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Brain-wide functional architecture remodeling by alcohol dependence and abstinence

Adam Kimbrough, Daniel J. Lurie, Andres Collazo, Max Kreifeldt, Harpreet Sidhu, Giovana Camila Macedo, Mark D’Esposito,Candice Contet, Olivier George

Olivier George Email: [email protected]

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Figures S1 to S8 Tables S1 to S1

1 www.pnas.org/cgi/doi/10.1073/pnas.1909915117

Fig. S1. Withdrawal behaviors for separate control groups (alcohol-nondependent and naive mice) compared with alcohol-dependent mice. A. The number of irritable-like responses was significantly higher in alcohol-dependent mice (black bar) compared with both alcohol- nondependent mice (white bar) and naive mice (hashed bar). B. Alcohol-dependent mice (black bar) exhibited a significant increase in digging behavior compared with both alcohol- nondependent mice (white bar) and naive mice (hashed bar). *p < 0.05, vs. naive; #p < 0.05, vs. alcohol-nondependent.

Fig. S2. Saccharin intake in alcohol-dependent, nondependent, and naive (water) mice, expressed at mg/kg/24 h. Average saccharin intake over 7 days of testing was not different between alcohol-dependent (black bar), alcohol-nondependent (white bar), and naive (hashed bar) mice.

Color Key and Histogram Color Key 0 2 1 0 t 8 n u o C 0

4 -1 -0.5 0 0.5 1

0 −1 −0.5 0 0.5 1 Naive Value

Cortical am ygdalar area poster ior par t Entorhinal area medial par t Entorhinal area later al par t Parasubiculum Later al visual area Agranular insular area v entral par t Gustator y areas Piriform area Postsubiculum Retrosplenial area v entral par t Cortical am ygdalar area Piriform−amygdalar area Anter ior cingulate area dorsal par t Presubiculum Primary auditor y area Prelimbic area Agranular insular area Subiculum Anter ior cingulate area v entr al par t Perirhinal area Ectorhinal area Dorsal auditor y area Primary somatosensor y area mouth Agranular insular area poster ior par t Supplemental somatosensor y area Ventral auditor y area Orbital area medial par t Infralimbic area posteromedial visual area Viscer al area Temporal association areas Dorsal peduncular area Primary motor area Orbital area later al par t Orbital area v entrolater al par t Frontal pole cerebr al cor tex Primary somatosensor y area lo wer limb Primary somatosensor y area upper limb Taenia tecta Primary visual area Anterolater al visual area Primary somatosensor y area tr unk Secondar y motor area Retrosplenial area dorsal par t Field CA1 Field CA3 Field CA2 Dentate gyr us Poster ior am ygdalar n ucleus Claustrum Later al am ygdalar n ucleus Endopir iform nucleus Basolater al am ygdalar n ucleus Central am ygdalar n ucleus Intercalated am ygdalar n ucleus Caudoputamen Olfactor y tubercle Nucleus accumbens Fundus of str iatum Anter ior am ygdalar area Later al septal comple x Medial am ygdalar n ucleus Magnocellular n ucleus Substantia innominata Diagonal band n ucleus Medial septal n ucleus Bed n uclei of the str ia ter minalis Globus pallidus e xternal segment Paraventricular n ucleus of the thalam us Medial haben ula Medial geniculate comple x Central medial n ucleus of the thalam us Later al haben ula Anterodorsal n ucleus Later al poster ior n ucleus of the thalam us Later al dorsal n ucleus of thalam us Poster ior comple x of the thalam us Ventral anter ior−later al comple x of the thalam us Mediodorsal n ucleus of thalam us Ventral medial n ucleus of the thalam us Parataenial n ucleus Reticular n ucleus of the thalam us Dorsal par t of the later al geniculate comple x Antero ventr al nucleus of thalam us Central later al nucleus of the thalam us Tuberal nucleus Parasubthalamic n ucleus Periventricular z one Supr achiasmatic n ucleus Subpar aventr icular z one Median preoptic n ucleus Antero ventr al per iventricular n ucleus Subthalamic n ucleus Zona incer ta Ventromedial h ypothalamic n ucleus Poster ior h ypothalamic n ucleus Later al hypothalamic area Dorsomedial n ucleus of the h ypothalam us Anter ior h ypothalamic n ucleus Later al preoptic area Paraventricular h ypothalamic n ucleus Periventricular h ypothalamic n ucleus poster ior par t Retrochiasmatic area Medial preoptic area Antero ventr al preoptic n ucleus Ventrolater al preoptic n ucleus Medial preoptic n ucleus Inter peduncular n ucleus Ventral tegmental area Substantia nigr a reticular par t Midbrain reticular n ucleus Substantia nigr a compact par t Pons motor related Inferior colliculus Pons Periaqueductal gr ay Super ior colliculus motor related Pedunculopontine n ucleus Culmen Olivary pretectal n ucleus Super ior colliculus sensor y related Precommissur al nucleus Medial pretectal area

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Fig. S3. Interbrain region Pearson correlations for naive mice with region labels.

