and i s c onv ert ed t o dopami ne i n t he brai n ( C otz i as et al . , 1 9 6 9 ; F ahn and P ark i ns on S t udy G r oup, 2 0 0 5 ) .
A l t houg h L - dopa r emai ns as g ol d s t andard t reat ment f or P D , t he prog r es s i on of t he di s eas e and l ong - t erm L - dopa t r eat ment i nduc e mot or c ompl i c at i ons . M os t P D pat i ent s ex peri enc e s hort er mot or res pons e t o eac h medi c at i on dos e ( w eari ng - of f f l uc t uati on) , s omet i mes ac c ompani ed w i t h dy s k i nes i a t hat appears duri ng hi g h pl as ma and br ai n l ev el of L - dopa( C enc i , 2 0 1 4 ) . L - dopa- i nduc ed dy s k i nes i a ( L I D ) denot es a c ombi nat i on of c horei f orm
( repet i t i v e, j erk y, and rapi d i nv ol unt ar y mov ement ) and dy s t oni c ( s us t ai ned mus c l e c ont rac t i on) mov ement s ( C enc i and L undbl ad, 2 0 0 6 ) . A bout 3 0 % of P D pat i ent s hav e L I D af t er 4 - 6 y ears of L - dopa t reat ment , and 9 0 % of P D pat i ent s dev el op t hi s c ompl i c at i on af t er 9 y ears of L - dopa t reat ment ( A hl s k og and M uent er, 2 0 0 1 ; C enc i and L undbl ad, 2 0 0 6 ) . T he ri s k s of dev el opi ng L I D i nc l ude y oung ag e at P D ons et , di s eas e s ev eri t y and durat i on, hi g her i ni t i al L - dopa dos e, and durat i on of L - dopa t reat ment . O nc e L I D appears , t he s ame i nv ol unt ar y mov ement s oc c ur on ev er y admi ni st rat i on of L - dopa( C enc i and L undbl ad, 2 0 0 6 ; J enner, 2 0 0 8 ; S c hrag and Q ui nn, 2 0 0 0 ) . T hus , prol ong ed L - dopa t reat ment s houl d i nduc e i rrev ers i bl e c hang es i n t he B G.
T he c el l ul ar mec hani sm underl y i ng L I D has been pos t ul at ed, s uc h as ( 1 ) abrupt dopami ne i nc reas e i n t he s t ri at um c aus ed b y unreg ul at ed dopami ne ef f l ux f rom s erot oni n neurons and def ec t i v e dopami ne c l earanc e ( C enc i and L i ndg ren, 2 0 0 7 ; L ee et al . , 2 0 0 8 ; R y l ander et al . , 2 0 1 0 ) , ( 2 ) up- reg ul at i on of i nt rac el l ul ar s i g nal i ng of s t ri at al di rec t pat hw ay neurons ( C al on et al . , 2 0 0 0 ; C enc i et al . , 1 9 9 8 ) , ( 3 ) mal adapt i v e pl as ti c i t y of c ort i c o- s t ri at al s y naps es , and ( 4 ) i nc reas ed G A B A erg i c and opi oi derg i c t rans mi s s i on i n t he G P i ( C enc i , 2 0 1 0 ; L i ndg ren et al . , 2 0 1 0 ) . O n t he ot her hand, el ec t rophy s i ol og i c al s t udi es of L I D are r at her l i mi t ed. A prev i ous s t udy report ed t hat i n t he pres enc e of dy s k i nes i a, f i ri ng r at es of G P i neurons dec l i ned prof oundl y i n L I D model monk ey s ( P apa et al . , 1 9 9 9 ) . H ow ev er, l os s of G P i ac t i v i t y b y pal l i dot omy al l ev i at es L I D s y mpt oms ( B aron et al . , 1 9 9 6 ; L oz ano et al . , 1 9 9 5 ) . I n t he pres ent s t udy, I rec orded neuronal ac t i v i t y of G P and S N r neurons f rom mi c e i n c ont rol , P D , dy s k i nes i a- of f , and dy s k i nes i a- on s t at es under aw ak e c ondi ti ons and t ri ed t o el uc i dat e the l at ent c hang es af t er l ong - t erm L - dopa t reat ment and el ec t r ophy s i ol og i c al mec hani s m underl y i ng L I D .