Color Key and Histogram 0

2 Color Key 1

0 t 8 n u o

C 0 4 -1 -0.5 0 0.5 1 0

−1 −0.5 0 0.5 1Alcohol Nondependent Value

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Fig. S4. Interbrain region Pearson correlations for alcohol nondependent mice with region labels.

Color Key and Histogram 0

5 Color Key 1 0 t 0 n u 1 o C 0

5 -1 -0.5 0 0.5 1 0 −1 −0.5 0 0.5 1 Alcohol Dependent Value

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P Fig. S5. Interbrain region Pearson correlations for alcohol dependent mice with region labels.

Color Key

0 12 Naive

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0 2 4 6 8 10 Value

Globus pallidus e xternal segment Medial haben ula Substantia innominata Poster ior h ypothalamic n ucleus Periventricular z one Ventromedial h ypothalamic n ucleus Dorsomedial n ucleus of the h ypothalam us Orbital area medial par t Paraventricular h ypothalamic n ucleus Primary somatosensor y area tr unk Later al am ygdalar n ucleus Basolater al am ygdalar n ucleus Ventral anter ior−later al comple x of the thalam us Later al preoptic area Orbital area later al par t Olfactor y tubercle Piriform area Subpar aventr icular z one Anter ior am ygdalar area Periaqueductal gr ay Field CA2 Medial am ygdalar n ucleus Later al haben ula Poster ior am ygdalar n ucleus Olivary pretectal n ucleus Medial geniculate comple x Parataenial n ucleus Midbrain reticular n ucleus Central medial n ucleus of the thalam us Fundus of str iatum Paraventricular n ucleus of the thalam us Anter ior cingulate area v entr al par t Anter ior cingulate area dorsal par t Prelimbic area Nucleus accumbens Taenia tecta Later al hypothalamic area Caudoputamen Agranular insular area poster ior par t Retrochiasmatic area Supr achiasmatic n ucleus Retrosplenial area v entral par t Dorsal auditor y area Ventral medial n ucleus of the thalam us Median preoptic n ucleus Tuberal nucleus Zona incer ta Subthalamic n ucleus Antero ventr al per iventricular n ucleus Parasubthalamic n ucleus Piriform−amygdalar area Precommissur al nucleus Medial preoptic n ucleus Ventrolater al preoptic n ucleus Pons Magnocellular n ucleus Claustrum Medial pretectal area Central am ygdalar n ucleus Intercalated am ygdalar n ucleus Endopir iform nucleus Cortical am ygdalar area Periventricular h ypothalamic n ucleus poster ior par t Central later al nucleus of the thalam us Agranular insular area Antero ventr al nucleus of thalam us Reticular n ucleus of the thalam us Medial septal n ucleus Poster ior comple x of the thalam us Field CA3 Anterodorsal n ucleus Later al dorsal n ucleus of thalam us Primary somatosensor y area mouth Medial preoptic area Primary visual area Inferior colliculus Culmen Dentate gyr us Super ior colliculus motor related Substantia nigr a compact par t Super ior colliculus sensor y related Mediodorsal n ucleus of thalam us Primary somatosensor y area upper limb Primary somatosensor y area lo wer limb Orbital area v entrolater al par t Later al septal comple x Bed n uclei of the str ia ter minalis Primary auditor y area Dorsal par t of the later al geniculate comple x Temporal association areas Ectorhinal area Entorhinal area later al par t Primary motor area Gustator y areas Entorhinal area medial par t Parasubiculum Pedunculopontine n ucleus posteromedial visual area Perirhinal area Later al poster ior n ucleus of the thalam us Later al visual area Ventral auditor y area Supplemental somatosensor y area Viscer al area Dorsal peduncular area Secondar y motor area Presubiculum Antero ventr al preoptic n ucleus Anterolater al visual area Retrosplenial area dorsal par t Postsubiculum Ventral tegmental area Pons motor related Inter peduncular n ucleus Subiculum Substantia nigr a reticular par t Cortical am ygdalar area poster ior par t Frontal pole cerebr al cor tex Infralimbic area Diagonal band n ucleus Agranular insular area v entral par t Field CA1 Anter ior h ypothalamic n ucleus t t t t t t t t t t t t t t t t s s x s s s s s s x s x s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s x s s s y s s s k s s s s 1 a d a a a a a a a a a a a a a b b d d n a a h 3 a a a a a a a n a a a a 2 a e a e a e a a r r r r r r r r r r r r r r r i l l l m m m m t m t t m t n l e e e e a u u u u u u a a u u u u u u u u u u u u u u n u u u u u u u u u u n u u u u u u u u u u n u u u u e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e n e e n A a a a a a a a a A a r a a a a A a a l l l t l c c u u r u t u u u m m t t r u u u a e r r r r r r r r r r r r r r r r r r r r r r r r r r r a e e e e e r e e l e l l e l e e i i e e e e e e o e e e e e e e e e e e e e u e e e r t o o r p p p p p p p p p e p p p p p p l l l p p l l u l l l l l l l l l l l l l l p l l l l l l l l l l l l l m m y m m m m m m e m m n g m m n C a r r m o C m C n a a r a a a a a a a a a a a a a a a a a a a t a a a a a a a a n

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o P a t m l l l l i l c l l l l l t c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c r r r r a a a a a l a a r r a g a a a a i e e l l l l l l a l a l l a s i r r r r r r r l m m l l l l l l l l l m l l c c c c c e e e u b r r d c y y y l c m d y c t c c r d c g a a a a a c n a a a a a u u i u i u i u i u u u u u u u u u u u u u u u u u u u u u u u u u o a o o b a b l i e e l i l i i a m i l i m r a a a a a a i a r r a a u i t i a r r r r r m r r r r m r i l o a o a i a a i a

a o o a a a a a a a a a o a a l i t y e t t u t t s s a a e n t u l r a l l l l n t n b n b n b t n b C n n n n n n n n n n n n n n t n t n n n n n n n n n n t r r r r r e b p o e u b a e l t l o a d t s u u n u n u a a e d r r r r r u o o e c o c e o c e w c i h h h i h h h h h n h h i h h a i i y p c l a m p s n o a p e p l l u l u a a l l l a r n u u u o t u o t t t t n n t t e t t r t t r r o t t e r t c t t t e r r r e c t r r r r s s s i p s h u u n h e a f e s l e c c o o c i o i r o c c c c c i c o c c c d e o t u f t i i i i t t e y l

F m h h t t o F e a m F o i i e i c c s i i i i n i i o i i i t l a a a a a a i e t s s s a e a t r d d e e e d a a m C c a f f f a a a a a a l a c a a o c l i l i b S u r t m o n t t t t t t i r n d r l r d a l o d l t d m t d t n l s l v n t l l l r l r s l l t l l i l l i v m v m v s d r e e e e r e a e e e i a s e e i m a n v n s n o v d v m o e i a a t o a g g g i a i i a o o o s a a r p r a e o i e m e m s p o s r p p m m p a n c o r m m m e u r t u o a o u y l l l t r p a a o u r r a i o a a u u u e o T e u a a a a a i e h i h h h o h h s h t h t n a r e t r u t l p y r y u l y r a y y a y l Z a a r r y c r t r t t t f t a h r t t P t a s s r r a a g o o V a n c p y r l o o a a o a a e e p a a a a c a e n a e o e s c a c m a a a t m s b p a s s s p i d d b i p d d d d i d f r r t r u t u n c n l P c e l l e l l l i m i t e d i e u e p a u e e e h r r r r o o D t f f f f r f f f f t l o l u e e l s l e e e e e r s a m e e e m e e P e t a m e l a n o d P r P r n r u u r s u u u i g g h r g g q g g e n a a a o e e P f i d a a c l l a a s a a a s t e t d c y s a s t c e t r r r r E s s r r t r r r s a r e e a o a n I o o o o o C o o f o i s a l c i a a a a a a a a e a u p r r o y y T c e r y y y y a t a e a v a e v t e e e p a l d i p h G l n h h a n h h x l u a h n p a e s u l a r p r a s l l p p p r n a i a g l u n a a i e e r e a M m m i n i n t e l I a l o m t t s L t t t i t l v y g − l n d l o a o r p r a a a s i i x s s s s s x h r n s o y r t l r d i r u e a n a l y i r c o l l l a c c c l l l e l l n m m m m O m m e e e t r h r e r e r r r h e d e o r u a n b b o o o r m m l t n a n a r a o a o e e n e n e s L u t t u u d u t h t u u e o u e o a e d a a l a m u i a n v o F i a t a u a u u l u a a m a i y l s o m e a a t a a t a a P l f a o c a s c c e g u i u g p e c g i i p p p o o P i P r i a t r e n o r l l g p a r r b r c e f i n e e i n r e e a e e P e p s P r c a o r P i n n n i t n s n n l i a l l l o a e p r p t l r s l l l l l a l l r u t a r o r l D N l p u y M s y y y s i a d i r s a u n b r l g l L t a d e S a r u e V r a e u l e o o c r i r M a n a l l A l E a b i t e e c h o c c a e d c c c a a a n c t R r e n f r u t t o d h e l a a b h h h l P M a l l o h t n e i n i t e s o o m r i u v m a r s t r i e b i r r i a A i a t e p S S r a l a a o r l u L M i n u r u u p e u u u l V e t t a g e r e n l t n r u a l r D a u l r r p n c r d l e a r l O n s p l o i g o e e u o e d t d n D t s s c p u d e M a O i a v t l n o l s n n n n n i m t a n n t t C a n i s e I s o o d t s a e A a o A r r S a t t c l o M i c o a r P n e i a e O t i n P s l i o e c t l a l l m n S i l r m t o P o r n r e r r a a c o n g o r s a o o o l r i c l p r p n t o a r M r t d i L s m o e l s u r c c r u t i a a a M s o e t a P e L o a a M y E r i r i e b t d d c C a e l b r o e i a l r l r o n o e c E a r b t n s v t u t s F T a r r t i r n r i r l m e o l d d y u e o s u e e u o u r e i r m a P i u o s u n e n i o e n t e e r m m e a l t e h y a e e r i a n d O m c r c t t p r S t e a R l V t l d i i o b r v r r a o S a A t h o R u A n e t l a e o e r a n s u e B l t p r f a o e o m m l e t t P s a s I e r t n e i t l s p e l t r o t m B a o p l l o S i n n − o g n v a d n

y M u a a m e n c p r r R G p u y a r a t i r i t e r a

P A e A e r A r r t L t l r r S y o r g A P t v t S i n a r V a n a a h r a P m a n n A

r o A e r p m r e o e e P m i

e t i C l a t r a s C V r l n C r a P a P u

P a o s L r c l i D o r a t r t D n n e e v i V r e P Fig. S6. Hierarchical clustering and modules for naive mice with region labels.