M a t er i a l a n d M et h od s
P D model mi c e w ere g ener at ed by uni l at er al i nj ec ti on of 6 - hy drox y dopami ne ( 6 - O H D A ) ( 3 . 0 µ g /µ l 6 - O H D A i n 0 . 0 2 % i c e- c ol d as c orbat e/s al i ne and us ed w i t hi n 2 hour) i nt o t he medi al f orebrai n bundl e. I n t hi s st udy I C R mal e mi c e w er e us ed. T he mi c e w er e di v i ded i nt o 3 g roups , c ont rol g roup ( w i t hout 6 - O H D A /s ham l esi on as w el l as w i t hout L - dopa t reat ment ) , 6 - O H D A - l es i on g roup and s ham- l es i oned g roup. B ehav i or al c hang es w ere obs erv ed t o ev al uat e P D s y mpt oms , 1 4 day s f ol l ow i ng 6 - O H D A /s ham l es i on s urg er y us i ng c y l i nder t es t . T hen L - dopa ( 9 mg /k g L - dopa pl us 1 5 mg /k g bens eraz i de) w as i nt raper i t oneal l y i nj ec t ed repeat edl y unt i l t he mi c e dev el op L I D . A t f i rs t L - dopa w as i nj ec t ed dai l y ( c hr oni c t reat ment ) f or 11 day s , and i n order t o mai nt ai n t he s ame dy s k i nes i a s c ore, L - dopa t hen w as g i v en 2 - 4 t i mes per w eek . S pont aneous neuronal ac t i v i t y and res pons e t o
mot or c ort i c al s t i mul ati on w ere rec orded i n t he G P and S N r f rom normal mi c e, P D mi c e, L I D mi c e duri ng “d y s k i nes i a- of f ” peri od ( at l eas t 2 4 hours af t er l as t L - dopa t r eat ment ) , and L I D mi c e duri ng “d y s k i nes i a- on” peri od ( 2 0 - 1 2 0 mi nut es af t er L - dopa t reat ment , w hen mi c e dev el op dy s k i nes i a) i n aw ak e c ondi ti ons .
E l ec t ri c al s ti mul at i on w as del i v ered t o t he mot or c ort ex t hroug h s ti mul ati ng el ec t rode. T w o pai rs of bi pol ar s t i mul at i ng el ec t rodes ( t i p di st anc e 3 0 0 - 4 0 0 µ m, made of T ef l on c oat ed 5 0 µ m- di amet er t ung s t en w i r es ) w ere i mpl ant ed c hroni c al l y i nt o t he pri mar y mot or c ort ex , one i nt o t he orof ac i al r eg i on and t he ot her i nt o t he f orel i mb reg i on ( c audal f orel i mb reg i on) , and t hen f i x ed usi ng ac r y l i c res i n ( C hi k en et al . , 2 0 0 8 ; S ano et al . , 2 0 1 3 ) .
A g l as s - c oat ed el g i l oy - mi c roel ec t rode ( 1 . 2 - 1 . 5 M Ω at 1 k H z ) f or s i ng l e- uni t rec ordi ng w as i ns ert ed v ert i c al l y i nt o the br ai n t hroug h t he dur a mat er us i ng a hy draul i c mi c rodri v e. U ni t ac t i v i t y of G P and S N r neurons rec orded f rom t he mi c roel ec t rode w as ampl i f i ed and f i l t ered ( 0 . 1 - 2 k H z ) , c onv ert ed t o di g i t al dat a w i t h a homemade w i ndow di s c ri mi nat or, and s ampl ed at 2 . 0 k H z us i ng a c omput er f or onl i ne dat a anal y s i s . S pont aneous di s c harg es and t he res pons e t o c ort i c al s t i mul at i on ( 2 0 0 µ s s i ng l e pul s e at 0 . 7 k H z , 2 0 - 5 0 µ A s t reng t h) w ere rec or ded ( C hi k en et al . , 2 0 0 8 ; S ano et al . , 2 0 1 3 ) .
T he s pont aneous f i ri ng rat e w as c al c ul at ed f rom c ont i nuous di g i t i z ed rec ordi ng f or 5 0 s . S ev eral paramet ers f or f i ri ng pat t erns w ere al s o c al c ul at ed f rom t he f i rs t 3 0 s of t he s ame r ec ordi ng s , w hi c h i nc l ude t he c oef f i c i ent of v ari anc e ( C V ) of i nt ers pi k e i nt erv al s ( I S I s ) , number of burs ts , and number of paus es . B urs t s w ere det ec t ed us i ng P oi s s on s urpri s e met hod, w hereas paus es duri ng 3 0 s of s pont aneous rec ordi ng w ere det ec t ed us i ng t he met hod of E l i as et al . ( 2 0 0 7 ) t hat bas i c al l y us ed s i mi l ar al g ori t hm f or burs t det ec t i on ( C hi k en et al . , 2 0 0 8 ; S ano et al . , 2 0 1 3 ) . T he s pont aneous f i ri ng pat t ern w as al so anal y z ed b y c ons t r uc t i ng aut oc orr el og rams ( bi n w i dt h of 0 . 5 ms ) f rom c ont i nuous di g i t i z ed rec ordi ng s f or 5 0 s .