Color Key

0 12

Alcohol Nondependent

Color Key

0 2 4 6 8 10 Value

Claustrum Piriform area Ventrolater al preoptic n ucleus Retrochiasmatic area Medial preoptic area Medial preoptic n ucleus Bed n uclei of the str ia ter minalis Anter ior am ygdalar area Tuberal nucleus Ventromedial h ypothalamic n ucleus Subiculum Piriform−amygdalar area Ectorhinal area Ventral tegmental area Retrosplenial area v entral par t Pons Anter ior cingulate area dorsal par t Magnocellular n ucleus Parasubthalamic n ucleus Agranular insular area v entral par t Nucleus accumbens Gustator y areas Dorsomedial n ucleus of the h ypothalam us Later al septal comple x Poster ior h ypothalamic n ucleus Anter ior cingulate area v entr al par t Pons motor related Precommissur al nucleus Medial septal n ucleus Medial pretectal area Medial haben ula Periaqueductal gr ay Super ior colliculus sensor y related Anter ior h ypothalamic n ucleus Culmen Presubiculum Cortical am ygdalar area poster ior par t Cortical am ygdalar area Midbrain reticular n ucleus Poster ior am ygdalar n ucleus Substantia nigr a reticular par t Substantia nigr a compact par t Postsubiculum Super ior colliculus motor related Parasubiculum Central am ygdalar n ucleus Pedunculopontine n ucleus Medial geniculate comple x Ventral medial n ucleus of the thalam us Fundus of str iatum Subthalamic n ucleus Zona incer ta Later al preoptic area Later al hypothalamic area Substantia innominata Paraventricular n ucleus of the thalam us Periventricular h ypothalamic n ucleus poster ior par t Agranular insular area Supr achiasmatic n ucleus Antero ventr al per iventricular n ucleus Orbital area medial par t Periventricular z one Olivary pretectal n ucleus Paraventricular h ypothalamic n ucleus Inter peduncular n ucleus Subpar aventr icular z one Antero ventr al preoptic n ucleus Olfactor y tubercle Parataenial n ucleus Diagonal band n ucleus Median preoptic n ucleus Central medial n ucleus of the thalam us Agranular insular area poster ior par t Viscer al area Primary somatosensor y area mouth Antero ventr al nucleus of thalam us Mediodorsal n ucleus of thalam us Later al haben ula Anterodorsal n ucleus Ventral anter ior−later al comple x of the thalam us Later al poster ior n ucleus of the thalam us Intercalated am ygdalar n ucleus Temporal association areas Poster ior comple x of the thalam us Caudoputamen Central later al nucleus of the thalam us Supplemental somatosensor y area Later al am ygdalar n ucleus Endopir iform nucleus Prelimbic area Reticular n ucleus of the thalam us Later al dorsal n ucleus of thalam us Globus pallidus e xternal segment Entorhinal area medial par t Dentate gyr us Entorhinal area later al par t Dorsal auditor y area Medial am ygdalar n ucleus Inferior colliculus Field CA2 Field CA3 Ventral auditor y area Anterolater al visual area Basolater al am ygdalar n ucleus Primary auditor y area Later al visual area posteromedial visual area Primary somatosensor y area lo wer limb Primary somatosensor y area tr unk Primary somatosensor y area upper limb Secondar y motor area Dorsal par t of the later al geniculate comple x Primary motor area Perirhinal area Retrosplenial area dorsal par t Field CA1 Primary visual area Orbital area later al par t Orbital area v entrolater al par t Frontal pole cerebr al cor tex Infralimbic area Dorsal peduncular area Taenia tecta t t t t t t t t t t t t t t t t x x k s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s x s s s s s y s s s x s s s s s s s s s s s a a a a 1 a a a b b a a a a a 3 2 a a a n a h a e e e a a a a a d a n d a a d a a a a a a a r r r r r r r r r r r r r r r i l l l t n t t t m m m m m m l e e e a e n u u u u u u u u u u a u u u u u u u u u u u u u u u u u u u u u u u u u u u u a n u u n u u u u e e e e e e e e e e e e e e e e n n e e e e e e e e e e e e e e e e a a A a A A a a a a a r a a a a a a a l l l t l c c u u r m m r e u a u u t u u t t u u r r r r r r r r r r r r r r r r r r r r r r r r r r r a r e e e e e i u i e e e e e e e e e e e e e e e e e l l e l e e e e e e o l e e e e r o o t r p p p p p p p p e p p p p p p p p l l u l l l l l l l l l p l l l l l l l p l l l l l l l l l l l l l l e y m m m m m m n m m m m m g n m C C C m r o n m a r r a a a a a a a a a a a a a a a a a a a a a a a a a a a a a t n

t e z z i u l u u l l l b u

o t m a P l l l l l l c l l l l i t c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c r r r r a a a a a a l a r r g a a e a a a i e l l l l l a a l l a l l s i r r r r r r r m l l l l l l l l l l l m m l c c c c c b e u e e r r c d y y d d l y g c y t m c c r c c a a a a a a n c a a a a u u u u u u u u u u u u u u u u u u i i u u i u u u u u u i u u u u o o a o b a b a i l e e l l l i m i i m i i a a a a a i a i i t r r a r a a u a r r r r r r r r r r m m a o o i a i l a i a a o a a a a a a a a a a a o o a i l t e u t y t t s e a a s t u n t l r l a l l l t n n n n n n n n n n n n n n n n n n b b n n b C n n n t n t n n t b n n n n t r r r r r b e p e e o b a t l l o a u t d s u n e u u u a d n a r r r r r e e c o o o e o c u c w c n i i i h h h h h h h h h h h h a i s m p y c i p a l p o a n e p l l u r l l l u a a l a t t o o t t t t u u u n n n u r t t r t t t t r t e o r c r t t t t e r r e t r r e c r r s p s s s i h u u n h a e e f s e l o i i i c c c c c o c c r o c o c o c c c o d e u t f e i i i i l t y t t

m F h F F t m t a o e h o c o c i i i i s n i i i i i e i i i l a a a a a t a i a a e a a r e s t s d s t e e e d d m c C a a f a a l f f c a c a a a a l o a i i l b u r n o t S m t i r t t t t t l l r d d d l n o a r d t t m t d l t v l l l l l s n i l i l t n l l l s r l r v m m v v s d r a a e r e e e e e e i e s e e i n m a n d s m n o v v v a i a o g e o t a g g i a o i a o o i r r a a p a s e o i e p n o p m c a r m s e m s m m m o m p r p o r y a u u u e o t l l l r t p T a a a a e a a o a u u o a a r a u o r i u u e i e i n h o h h h h h t t h s h a r e t u r l u l y r p t y y a y a y y a Z r l a r r y c r t r f t t t t t t a h t r a P r r s s a y V o e o a e a r p a o c a n a a a a l a g a o p o e e a a a o c c n c e s t a a a m m s d d s i d d s s p b p i d a d p d b i f r r r u t c n n t u e e l l P l l l c l t i m i d e e u i e a u p e e h e o r r r r D o t f r f f f f f f f t l l e l e o e s u l r e P e a e e a t m s e e e e e m m e e d l n o a n r r P r r P u u g g u i g g u u g g q e r s h n a a a e e o f a d P i c a s l a a l a a a e c d y t t t e c s a s s t r r s s r r t s r r r E r r a e e o a n r a I o o C o o o o f o o i a a i s l c a a a a a a a e r y y y y o a u r p y r y e T c e a a t a v v e a t e p e e l a d p i n x a h n h h l G h h h u a l p e a s a r u n l n r a l l s p p i a r p p l n u g i a a a r e a e M e m m i n n i e I s L t t l l t a m t t o t v l y t l g i − l a n r a d p o r o i i a a s s x s x s r s s h n o t y s r l e r u r i d n a l y r i c a l c a c c l l e l o l l l e m l m m m n O m m e e t r e r r e h r r r h e e d o b u a o o r b n o m m l t r a a r n a a n o e e n o e s n e L u d u u t u e u h u t t t o u e o a a d e a l a m u i o a a v F n i a s u l l u u a y u i a t m a a t m a o a a a e a a t l P f o s a c a c c e g i u g u p c p p e g i p i i P P o i o t r a o e n r l r a g p r b l r c r e n e e n e P e e i i a r f e e s p P a r i c r P o n o l l i n n l n n s i l a t n e p p r a s r l l l l t l l l a l r a r t u o l D u p r l N y y y s y M i s a d r b s u a i n t r g L l l d a a S r e r e V a u u e l e o o r c i r M l E A l l a b n a a e a a h c a c c o c d i e c c a t e r n c R t n e r u f t t d o a l b e h a h h h P l l M a o l i h n t e n t i e a m o m v r r o u s s i t r r i r e i b i a A i a t p S e r S a a a o l r l i u L M r l u u u u e p u u n t e t g V a e e r l n t n u r a l u D r l a r r p d l c n r O e r a l l s e e o p o g u n i o d e t d D t n s s u c p e O d a M t v l a i m s o n n n n n n i l t t t a n n C a n s i e s I o t s e a a d o o A A a r r S t c l c M t i o a o r P n e i a O e t n l i i s P l l o a l e t c n m S i l t o o m r P a n r a r r e r c o n o g a o o l o s r r i l p c t p n a r r o M r d t i L s m o l e u s r c c r t s M a a a i u e o t L e P a a o a M y E i i r r t d c a d C b e e b o r l a l i e l r o r o e n c E r a b s v s t t u t n F a T r r i r t n r i r l e m o y l d d e s o u e u u u e o r e r i a P m u i o u s n n e e o i r t e n e m m e l a t h a e y e e a r i O m c r c n d t t p r e t S R l a V t l b i d i o r v a r r o a S t h A o u R A n t e l