T he res pons es t o c ort i c al s t i mul at i on w ere anal y z ed b y mak i ng peri - s ti mul us t i me hi s t og r am ( P S T H s ) ( bi n w i dt h of 1 ms ) f or 1 0 0 s t i mul at i on t ri al s . T he mean v al ue and s t andard dev i at i on ( S D ) of t he di s c harg e rat e duri ng 1 0 0 ms prec edi ng ons et of s t i mul at i on w ere c ons i der ed as t he bas el i ne of di s c harg e r at e. C hang es i n neuronal ac t i v i t y i n res pons e t o c ort i c al s ti mul ati on w ere j udg ed s i g ni f i c ant i f t he di s c harg e rat e duri ng at l eas t t w o c ons ec ut i v e bi ns reac hed a s i g ni f i c anc e l ev el of p < 0 . 0 5 ( one- t ai l ed t t est ) ( C hi k en et al . , 2 0 0 8 ; S ano et al . , 2 0 1 3 ) . T he l at enc y of eac h r es pons e w as def i ned as t he t i me at w hi c h t he di s c harg e rat e f i rs t ex c eeded t hi s l ev el . T he res pons es w ere j udg ed t o end w hen f our c ons ec ut i v e bi ns f el l bel ow t he
s i g ni f i c anc e l ev el . F or popul at i on P S T H s , t he P S T H of eac h neuron w i t h s i g ni f i c ant res pons e t o mot or c ort i c al s t i mul at i on w as s moot hed w i t h S av i t z k y - G ol ay f i l t er ( O ri g i nP ro 2 0 1 5 ; pol y nomi al order, 2 ; poi nt s of w i ndow, 1 0 ) and av erag ed.
A f t er f i nal rec ordi ng , s ev eral G P and S N r rec ordi ng s i t es w ere mark ed by pas s i ng c at hodal D C c urrent ( 2 0 µ A f or 2 0 s ) t hroug h t he rec ordi ng el ec t rode. T hen mi c e w ere perf us ed t rans c ardi al l y w i t h 0 . 0 1 M P B S f ol l ow ed by 1 0 % f ormal i n i n 0 . 0 1 M P B S . F ront al s ec t i ons ( 4 0 µ m) w ere c ut w i t h f reez i ng mi c rot ome and c ol l ec t ed i n 0 . 0 1 M P B S ( S ano et al . , 2 0 1 3 ) . B rai n s ec t i ons c ont ai ni ng t he mot or c ort ex , G P or S N r w ere mount ed on M A S - c oat ed s l i des ( M at s unami G l as s ) , ai r dr i ed, and s t ai ned w i t h N eut ral R ed. T he c ort i c al s t i mul at i ng s i t es and t he r ec ordi ng s i t es i n t he G P and S N r w ere c onf i rmed ac c ordi ng t o t he l es i ons made by c at hodal D C c urrent and t rac es of t he el ec t rode t rac k s . O ther s ec t i ons c ont ai ni ng t he S N c w ere us ed f or i mmunohi st oc hemi s t r y t o ev al uat e t y ros i ne hy drox y l as e ( T H ) posi t i v e c el l s i n l es i on hemi s phere. F ree- f l oat i ng s ec ti ons w ere i nc ubat ed w i t h pri mar y ant i bodi es ag ai ns t mous e T H ( 1 : 1 0 0 0 ) , t hen v i s ual i z ed w i t h bi ot i ny l at ed s ec ondar y ant i body ( 1 : 5 0 0 ) , and t he A B C met hod.
R es u l t s a n d D i s c u s s i on s
T he f ol l ow i ng res ul t s w ere obt ai ned: ( 1 ) S pont aneous ac t i v i t y of G P and S N r neurons s how ed a l i tt l e c hang es i n t erm of i t s f i ri ng rat e, i rreg ul ari t y and number of burs t s i n P D , dy s k i nes i a- of f and dy s k i nes i a- on s t at es c ompared t o c ont rol s t at e. ( 2 ) C orti c al l y ev ok ed i nhi bi ti on of G P neurons i n P D , dy s k i nes i a- of f and dy s k i nes i a- on s t at es w as i nc reas ed c ompared t o c ont rol s t at e, and l at e ex c i t at i on of G P neurons w as i nc r eas ed i n P D and d y s k i nes i a- of f s t at es . ( 3 ) C ort i c al l y ev ok ed i nhi bi t i on and l at e ex c i t at i on of S N r neurons w ere dec reas ed i n P D and dy s k i nes i a- of f s t at es . ( 4 ) I n dy s k i nes i a- on s t at e, c ort i c al l y ev ok ed i nhi bi t i on of S N r neurons w as prol ong ed c ompared t o c ont rol , P D and dy s k i nes i a- of f s t at e, and l at e ex c i t at i on w as dec reas ed c ompared t o c ont rol s t at e. ( 5 ) R epeat ed L - dopa i nj ec t i on t o s ham- l es i oned mi c e had l i t t l e ef f ec t s on G P and S N r ac ti v i t y.
M otor c ort i c al s ti mul ati on c an i nduc e r es pons es i n B G nuc l ei t hat mi mi c i nf ormat i on proc es s i ng duri ng v ol unt ar y mov ement s ( C hi k en et al . , 2 0 0 8 ; N ambu et al . , 2 0 0 2 ; T ac hi bana et al . , 2 0 0 8 ) . C ort i c al s t i mul at i on ev ok es a t ri phasi c res pons e c ons i s t i ng of earl y ex c i t at i on, i nhi bi t i on, and l at e ex c i t at i on i n t he G P and G P i /S N r. I nhi bi t i on w as medi at ed by t he s t ri at um, w hereas earl y and l at e ex c i t at i on w er e medi at ed b y t he S T N ( F uj i mot o and K i t a, 1 9 9 2 ; K i t a, 1 9 9 2 ; K i t ano et al . , 1 9 9 8 ; M auri c e et al . , 1 9 9 9 ; N ambu et al . , 2 0 0 0 ; R y an and C l ark , 1 9 9 1 ; T ac hi bana et al . , 2 0 0 8 ; Y os hi da et al . , 1 9 9 3 ) .
C orti c al l y ev ok ed res pons es i n t he B G ar e al t ered i n hy perk i net i c and hy pok i net i c mov ement di s orders ( C hi k en et al . , 2 0 0 8 ; K i t a and K i t a, 2 0 11 ; N i s hi bay as hi et al . , 2 0 11 ) .
A n i mport ant i s s ue on t he mec hani s ms underl y i ng L I D i s how ac t i v i t y i n mot or c ort i c al neur ons i s t rans mi t t ed t o t he B G. B y modi f y i ng t he f i ri ng rat e model of B G f unc t i ons , t he dy nami c ac t i v i t y c hang es i n t he G P i /S N r c oul d ex pl ai n the pat hophy s i ol og i c al mec hani sm of hy pok i net i c and hy perk i net i c mov ement di s orders ( N ambu, 2 0 0 8 ) .
B as ed on t he dy nami c model of t he B G f unc t i on, s i g nal s throug h t he c ort i c o- S T N - S N r hy perdi rec t pat hw ay ex c i t e t he S N r. T hen, s i g nal s t hroug h t he c ort i c o- s t ri at o- S N r di rec t pat hw ay i nhi bi t t he S N r and rel eas e appropri at e mov ement s, and f i nal l y s i g nal s t hroug h t he c ort i c o- s t ri at o- G P - S T N - S N r i ndi rec t pat hw ay ex c i t e t he S N r ag ai n and s t op mov ement s rel eas ed by t he s i g nal s t hroug h t he di rec t pat hw ay. T hi s model c an be us ed t o ex pl ai n t he res ul t s of t he pres ent s t udy. I n P D s t at e, i nhi bi t i on t hroug h t he di rec t pat hw ay i s si g ni f i c ant l y dec reas ed; as a res ul t , s i g nal s t hroug h t he di rec t pat hw ay c annot rel eas e mov ement s , res ul t i ng i n ak i nes i a. I n d y s k i nes i a- of f s t at e, i nhi bi ti on t hroug h t he di rec t pat hw ay remai ns dec reas ed and ex c i t at i on t hroug h t he i ndi rec t pat hw ay i s dec reas ed. A s a res ul t , rel eas e s i g nal s t hroug h t he di rec t pat hw ay are s t i l l w eak t o r el eas e mov ement s . I n d y s k i nes i a- on s t at e, i nhi bi t i on t hroug h t he di rec t pat hw ay i s res t ored t o normal l ev el and l at e ex c i t at i on t hroug h t he i ndi rec t pat hw ay i s s i g ni f i c ant l y dec reas ed; as a res ul t , rel eas e s i g nal s are i nc reas ed, s t op s i g nal s are reduc ed, and dy s k i nes i a i s i nduc ed.
R ef er en c es
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