o a e r a e n B s u e t l p r f o a l e m o m e t t P s s I a e r t n l e i t s e l p t r m o t B o a p l l o S i − n n o v g n a d n

y a M u a m e n r p r c G R p y u r a a t r i t e i r a

P A e A e r r A r L t t r l r o y S r g A P t v t S i n a r V a n a a h r a P m a n n A

r o A e r p m e r o e P e m i

e t i l a C r t a s C V r l n C r a P a P u P a o s L r c l i D o r a t r t D n n e e v i V r e P

Fig. S7. Hierarchical clustering and modules for alcohol nondependent mice with region labels.

Color Key

0 12 Alcohol Dependent

Color Key

0 5 10 15 Value

Primary motor area Dorsal peduncular area Temporal association areas Viscer al area posteromedial visual area Infralimbic area Orbital area medial par t Diagonal band n ucleus Ventral auditor y area Dorsal auditor y area Antero ventr al preoptic n ucleus Supplemental somatosensor y area Medial preoptic area Anterodorsal n ucleus Primary somatosensor y area upper limb Primary somatosensor y area lo wer limb Frontal pole cerebr al cor tex Medial preoptic n ucleus Ventrolater al preoptic n ucleus Dentate gyr us Field CA2 Field CA3 Field CA1 Retrosplenial area dorsal par t Secondar y motor area Primary somatosensor y area tr unk Anterolater al visual area Primary visual area Taenia tecta Later al poster ior n ucleus of the thalam us Inter peduncular n ucleus Poster ior comple x of the thalam us Later al dorsal n ucleus of thalam us Subthalamic n ucleus Parataenial n ucleus Reticular n ucleus of the thalam us Zona incer ta Antero ventr al per iventricular n ucleus Central later al nucleus of the thalam us Antero ventr al nucleus of thalam us Dorsal par t of the later al geniculate comple x Orbital area v entrolater al par t Ventral medial n ucleus of the thalam us Mediodorsal n ucleus of thalam us Ventral tegmental area Caudoputamen Orbital area later al par t Ventral anter ior−later al comple x of the thalam us Central medial n ucleus of the thalam us Piriform−amygdalar area Later al hypothalamic area Anter ior h ypothalamic n ucleus Dorsomedial n ucleus of the h ypothalam us Bed n uclei of the str ia ter minalis Anter ior cingulate area dorsal par t Poster ior h ypothalamic n ucleus Globus pallidus e xternal segment Ventromedial h ypothalamic n ucleus Perirhinal area Paraventricular h ypothalamic n ucleus Ectorhinal area Agranular insular area poster ior par t Primary somatosensor y area mouth Subpar aventr icular z one Subiculum Primary auditor y area Retrochiasmatic area Presubiculum Olfactor y tubercle Agranular insular area Prelimbic area Later al preoptic area Medial septal n ucleus Anter ior cingulate area v entr al par t Medial geniculate comple x Nucleus accumbens Periventricular h ypothalamic n ucleus poster ior par t Later al haben ula Poster ior am ygdalar n ucleus Anter ior am ygdalar area Substantia nigr a reticular par t Magnocellular n ucleus Medial am ygdalar n ucleus Later al septal comple x Cortical am ygdalar area Midbrain reticular n ucleus Substantia innominata Periventricular z one Substantia nigr a compact par t Fundus of str iatum Postsubiculum Supr achiasmatic n ucleus Median preoptic n ucleus Pedunculopontine n ucleus Super ior colliculus motor related Parasubiculum Periaqueductal gr ay Paraventricular n ucleus of the thalam us Pons Inferior colliculus Pons motor related Agranular insular area v entral par t Later al visual area Cortical am ygdalar area poster ior par t Intercalated am ygdalar n ucleus Later al am ygdalar n ucleus Super ior colliculus sensor y related Entorhinal area medial par t Central am ygdalar n ucleus Tuberal nucleus Entorhinal area later al par t Parasubthalamic n ucleus Medial pretectal area Precommissur al nucleus Basolater al am ygdalar n ucleus Endopir iform nucleus Medial haben ula Claustrum Gustator y areas Piriform area Retrosplenial area v entral par t Olivary pretectal n ucleus Culmen t t t t t t t t t t t t t t t t s s s s s s s s s s s s s y s s s s x s s s s x s s s s s s s s s s s x s s s s s s s s s s k s s s x s s s s n a a a d a d d e a a a a a a a e a a e h a a a a n a a a a a a 1 3 2 b b a a a a a a a a a r r r r r r r r r r r r r r r i l l l m m m m t m m t n t t l a e e e e u a u u u u u u u u u n u u u u u u u u n u u u u u u u u u u u u u u u u u u u u n u u u u u u a e e e e e e e n e e e e e e e n e e e e e e e e e e e e e e e e e e a a a a a a a a a a a a a r a A A A a l l l l c t u u c r u t t u t u u a u u u e r m m r r r r r r r r r r r r r r r r r r r r r r r r r r r a e e e r e e e e e e e e e e o l e e e l e e e e e l l e e e e e e e u e e i i e e e t o o r r p p p p p p p p p p p p p e p p l l l l l l u l l l p l l l p l l l l p l l l l l l l l l l l l l l l l n m g n m m m m m m m m m m m e y m r a n o m C C C r a a r a t a a a a a a a a a a a a a a a a a a a a a a a a a a n

l l l u l u z i b e u u z t

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Fig. S8. Hierarchical clustering and modules for alcohol dependent mice with region labels.

Table S1. Brain region names, abbreviations, Allen Brain atlas grouping, abstinence module, participation coefficient, and within-module degree Z score values for abstinence network.

Brain Region Abbreviation Allen Group Abstinence PC WMDz Name Module Agranular insular area AI Cortical Plate C 0 -1.46 Agranular insular area, AIp Cortical Plate C 0 -0.51 posterior part Agranular insular area, AIv Cortical Plate B 0.67 -1.02 ventral part Anterior cingulate area, ACAd Cortical Plate C 0.26 -0.77 dorsal part Anterior cingulate area, ACAv Cortical Plate C 0.25 -1.83 ventral part Anterolateral visual area VISal Cortical Plate C 0 0.73 Cortical amygdalar area COA Cortical Plate B 0.49 0.74 Cortical amygdalar area, COAp Cortical Plate A 0.16 1.61 posterior part Dentate gyrus DG Cortical Plate C 0 1.13 Dorsal auditory area AUDd Cortical Plate C 0 -0.37 Dorsal peduncular area DP Cortical Plate C 0 0.58 Ectorhinal area ECT Cortical Plate C 0.08 -0.12 Entorhinal area, lateral ENTl Cortical Plate A 0.44 -0.12 part Entorhinal area, medial ENTm Cortical Plate A 0.45 0.41 part Field CA1 CA1 Cortical Plate C 0 1.33 Field CA2 CA2 Cortical Plate C 0 1.41 Field CA3 CA3 Cortical Plate C 0 1.39 Frontal pole, cerebral FRP Cortical Plate C 0 0.96 cortex Gustatory areas GU Cortical Plate A 0.49 -1.26 Infralimbic area ILA Cortical Plate C 0 0.35 Lateral visual area VISl Cortical Plate B 0.65 -1.04 Orbital area, lateral part ORBl Cortical Plate C 0 1.13 Orbital area, medial part ORBm Cortical Plate C 0 -0.03 Orbital area, ORBvl Cortical Plate C 0 1.10 ventrolateral part Parasubiculum PAR Cortical Plate B 0.27 0.52 Perirhinal area PERI Cortical Plate C 0.06 -0.85 Piriform area PIR Cortical Plate A 0.50 -0.88 Piriform-amygdalar area PAA Cortical Plate C 0.30 -0.60 Posteromedial visual VISpm Cortical Plate C 0 0.21 area Postsubiculum POST Cortical Plate B 0.64 -1.55 Prelimbic area PL Cortical Plate C 0 -0.32 Presubiculum PRE Cortical Plate C 0.31 -1.31 Primary auditory area AUDp Cortical Plate C 0.44 -2.18 Primary motor area Mop Cortical Plate C 0 0.57 Primary somatosensory SSp-ll Cortical Plate C 0 0.93 area, lower limb Primary somatosensory SSp-m Cortical Plate C 0 -0.15 area, mouth 10

Primary somatosensory SSp-tr Cortical Plate C 0 1.09 area, trunk Primary somatosensory SSp-ul Cortical Plate C 0 0/86 area, upper limb Primary visual area VISp Cortical Plate C 0 0.73 Retrosplenial area, RSPd Cortical Plate C 0 1.06 dorsal part Retrosplenial area, RSPv Cortical Plate A 0.50 -1.66 ventral part Secondary motor area MOs Cortical Plate C 0 1.11 Subiculum SUB Cortical Plate C 0.13 -1.75 Supplemental SSs Cortical Plate C 0 0.68 somatosensory area Taenia tecta TT Cortical Plate C 0 0.89 Temporal association Tea Cortical Plate C 0 0.51 areas Ventral auditory area AUDv Cortical Plate C 0 0.46 Visceral area VISC Cortical Plate C 0 0.61 Basolateral amygdalar BLA Cortical Subplate A 0 1.25 nucleus Claustrum CLA Cortical Subplate A 0.47 -1.28 Endopiriform nucleus EP Cortical Subplate A 0.17 0.79 Lateral amygdalar LA Cortical Subplate A 0.32 0.36 nucleus Posterior amygdalar PA Cortical Subplate C 0.42 -2.43 nucleus Anterior amygdalar area AAA Striatum B 0.48 -0.04 Caudoputamen CP Striatum C 0 1.26 Central amygdalar CEA Striatum A 0.47 0.81 nucleus Fundus of striatum FS Striatum B 0.12 1.29 Intercalated amygdalar IA Striatum A 0.35 1.37 nucleus Lateral septal complex LSX Striatum B 0.50 0.96 Medial amygdalar MEA Striatum B 0.50 1.01 nucleus Nucleus accumbens ACB Striatum C 0.38 -1.85 Olfactory tubercle OT Striatum C 0.07 -0.99 Bed nuclei of the stria BST Pallidum C 0.33 -0.84 terminalis Diagonal band nucleus NDB Pallidum C 0 0.34 Globus pallidus external GPe Pallidum C 0.21 -0.66 segment Magnocellular nucleus MA Pallidum B 0.41 -0.60 Medial septal nucleus MS Pallidum C 0 -0.71 Substantia innominata SI Pallidum B 0.47 1.26 Anterodorsal nucleus AD Thalamus C 0 0.77 Anteroventral nucleus AV Thalamus C 0 0.94 of the thalamus Central lateral nucleus CL Thalamus C 0 0.92 of the thalamus Central medial nucleus CM Thalamus C 0.32 -0.60 of the thalamus

Lateral geniculate LGd Thalamus C 0 1.10 complex, dorsal part Lateral dorsal nucleus of LD Thalamus C 0 1.14 the thalamus Lateral habenula LH Thalamus C 0.22 -1.68 Lateral posterior LP Thalamus C 0 1.07 nucleus of the thalamus Medial geniculate MG Thalamus C 0.32 -1.83 complex Medial habenula MH Thalamus A 0 -1.33 Mediodorsal nucleus of MD Thalamus C 0.10 0.58 the thalamus Parataenial nucleus PT Thalamus C 0.04 0.34 Paraventricular nucleus PVT Thalamus B 0.40 -0.64 of the thalamus Posterior complex of the PO Thalamus C 0 0.59 thalamus Reticular nucleus of the RT Thalamus C 0.04 0.26 thalamus Ventral anterior-lateral VAL Thalamus C 0 1.00 complex of the thalamus Ventral medial nucleus VM Thalamus C 0.18 0.13 of the thalamus Anterior hypothalamic AHN Hypothalamus C 0.24 -0.22 nucleus Anteroventral AVPV Hypothalamus C 0.08 0.05 periventricular nucleus Anteroventral preoptic AVP Hypothalamus C 0 -0.05 nucleus Dorsomedial nucleus of DMH Hypothalamus C 0.23 -0.15 the hypothalamus Lateral hypothalamic LHA Hypothalamus C 0.31 -0.71 area Lateral preoptic area LPO Hypothalamus C 0 -0.37 Medial preoptic area MPO Hypothalamus C 0 0.75 Medial preoptic nucleus MPN Hypothalamus C 0 0.23 Median preoptic nucleus MEPO Hypothalamus B 0.32 -1.82 Parasubthalamic nucleus PSTN Hypothalamus A 0 1.12 Paraventricular PVH Hypothalamus C 0 -0.45 hypothalamic nucleus Periventricular PVp Hypothalamus C 0 -1.41 hypothalamic nucleus, posterior part Periventricular zone PVZ Hypothalamus B 0.13 1.12 Posterior hypothalamic PH Hypothalamus C 0.22 -0.82 nucleus Retrochiasmatic area RCH Hypothalamus C 0.11 -1.56 Subparaventricular zone SBPV Hypothalamus C 0.18 -1.95 Subthalamic nucleus STN Hypothalamus C 0.04 0.28 Suprachiasmatic nucleus SCH Hypothalamus B 0.50 -1.55 Tuberal nucleus TU Hypothalamus A 0.49 -0.31 Ventrolateral preoptic VLPO Hypothalamus C 0 0.32 nucleus

Ventromedial VMH Hypothalamus C 0.31 -0.92 hypothalamic nucleus Zona incerta ZI Hypothalamus C 0.04 0.19 Inferior colliculus IC Midbrain B 0.58 -0.78 Interpeduncular nucleus IPN Midbrain C 0 0.91 Medial pretectal area MPT Midbrain A 0 -0.15 Midbrain reticular MRN Midbrain B 0.35 1.27 nucleus Olivary pretectal OP Midbrain A 0.30 -0.91 nucleus Pedunculopontine PPN Midbrain B 0.45 0.43 nucleus Periaqueductal gray PAG Midbrain B 0.50 0.12 Precommissural nucleus PRC Midbrain A 0 0.17 Substantia nigra, SNc Midbrain B 0.14 0.78 compact part Substantia nigra, SNr Midbrain B 0.50 0.67 reticular part Superior colliculus, SCm Midbrain B 0.39 0.70 motor related Superior colliculus, SCs Midbrain A 0.38 0.90 sensory related Ventral tegmental area VTA Midbrain C 0.03 0.57 Pons P Hindbrain B 0.63 -0.76 Pons, motor related P-mot Hindbrain B 0.49 -1.07 Culmen CUL Cerebellum A 0 -0.90